Publications by authors named "Yi-Ju Li"

123 Publications

Allopurinol hepatotoxicity is associated with HLA Class I Alleles.

Liver Int 2021 Apr 25. Epub 2021 Apr 25.

Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD.

Background/ Aims: Allopurinol can cause HLA class I associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown.

Methods: 11 of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug Induced Liver Injury Network were adjudicated as definite, highly likely or probable. High resolution HLA sequencing was undertaken in cases and compared to population and other DILI controls.

Results: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and 6 were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dL, respectively, with a median R ratio of 2.7 at onset. During follow-up, 9 patients were treated with corticosteroids including 5 of the 6 with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining 8 recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA- B * 58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02 all of which are more frequently found in African-Americans than European-Americans or Latinos.

Conclusions: Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African American race and 3 HLA risk alleles, HLA-B*58:01, HLA-B*53:01 and HLA-A*34:02. HLA- 58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol treated patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14903DOI Listing
April 2021

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.

J Alzheimers Dis 2021 ;80(3):1281-1297

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Background: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD.

Objective: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD.

Methods: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis.

Results: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13).

Conclusion: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-201544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052629PMC
January 2021

Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion.

Invest Ophthalmol Vis Sci 2021 Jan;62(1):17

Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States.

Purpose: To characterize inheritance, penetrance, and trinucleotide repeat expansion stability in Fuchs endothelial corneal dystrophy (FECD).

Methods: One thousand unrelated and related subjects with and without FECD were prospectively recruited. CTG18.1 repeat length (CTG18.1L) was determined via short tandem repeat assay and Southern blotting of leukocyte DNA. Multivariable logistic regression and generalized estimating equation models were employed.

Results: There were 546 unrelated FECD cases (67.6% female; 70 ± 10 years) and 235 controls (63.8% female; 73 ± 8 years; all ≥ 50 years). CTG18.1 expansion (CTG18.1exp+) was observed in 424 (77.7%) cases and 18 (7.7%) controls (P = 2.48 × 10-44). CTG18.1 expansion was associated with FECD severity (P = 5.62 × 10-7). The family arm of the study included 331 members from 112 FECD-affected families; 87 families were CTG18.1exp+. Autosomal dominant inheritance with variable expression of FECD was observed, regardless of expansion status. FECD penetrance of CTG18.1 expansion increased with age, ranging from 44.4% in the youngest (19-46 years) to 86.2% in the oldest (64-91 years) age quartiles. Among 62 parent-offspring transmissions of CTG18.1exp+, 48 (77.4%) had a change in CTG18.1L ≤ 10 repeats, and eight (12.9%) were ≥50 repeats, including five large expansions (∼1000-2000 repeats) that contracted. Among 44 offspring who did not inherit the CTG18.1exp+ allele, eight (18.2%) exhibited FECD.

Conclusions: CTG18.1 expansion was highly associated with FECD but demonstrated incomplete penetrance. CTG18.1L instability occurred in a minority of parent-offspring transmissions, with large expansions exhibiting contraction. The observation of FECD without CTG18.1 expansion among family members in CTG18.1exp+ families highlights the complexity of the relationship between the FECD phenotype and CTG18.1 expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/iovs.62.1.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814354PMC
January 2021

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

J Cardiothorac Vasc Anesth 2021 May 24;35(5):1310-1318. Epub 2020 Nov 24.

Department of Anesthesiology & Critical Care, Duke University School of Medicine, Durham, NC.

Objective: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described.

Design: Retrospective cohort.

Setting: Single-center university hospital.

Participants: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015.

Interventions: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution.

Measurements And Main Results: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q = 32.6 v CUF < Q = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001).

Conclusions: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jvca.2020.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009835PMC
May 2021

Loss of the tumor suppressor BTG3 drives a pro-angiogenic tumor microenvironment through HIF-1 activation.

Cell Death Dis 2020 12 11;11(12):1046. Epub 2020 Dec 11.

Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Road, Taipei, 115, Taiwan.

B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and is a downstream target of p53. Here, we show that senescence triggered by BTG3 depletion was accompanied by a secretome enriched with cytokines, growth factors, and matrix-remodeling enzymes, which could promote angiogenesis and cell scattering in vitro. We present evidence that at least part of these activities can be explained by elevated HIF-1α activity. Mechanistically, the BTG3 C-terminal domain competes with the coactivator p300 for binding the HIF-1α transactivation domain. The angiogenic promoting effect of BTG3 knockdown was largely diminished upon co-depletion of HIF-1α, indicating that HIF-1α is a major downstream target of BTG3 in the control of angiogenesis. In vivo, ectopic expression of BTG3 suppresses angiogenesis in xenograft tumors; and syngenic tumor growth and metastasis were enhanced in Btg3-null mice. Moreover, analysis of clinical datasets revealed that a higher BTG3/VEGFA expression ratio correlates with improved patient survival in a number of cancer types. Taken together, our findings highlight the non-autonomous regulation of tumor microenvironment by BTG3 while suppressing tumor progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-03248-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732837PMC
December 2020

An exploration of genetic association tests for disease risk and age at onset.

Genet Epidemiol 2021 Apr 19;45(3):249-279. Epub 2020 Oct 19.

Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, North Carolina, USA.

Risk genes influence the chance of an individual developing disease over their lifetime, although the age at onset (AAO) genes influence disease timing. These two categories are not disjoint; a gene that influences AAO might also appear to influence the risk. When an allele influences both AAO and risk, a reasonable question is whether we would have more power to detect association using a statistical test based on risk or AAO. To address this question, we compared power analytically for the Cochran-Armitage trend case-control test for risk and a linear regression case-only test for AAO. We also used simulations to compare the power of these tests with a 2-degree of freedom joint test (which combines the risk and AAO statistics) and the Cox proportional hazards survival model testing AAO (with censored data in controls). We found that when there is little heterogeneity, the case-control risk test has more power than the case-only AAO test (with equivalent sample sizes), but when the model is complex (e.g., with heterogeneity or reduced penetrance), the relationship reverses. The joint test generally outperforms the risk or AAO test alone and ultimately is our recommendation as a powerful alternative in many scenarios.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005406PMC
April 2021

Unplanned hospital admission after ambulatory surgery: a retrospective, single cohort study.

Can J Anaesth 2021 Jan 14;68(1):30-41. Epub 2020 Oct 14.

Department of Anesthesiology, Duke University Medical Center, DUMC, Box #3094, Stop# 4, Durham, NC, 27110, USA.

Purpose: We estimated the rate of unplanned hospital and intensive care unit (ICU) admissions following ambulatory surgery centre (ASC) procedures, and identified factors associated with their occurrence.

Methods: This retrospective cohort included adult patients who underwent ASC procedures within a large community practice from January 2010 to December 2014. Patients were categorized into two groups: unplanned postoperative hospital/ICU admission within 24 hr of procedure or uneventful discharge. Demographics, comorbidities, anesthesia type, procedure type, procedure group, and ASC facility were assessed.

Results: Of the 211,389 patients included, there were 211,147 uneventful discharges (99.89%) and 242 unplanned hospital admissions (0.11%), of which 75 were ICU admissions (0.04%). The multivariable logistic regression model for hospital admission showed an increased risk associated with age > 50 yr (odds ratio [OR], 1.53); American Society of Anesthesiologists (ASA) physical status (III vs II: OR, 1.45; IV vs II: OR, 1.88), comorbidity (chronic obstructive pulmonary disease: OR, 2.63; diabetes mellitus: OR, 1.62; transient ischemic attack: OR, 2.48) procedure (respiratory: OR, 2.92; digestive: OR, 2.66; musculoskeletal system: OR, 2.53), anesthetic management (general anesthesia [GA] and peripheral nerve block vs GA: OR, 1.79), and ASC facility (189BB: OR, 2.29; 30E9A: OR, 7.41; and BD21F: OR, 1.69). The multivariable logistic regression model for ICU admission showed increased risk of unplanned ICU admission associated with ASA physical status (ASA III vs II: OR, 3.0; ASA IV vs II: OR, 8.52), procedure (musculoskeletal system: OR, 2.45), and ASC facility (00E6C: OR, 3.14; 189BB: OR, 2.77; 30E9A: OR, 2.59; and BD21F: OR, 3.71).

Conclusion: While a small percentage of adult patients who underwent ASC procedures required unplanned hospital admission (0.07%), approximately one-third of these admissions were to the ICU (0.04%). Facility was at least as strong a predictor of hospital admission as the patient- and/or procedure-specific variables.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12630-020-01822-1DOI Listing
January 2021

HLA-B*35:01 and Green Tea Induced Liver Injury.

Hepatology 2020 Sep 5. Epub 2020 Sep 5.

Department of Medicine, Einstein Healthcare Network, Philadelphia, PA, United States.

Background: Herbal supplements and particularly multi-ingredient products have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial.

Methods: Among 1414 patients enrolled in the U.S. Drug Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1142 to conventional drugs. The clinical features of green tea cases and representation of HLA class I and II alleles in cases and control groups were analyzed in detail.

Results: Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15 to 448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% CI: 58% to 87%) of green tea cases but only 15% (95% CI: 10% to 20%) caused by other supplements and 12% (95% CI: 10% to 14%) attributed to drugs, the latter rate being similar to population controls (95% CI: 11%: 10.5% to 11.5%).

Conclusions: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01 suggesting that it is idiosyncratic and immune-mediated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052949PMC
September 2020

Apolipoprotein L1 (APOL1) Coding Variants Are Associated With Creatinine Rise After Cardiac Surgery.

J Cardiothorac Vasc Anesth 2020 Dec 11;34(12):3314-3320. Epub 2020 May 11.

Department of Anesthesiology, Duke University Medical Center, Durham, NC.

Objective: Acute kidney injury (AKI) is a complication of cardiac surgery that is considerably more common in African Americans (1.5-fold). Although homozygous status for apolipoprotein L1 (APOL1) risk alleles is associated with chronic kidney disease in individuals of African ancestry, whether these coding variants confer AKI risk is unknown. The present study examined whether APOL1 homozygous risk allele status was associated with AKI in African Americans after cardiac surgery.

Design: Retrospective analysis of a cohort.

Setting: Single-center university hospital.

Participants: African American patients from the CATHeterization GENetics study cohort who underwent cardiac surgery with cardiopulmonary bypass.

Interventions: Genotyping of APOL1 alleles.

Measurements And Main Results: Data from 125 African American patients included 12 APOL1 risk (ie, homozygous for risk alleles) patients and 113 APOL1 control (ie, wildtype or heterozygous for risk alleles) patients. The primary outcome to reflect AKI was peak serum creatinine rise after surgery relative to the preoperative creatinine (%ΔCr). The secondary outcome was Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria. In the primary analysis, peak creatinine rise was higher in risk compared with control patients in both univariate (%ΔCr 69.1 v 29.6%; p = 0.005) and multivariate regression (%ΔCr 88.5 v 43.7%; p = 0.006) analyses. For the secondary outcome, a trend toward KDIGO AKI development was noted in APOL1 risk patients, but this was not statistically significant.

Conclusions: African American cardiac surgery patients homozygous for APOL1 chronic kidney disease risk variants averaged a more than 2-fold higher postoperative creatinine rise even after adjustment for other risk factors, suggesting these alleles also are independent risk factors for AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.jvca.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655610PMC
December 2020

Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim-Sulfamethoxazole Induced Liver Injury.

Hepatology 2021 Jan;73(1):268-281

Division of Gastroenterology and Hepatology, School of Medicine, Indiana University, Indianapolis, IN.

Background And Aims: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI.

Approach And Results: European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 × 10 ). For the African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at position 67 in HLA-B*35:01 to be the predictive binding sites for SMX metabolites.

Conclusions: HLA-B*14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B*35:01 may be a potential genetic risk factor for African Americans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544638PMC
January 2021

Analgesic use after vaginal delivery in women with perineal lacerations: a retrospective cohort study.

Curr Med Res Opin 2020 06 22;36(6):1009-1013. Epub 2020 Apr 22.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

To evaluate opioid consumption among parturients with varying degrees of perineal lacerations. This was a retrospective analysis of women who delivered vaginally at our institution from 1 January 2014 to 12 April 2015. We collected information regarding the degree of perineal lacerations (no lacerations, first-/second-degree, third-/fourth-degree), analgesic consumption, and postpartum pain scores. The primary outcome was opioid use from 0-48 h postpartum. Univariate and multivariable regression analyses were performed to test for the association of laceration severity with opioid use. We included 5598 women in the analysis; 1948 had no lacerations, 3434 had first-/second-degree lacerations, and 216 had third-/fourth-degree lacerations. In univariate analysis, parturients with third-/fourth-degree lacerations had significantly higher use of opioids within 48 h postpartum (53.2%) compared to women with no lacerations (30.03%) or first-/second-degree lacerations (28.6%) ( < .001). In the multivariable analysis, women with third-/fourth-degree lacerations had higher odds of opioid use than those without laceration [OR (95% CI) = 2.61 (1.75-3.85),  < .001]. In pairwise comparisons, those with third-/fourth-degree lacerations had higher odds of opioid use than those without lacerations [OR (95% CI) = 3.55 (2.20-5.74)], and those with first-/second-degree lacerations [OR (95% CI) = 2.15 (1.49-3.10)] ( < .001). Oxycodone equivalent consumption was significantly different among groups with a median (IQR) of 5.00 mg (0.00-27.50), 0.00 mg (0.00-5.00) and 0.00 mg (0.00-5.00) in women with third-/fourth-degree, first-/second-degree, and no lacerations, respectively, during the 0-48 h postpartum ( < .001). The use of opioids and opioid doses are higher in women with third-/fourth-degree perineal lacerations compared to those with first-/second-degree or no lacerations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03007995.2020.1754185DOI Listing
June 2020

Prevalence of a Good Perinatal Outcome With Cryopreserved Compared With Fresh Donor Oocytes.

Obstet Gynecol 2020 03;135(3):709-716

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, and the Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; and the Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Colorado, Aurora, Colorado.

Objective: To compare the odds of a good perinatal outcome between cryopreserved and fresh donor oocytes.

Methods: We used the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System to conduct a retrospective cohort study of women undergoing donor oocyte in vitro fertilization (IVF) from 2012 to 2015. Cycles using cryopreserved embryos, a gestational carrier, or preimplantation genetic testing were excluded. The primary outcome was a good perinatal outcome, defined as a singleton live birth at 37 weeks of gestation or more with birth weight at or within 2,500 g and 4,000 g. Secondary outcomes included live birth, multiple birth, and prematurity. Generalized estimating equation models were used to test the effect of oocyte type on the primary outcome while accounting for covariates and the correlation induced by repeated cycles within a patient.

Results: Of the 36,925 cycles included in the analysis, 8,381 (22.7%) used cryopreserved and 28,544 (77.3%) used fresh oocytes. The odds of a good perinatal outcome were marginally but significantly lower with cryopreserved than with fresh oocytes before and after covariate adjustment (22.0% vs 24.1%, unadjusted odds ratio [OR] 0.90, 95% CI 0.85-0.96, adjusted OR 0.88, 95% CI 0.81-0.95). Compared with fresh oocytes, cryopreserved oocytes were associated with lower rates of live birth (39.6% vs 47.7%, OR 0.75, 95% CI 0.72-0.79), multiple birth (22.3% vs 31.2%, OR 0.63, 95% CI 0.58-0.69), and prematurity (27.6% vs 30.6%, OR 0.86, 95% CI 0.79-0.94).

Conclusion: This retrospective national study demonstrated that the use of cryopreserved compared with fresh donor oocytes in IVF cycles is associated with marginally lower odds of a good perinatal outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000003695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036005PMC
March 2020

A comparison of antibiotic prophylaxis regimens to decrease the risk of post-procedure urinary tract infection after onabotulinum toxin A injection.

Int Urogynecol J 2020 09 27;31(9):1907-1912. Epub 2020 Jan 27.

Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA.

Introduction And Hypothesis: To evaluate the risk of post-injection urinary tract infection (UTI) after onabotulinumtoxin A (BTX-A) treatment based on the timing of when antibiotic prophylaxis is started.

Methods: This is a retrospective cohort study of 111 women with refractory idiopathic overactive bladder who underwent intradetrusor injection of BTX-A. Two cohorts were identified: (1) 67 women who started antibiotic prophylaxis with ciprofloxacin 1 day prior to injection; (2) 44 women who received antibiotic prophylaxis with ciprofloxacin after injection only. We assessed for post-injection UTI within 90 days after BTX-A. Multivariable logistic regression was performed to adjust for potential confounders.

Results: One hundred eleven women underwent BTX-A. In total, 30 (27%) had a UTI within 90 days; these included 15/67 (22%) of those who started antibiotics 1 day prior to injection and 15/44 (34%) of those receiving antibiotics after injection. While the unadjusted analysis showed no significant associations between timing of antibiotic administration and UTI (OR = 0.56; 95% CI = 0.24, 1.30; p = 0.18), an adjusted analysis showed the pre-procedure antibiotic group had a significant reduction in post-procedure UTI after controlling for age, history of UTI, diabetes, and urinary retention requiring catheterization (OR = 0.23; 95% CI = 0.07, 0.73; p = 0.01).

Conclusions: Starting antibiotics 1 day prior to BTX-A injection decreases the odds of post-injection UTI compared with women who use post-procedure antibiotic prophylaxis over shorter duration. Consideration should be given to beginning antibiotic prophylaxis prior to the procedure and continuing it for 4 total days to decrease the risk of UTI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00192-020-04230-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498079PMC
September 2020

Intraoperative renal resistive index threshold as an acute kidney injury biomarker.

J Clin Anesth 2020 May 4;61:109626. Epub 2019 Nov 4.

Duke University Medical Center, Department of Anesthesiology, 2301 Erwin Road, Durham, NC 27710, USA. Electronic address:

Study Objective: The lag in creatinine-mediated diagnosis of cardiac surgery-associated acute kidney injury (AKI) may be impeding the development of renoprotection therapies. Postoperative renal resistive index (RRI) measured by transabdominal Doppler ultrasound is a promising early AKI biomarker. RRI measured intraoperatively by transesophageal echocardiography (TEE) is available even earlier but is less evaluated. Therefore, we conducted an assessment of intraoperative RRI as an AKI biomarker using previously reported post-renal insult thresholds.

Design: Retrospective convenience sample.

Setting: Intraoperative.

Patients: 180 adult cardiac surgical patients between July 2013 and July 2014.

Intervention: None.

Measurements: Pre- and post-cardiopulmonary bypass (CPB) RRI thresholds, measured using intraoperative TEE, exceeding 0.74 or 0.79 were used to evaluate for an association with KDIGO AKI risk using the Chi-square test. Other consensus AKI criteria (AKIN, RIFLE) were similarly evaluated. Additional t-test analyses examined the relationship of pre- and pre-to-post (delta) CPB RRI with AKI.

Main Results: Post-CPB RRI for 99 patients included 36 and 23 with values exceeding 0.74 and 0.79, respectively. Analyses confirmed associations of both RRI thresholds with all consensus AKI definitions (0.74; KDIGO: p = 0.05, AKIN: p = 0.03, RIFLE: p = 0.03, 0.79; KDIGO: p = 0.002, AKIN: p = 0.001, RIFLE: p = 0.004). In contrast, pre-CPB and pre-to post-CPB RRI were not associated with AKI.

Conclusions: RRI obtained intraoperatively in cardiac surgery patients, assessed using previously reported thresholds, is highly associated with AKI and warrants further evaluation as a promising "earliest" AKI biomarker. These significant findings suggest that RRI assessment should be included in the standard intraoperative TEE exam.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jclinane.2019.109626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962557PMC
May 2020

The Utility of the Early Postoperative Follow-up and Radiographs After Operative Treatment of Supracondylar Humerus Fractures in Children.

J Pediatr Orthop 2020 May/Jun;40(5):218-222

Department of Orthopedics and Sports Medicine, Seattle Children's Hospital.

Background: Supracondylar humerus (SCH) fractures are common elbow injuries in pediatric patients. The American Academy of Orthopedic Surgeons published guidelines for the standard of care in the treatment of displaced SCH fractures, however, no recommendations for follow-up care were made. With the recent push to eliminate unnecessary radiographs and decrease health care costs, many are questioning postoperative protocols. The purpose of our study was to evaluate the utility of the 1-week follow-up appointment after closed reduction and percutaneous pinning (CRPP) of displaced SCH fractures.

Methods: A retrospective review performed at a single institution from 2014 to 2016 included patients under 14 years of age with a closed, displaced SCH fracture treated with CRPP. Exclusion criteria included patients without complete clinical or radiographic follow-up. Variables examined included time to initial follow-up, change in treatment plan after 1-week x-rays, complications, demographics, fracture type, pin number and configuration, reduction parameters, immobilization, time to pin removal, duration of casting, and clinical outcome.

Results: A total of 412 patients were divided into 2 groups based on time to initial follow-up. Overall, 368 had an initial follow-up at 7 to 10 days (group 1) and 44 at 21 to 28 days (group 2). There was no difference in age, sex, fracture type, pin configuration, or a number of pins between groups. Statistically significant findings included time to initial follow-up and days to pin removal (group 1 at 26.2 d vs. group 2 at 23.8 d), type of immobilization (group 1 with 5% circumferential casts and group 2 with 70%), and time to surgery (26.2 vs. 62.9 h, respectively). There was no significant difference in complication rates and only a 0.5% rate of change in management in group 1.

Conclusions: Early postoperative follow-up and radiographs did not change the patient outcome and might be eliminated in children with displaced SCH fractures treated with CRPP. Given the current focus of on efficiency and cost-effective care, eliminating the 1-week postoperative appointment would improve appointment availability and decrease medical cost.

Level Of Evidence: Level III-Therapeutic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BPO.0000000000001432DOI Listing
October 2020

Does a Recent Urinary Tract Infection Increase the Risk of Postprocedure Urinary Tract Infection After Onabotulinum Toxin A?

Female Pelvic Med Reconstr Surg 2021 Feb;27(2):121-125

From the Department of Obstetrics and Gynecology, Duke University, Durham, NC.

Objectives: The objective of this study was to evaluate the risk of postprocedure urinary tract infection (UTI) after injection of onabotulinum toxin A (BTX-A) in women who had a UTI within 30 days before procedure.

Methods: This was a retrospective cohort study of women who underwent their first injection of BTX-A from 2010 to 2016. Two cohorts were identified: (1) recent UTI (within 30 days before injection) and (2) no recent UTI. Our primary outcome was UTI within 90 days after BTX-A. Continuous variables were analyzed using the Wilcoxon rank sum test, and categorical variables were analyzed using Fisher exact or χ2 tests.

Results: One hundred sixty-six women underwent their first BTX-A injection. Twenty-five (15%) had a recent UTI and 141 (85%) did not. Women with a recent UTI were more likely to have a subsequent infection (52% vs 26%, P < 0.01). However, in a logistic regression model, controlling for history of recurrent UTI, age, history of diabetes mellitus, periprocedural antibiotics, and urinary retention requiring catheterization, the association between having a recent UTI, and a subsequent UTI was no longer significant (adjusted odds ratio, 1.98; 95% confidence interval, 0.60-6.50; P = 0.26).

Conclusions: Performing a first injection of BTX-A within 30 days of a UTI does not increase the odds of postprocedure UTI. Therefore, BTX-A therapy does not need to be delayed after a recent UTI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SPV.0000000000000753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423448PMC
February 2021

Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation.

Arthritis Res Ther 2019 06 13;21(1):146. Epub 2019 Jun 13.

Duke Molecular Physiology Institute, Duke University School of Medicine, Box 104775, 300 North Duke St, Durham, NC, 27701, USA.

Background: To identify a synovial fluid (SF) biomarker profile characteristic of individuals with an inflammatory osteoarthritis (OA) endotype.

Methods: A total of 48 knees (of 25 participants) were characterized for an extensive array of SF biomarkers quantified by Rules Based Medicine using the high-sensitivity multiplex immunoassay, Myriad Human InflammationMAP® 1.0, which included 47 different cytokines, chemokines, and growth factors related to inflammation. Multivariable regression with generalized estimating equations (GEE) and false discovery rate (FDR) correction was used to assess associations of SF RBM biomarkers with etarfolatide imaging scores reflecting synovial inflammation; radiographic knee OA severity (based on Kellgren-Lawrence (KL) grade, joint space narrowing, and osteophyte scores); knee joint symptoms; and SF biomarkers associated with activated macrophages and knee OA progression including CD14 and CD163 (shed by activated macrophages) and elastase (shed by activated neutrophils).

Results: Significant associations of SF biomarkers meeting FDR < 0.05 included soluble (s)VCAM-1 and MMP-3 with synovial inflammation (FDR-adjusted p = 0.025 and 1.06 × 10); sVCAM-1, sICAM-1, TIMP-1, and VEGF with radiographic OA severity (p = 1.85 × 10 to 3.97 × 10); and VEGF, MMP-3, TIMP-1, sICAM-1, sVCAM-1, and MCP-1 with OA symptoms (p = 2.72 × 10 to 0.050). All these SF biomarkers were highly correlated with macrophage markers CD163 and CD14 in SF (r = 0.43 to 0.90, FDR < 0.05); all but MCP-1 were also highly correlated with neutrophil elastase in SF (r = 0.62 to 0.89, FDR < 0.05).

Conclusions: A subset of six SF biomarkers was related to synovial inflammation in OA, as well as radiographic and symptom severity. These six OA-related SF biomarkers were specifically linked to indicators of activated macrophages and neutrophils. These results attest to an inflammatory OA endotype that may serve as the basis for therapeutic targeting of a subset of individuals at high risk for knee OA progression.

Trial Registration: Written informed consent was received from participants prior to inclusion in the study; the study was registered at ClinicalTrials.gov ( NCT01237405 ) on November 9, 2010, prior to enrollment of the first participant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-019-1923-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567574PMC
June 2019

Three-factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis.

Vox Sang 2019 May 2;114(4):374-385. Epub 2019 Apr 2.

Department of Anesthesiology & Critical Care, Divisions of Cardiothoracic Anaesthesia & Critical Care Medicine, Duke University School of Medicine, Durham, NC, USA.

Background/objectives: Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications.

Materials/methods: After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing.

Results: Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P < 0·001). The mean PCC dose was 15·8 ± 7·1 IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%.

Conclusions: 3F-PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525021PMC
May 2019

Exogenous GDF11 attenuates non-canonical TGF-β signaling to protect the heart from acute myocardial ischemia-reperfusion injury.

Basic Res Cardiol 2019 03 21;114(3):20. Epub 2019 Mar 21.

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-β signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-β signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00395-019-0728-zDOI Listing
March 2019

Family-based association tests for rare variants with censored traits.

PLoS One 2019 25;14(1):e0210870. Epub 2019 Jan 25.

Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States of America.

We propose a set of family-based burden and kernel tests for censored traits (FamBAC and FamKAC). Here, censored traits refer to time-to-event outcomes, for instance, age-at-onset of a disease. To model censored traits in family-based designs, we used the frailty model, which incorporated not only fixed genetic effects of rare variants in a region of interest but also random polygenic effects shared within families. We first partitioned genotype scores of rare variants into orthogonal between- and within-family components, and then derived their corresponding efficient score statistics from the frailty model. Finally, FamBAC and FamKAC were constructed by aggregating the weighted efficient scores of the within-family components across rare variants and subjects. FamBAC collapsed rare variants within subject first to form a burden test that followed a chi-squared distribution; whereas FamKAC was a variant component test following a mixture of chi-squared distributions. For FamKAC, p-values can be computed by permutation tests or for computational efficiency by approximation methods. Through simulation studies, we showed that type I error was correctly controlled by FamBAC for various variant weighting schemes (0.0371 to 0.0527). However, FamKAC type I error rates based on approximation methods were deflated (max 0.0376) but improved by permutation tests. Our simulations also demonstrated that burden test FamBAC had higher power than kernel test FamKAC when high proportion (e.g. ≥ 80%) of causal variants had effects in the same direction. In contrast, when the effects of causal variants on the censored trait were in mixed directions, FamKAC outperformed FamBAC and had comparable or higher power than an existing method, RVFam. Our proposed framework has the flexibility to accommodate general nuclear families, and can be used to analyze sequence data for censored traits such as age-at-onset of a complex disease of interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210870PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347269PMC
November 2019

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.

Gastroenterology 2019 05 18;156(6):1707-1716.e2. Epub 2019 Jan 18.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, North Carolina.

Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.

Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.

Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01.

Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2019.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511989PMC
May 2019

Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings.

Circ Genom Precis Med 2018 09;11(9):e002228

Department of Medicine (B.P., K.S., G.T., D.V.), Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC. United States (S.B.H., M.D.M., D.V.).

Background: Outcomes of tailoring statin-type based on solute carrier organic anion transporterfamily member 1B1 ( SLCO1B1)pharmacogenetic toxicity information on patient, provider, and pharmacological outcomes are unknown.

Methods: The trial randomized 159 patients not taking statins because of prior statin myalgia 1:1 to receiving SLCO1B1 GIST (Genotype Informed Statin Therapy) versus usual care (UC) and followed for up to 8 months. The UC arm received their SLCO1B1 results post-trial. The primary outcome was statin adherence using the Morisky Medication Adherence Scale, which was assessed in those patients who reinitiated statins. Secondary outcomes assessed in all participants included statin reinitiation and LDLc (low-density lipoprotein cholesterol), within and post-trial. Using commercial laboratory data, serial LDLc were compared between 1907 patients receiving SLCO1B1 testing and propensity-matched, untested controls.

Results: Trial participants were 25% SLCO1B1*5 carriers. Statin adherence was similar between arms (Morisky Medication Adherence Scale in GIST versus UC, 6.8±1.5 versus 6.9±1.6, P=0.96). GIST led to more new statin prescriptions (55.4% versus 38.0%, P=0.04) and lower LDLc at 3 months (131.9±42.0 versus 144.4±43.0 mg/dL; P=0.048) with similar magnitude at 8 months (128.6±37.9 versus 141.0±44.4; P=0.12). SLCO1B1*5 carriers exhibited a greater drop in LDLc with GIST versus UC (interaction P=0.048). Post-trial, LDLc decreased in UC participants who crossed over to GIST compared with those allocated to GIST (-14.9±37.8 versus +9.0±37.3 mg/dL, P=0.03). Patients tested for SLCO1B1 though a commercial laboratory had a greater LDLc decrease ( P=0.04) compared with controls.

Conclusions: Delivery of SLCO1B1 pharmacogenetic testing that addresses statin myalgia improved statin reinitiation and LDLc but did not improve self-reported statin adherence.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01894230.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.118.002228DOI Listing
September 2018

Facilitating the Calculation of the Efficient Score Using Symbolic Computing.

Am Stat 2018 30;72(2):199-205. Epub 2017 Oct 30.

Biostatistics and Bioinformatics, Duke University School of Medicine Duke Cancer Institute, Duke University Medical Center.

The score statistic continues to be a fundamental tool for statistical inference. In the analysis of data from high-throughput genomic assays, inference on the basis of the score usually enjoys greater stability, considerably higher computational efficiency, and lends itself more readily to the use of resampling methods than the asymptotically equivalent Wald or likelihood ratio tests. The score function often depends on a set of unknown nuisance parameters which have to be replaced by estimators, but can be improved by calculating the efficient score, which accounts for the variability induced by estimating these parameters. Manual derivation of the efficient score is tedious and error-prone, so we illustrate using computer algebra to facilitate this derivation. We demonstrate this process within the context of a standard example from genetic association analyses, though the techniques shown here could be applied to any derivation, and have a place in the toolbox of any modern statistician. We further show how the resulting symbolic expressions can be readily ported to compiled languages, to develop fast numerical algorithms for high-throughput genomic analysis. We conclude by considering extensions of this approach. The code featured in this report is available online as part of the supplementary material.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00031305.2017.1392361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092959PMC
October 2017

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

Thromb Haemost 2018 Sep 13;118(9):1572-1585. Epub 2018 Aug 13.

Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States.

Introduction:  Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery.

Materials And Methods:  Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 10/L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort ( = 860) and validated significant findings in a replication cohort ( = 296). Protein expression was assessed in isolated platelets by immunoblot.

Results:  A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 () met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67,  = 9.76 × 10) with the overall association confirmed by meta-analysis (meta- = 7.88 × 10). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation.

Conclusion:  We identified the association of a genetic polymorphism in the intergenic region of with a decreased incidence of thrombocytopenia after CABG surgery. Because -an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for as a novel modulator of platelet responses after cardiac surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0038-1667199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428429PMC
September 2018

Sex Differences in Gene and Protein Expression After Intracerebral Hemorrhage in Mice.

Transl Stroke Res 2019 04 13;10(2):231-239. Epub 2018 May 13.

Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, 22710, USA.

Sex dimorphism has been demonstrated after experimental intracerebral hemorrhage (ICH). Decreased mortality and improved neurobehavioral outcomes occur in female compared to male mice after intrastriatal autologous blood or collagenase injection. Sex-specific differences in post-ICH gene and protein expression may provide mechanistic insight into this phenomenon. Ten- to 12-week-old C57BL/6 male (M) and female in high estrous state (HE-F) underwent left intrastriatal collagenase injection. We assessed neurobehavioral outcomes over the first 30 days, hematoma volume and cerebral edema evolution over the first 24 h, and transcriptomic gene and protein expression at pre-selected time points during the acute phase of injury. Genome-wide expression profiling was performed with Affymetrix GeneChip Mouse Genome 2.0 Probes, and proteomics analyses were performed using mass spectroscopy. Sex does not affect hemorrhage evolution, but female sex is associated with improved neurobehavioral recovery after ICH. A total of 7037 probes qualified for our filtering criteria, representing 5382 mapped genes and 256 unmapped genes. Female-unique pathways involved cell development, growth, and proliferation, while male-unique pathways involved molecular degradation. At 6 and 24 h post-ICH, differential expression was observed in 850 proteins vs baseline in males, 608 proteins vs baseline in females, and 1 protein in females vs males. Female sex is associated with improved neurobehavioral recovery, and differential gene and protein expression after intrastriatal collagenase injection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12975-018-0633-zDOI Listing
April 2019

18F-florbetapir Positron Emission Tomography-determined Cerebral β-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery.

Anesthesiology 2018 04;128(4):728-744

From the Department of Anesthesiology (R.Y.K., T.B., M.B., N.T., M.F.N., J.P.M.), Department of Radiology (O.G.J., S.B.-N.), Department of Biostatistics and Bioinformatics (Y.-J.L., W.Q.), and the Department of Psychiatry and Behavioral Science (P.M.D.), Duke University, Durham, North Carolina. University of California, San Francisco University of Southern California University of California, San Francisco University of Southern California Mayo Clinic, Rochester Mayo Clinic, Rochester University of California, Berkeley University of Pennsylvania University of Southern California University of California, Davis Brigham and Women's Hospital/Harvard Medical School Indiana University Washington University St. Louis University of Pennsylvania Prevent Alzheimer's Disease 2020 (Chair) Siemens Alzheimer's Association University of Pittsburgh Washington University St. Louis Cornell University Albert Einstein College of Medicine of Yeshiva University AD Drug Discovery Foundation Acumen Pharmaceuticals Washington University St. Louis Northwestern University National Institute of Mental Health Brown University Eli Lilly (Chair) BWH/HMS (Chair) University of Washington (Chair) Mayo Clinic, Rochester (Core Principal Investigator) University of Southern California University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, Davis (Core Principal Investigator) University of California, Davis University of California, San Diego Mayo Clinic, Rochester (Core Principal Investigator) Mayo Clinic, Rochester University of London University of California, Los Angeles School of Medicine University of California, San Francisco Magnetic Resonance Imaging University of California, Davis Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic University of California, Berkeley (Core Principal Investigator) University of Michigan University of Utah Banner Alzheimer's Institute Banner Alzheimer's Institute University of Pittsburgh University of California, Berkeley Washington University St. Louis Washington University St. Louis Washington University St. Louis Washington University St. Louis (ASCP) - Past Investigator University of Pennsylvania School of Medicine University of Pennsylvania School of Medicine University of Pennsylvania School of Medicine University of Pennsylvania School of Medicine University of Pennsylvania School of Medicine University of Southern California (Core Principal Investigator) University of Southern California University of Southern California Indiana University Indiana University University of California, Irvine Indiana University Indiana University Indiana University Indiana University University of California, San Francisco University of California, San Diego Prevent Alzheimer's Disease 2020 University of California, San Diego National Institute on Aging University of California, San Francisco Brown University National Institute of Mental Health Cornell University Johns Hopkins University Richard Frank Consulting Prevent Alzheimer's Disease 2020 National Institute on Aging Oregon Health & Science University Oregon Health & Science University Oregon Health & Science University Oregon Health & Science University Oregon Health & Science University Oregon Health & Science University University of Southern California University of Southern California University of Southern California University of Southern California University of Southern California University of California, San Diego University of California, San Diego University of California, San Diego University of Michigan University of Michigan Mayo Clinic, Rochester Mayo Clinic, Rochester Mayo Clinic, Rochester Mayo Clinic, Rochester Mayo Clinic, Rochester Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine Baylor College of Medicine Columbia University Medical Center Columbia University Medical Center Columbia University Medical Center Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis University of Alabama - Birmingham University of Alabama - Birmingham University of Alabama - Birmingham University of Alabama - Birmingham University of Alabama - Birmingham University of Alabama - Birmingham University of Alabama - Birmingham Mount Sinai School of Medicine Mount Sinai School of Medicine Rush University Medical Center Rush University Medical Center Wien Center Wien Center Wien Center Johns Hopkins University Johns Hopkins University Johns Hopkins University Johns Hopkins University New York University New York University New York University New York University Duke University Medical Center Duke University Medical Center Duke University Medical Center University of Pennsylvania University of Pennsylvania University of Pennsylvania University of Pennsylvania University of Kentucky University of Kentucky University of Kentucky University of Kentucky University of Kentucky University of Kentucky University of Pittsburgh University of Pittsburgh University of Pittsburgh University of Rochester Medical Center University of Rochester Medical Center University of Rochester Medical Center University of Rochester Medical Center University of Rochester Medical Center University of Rochester Medical Center University of California, Irvine University of California, Irvine University of California, Irvine University of Texas Southwestern Medical School University of Texas Southwestern Medical School University of Texas Southwestern Medical School Emory University Emory University Emory University University of Kansas, Medical Center University of Kansas, Medical Center University of Kansas, Medical Center University of California, Los Angeles University of California, Los Angeles University of California, Los Angeles University of California, Los Angeles University of California, Los Angeles University of California, Los Angeles Mayo Clinic, Jacksonville Mayo Clinic, Jacksonville Mayo Clinic, Jacksonville Indiana University Indiana University Indiana University Indiana University Indiana University Yale University School of Medicine Yale University School of Medicine Yale University School of Medicine Yale University School of Medicine McGill Univ., Montreal-Jewish General Hospital McGill Univ., Montreal-Jewish General Hospital McGill Univ., Montreal-Jewish General Hospital Sunnybrook Health Sciences, Ontario Sunnybrook Health Sciences, Ontario Sunnybrook Health Sciences, Ontario UBC Clinic for AD & Related Disorders UBC Clinic for AD & Related Disorders UBC Clinic for AD & Related Disorders UBC Clinic for AD & Related Disorders UBC Clinic for AD & Related Disorders UBC Clinic for AD & Related Disorders Cognitive Neurology - St. Joseph's, Ontario Cognitive Neurology - St. Joseph's, Ontario Cognitive Neurology - St. Joseph's, Ontario Cognitive Neurology - St. Joseph's, Ontario Cognitive Neurology - St. Joseph's, Ontario Cleveland Clinic Lou Ruvo Center for Brain Health Cleveland Clinic Lou Ruvo Center for Brain Health Northwestern University Northwestern University Northwestern University Northwestern University Northwestern University Northwestern University Northwestern University Northwestern University Premiere Research Inst (Palm Beach Neurology) Premiere Research Inst (Palm Beach Neurology) Georgetown University Medical Center Georgetown University Medical Center Georgetown University Medical Center Brigham and Women's Hospital Brigham and Women's Hospital Brigham and Women's Hospital Stanford University Stanford University Stanford University Stanford University Stanford University Banner Sun Health Research Institute Banner Sun Health Research Institute Banner Sun Health Research Institute Banner Sun Health Research Institute Boston University Boston University Boston University Boston University Boston University Howard University Howard University Howard University Case Western Reserve University Case Western Reserve University Case Western Reserve University Case Western Reserve University University of California, Davis - Sacramento University of California, Davis - Sacramento University of California, Davis - Sacramento University of California, Davis - Sacramento University of California, Davis - Sacramento Neurological Care of CNY Parkwood Hospital Parkwood Hospital Parkwood Hospital University of Wisconsin University of Wisconsin University of Wisconsin University of California, Irvine - BIC University of California, Irvine - BIC University of California, Irvine - BIC Banner Alzheimer's Institute Banner Alzheimer's Institute Banner Alzheimer's Institute Banner Alzheimer's Institute Banner Alzheimer's Institute Banner Alzheimer's Institute Dent Neurologic Institute Dent Neurologic Institute Dent Neurologic Institute Ohio State University Ohio State University Ohio State University Albany Medical College Albany Medical College Albany Medical College Hartford Hospital, Olin Neuropsychiatry Research Center Hartford Hospital, Olin Neuropsychiatry Research Center Hartford Hospital, Olin Neuropsychiatry Research Center Dartmouth-Hitchcock Medical Center Dartmouth-Hitchcock Medical Center Dartmouth-Hitchcock Medical Center Dartmouth-Hitchcock Medical Center Wake Forest University Health Sciences Wake Forest University Health Sciences Wake Forest University Health Sciences Wake Forest University Health Sciences Wake Forest University Health Sciences Rhode Island Hospital Rhode Island Hospital Rhode Island Hospital Butler Hospital Butler Hospital Butler Hospital UC San Francisco UC San Francisco UC San Francisco Medical University South Carolina Medical University South Carolina Medical University South Carolina St. Joseph's Health Care St. Joseph's Health Care St. Joseph's Health Care St. Joseph's Health Care St. Joseph's Health Care St. Joseph's Health Care Nathan Kline Institute Nathan Kline Institute Nathan Kline Institute University of Iowa College of Medicine University of Iowa College of Medicine University of Iowa College of Medicine University of Iowa College of Medicine University of Iowa College of Medicine Cornell University Cornell University Cornell University Cornell University University of South Florida: USF Health Byrd Alzheimer's Institute University of South Florida: USF Health Byrd Alzheimer's Institute University of South Florida: USF Health Byrd Alzheimer's Institute University of California, San Francisco University of Southern California University of California, San Francisco University of Southern California Mayo Clinic, Rochester Brigham and Women's Hospital/ Harvard Medical School University of California, Davis Mayo Clinic, Rochester University of California, Berkeley Washington University St. Louis Indiana University Perelman School of Medicine, University of Pennsylvania University of Southern California Perelman School of Medicine, University of Pennsylvania University of California, San Francisco Rehabilitation Institute of Chicago, Feinberg School of Medicine, Northwestern University University of Washington (Chair) Core Principal Investigator Mayo Clinic, Rochester (Core Principal Investigator) University of Southern California University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Diego University of California, San Francisco University of California, San Francisco University of California, San Francisco Neylan Davis (Core Principal Investigator) Neylan San Diego Mayo Clinic, Rochester (Core Principal Investigator) Mayo Clinic, Rochester Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic Mayo Clinic Senjem Berkeley (Core Principal Investigator) University of Michigan University of Utah Banner Alzheimer's Institute Banner Alzheimer's Institute Senjem Berkeley Washington University, St. Louis Washington University, St. Louis Washington University, St. Louis Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine, University of Pennsylvania University of Southern California (Core Principal Investigator) University of Southern California University of Southern California Indiana University Indiana University University of California, Irvine Indiana University Indiana University Indiana University Indiana University University of California, San Francisco Department of Defense (retired) University of Southern California University of Southern California University of Southern California University of California, San Diego University of California, San Diego Columbia University Medical Center Columbia University Medical Center Columbia University Medical Center Rush University Medical Center Rush University Medical Center Rush University Medical Center Wien Center Wien Center Wien Center Duke University Medical Center University of Rochester Medical Center University of Rochester Medical Center University of Rochester Medical Center University of California, Irvine University of California, Irvine University of California, Irvine Medical University South Carolina Medical University South Carolina Medical University South Carolina Premiere Research Institute (Palm Beach Neurology) Premiere Research Institute (Palm Beach Neurology) Premiere Research Institute (Palm Beach Neurology) University of California, San Francisco University of California, San Francisco University of California, San Francisco University of California, San Francisco Georgetown University Medical Center Georgetown University Medical Center Georgetown University Medical Center Brigham and Women's Hospital Brigham and Women's Hospital Brigham and Women's Hospital Banner Sun Health Research Institute Banner Sun Health Research Institute Banner Sun Health Research Institute Howard University Howard University Howard University University of Wisconsin University of Wisconsin University of Wisconsin University of Washington University of Washington University of Washington Stanford University Stanford University Stanford University Stanford University Cornell University Cornell University Cornell University.

Background: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.

Methods: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.

Results: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.

Conclusions: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ALN.0000000000002103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849499PMC
April 2018

Preterm Delivery and Low Birth Weight Among Neonates Conceived With Intracytoplasmic Sperm Injection Compared With Conventional In Vitro Fertilization.

Obstet Gynecol 2018 02;131(2):262-268

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, and the Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.

Objective: To examine the prevalence of prematurity and low birth weight (LBW) among singletons conceived with intracytoplasmic sperm injection (ICSI) compared with those conceived with conventional in vitro fertilization (IVF).

Methods: Using the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, we conducted a retrospective cohort study of women undergoing a first, fresh autologous ICSI or conventional IVF cycle from 2004 to 2013. Singleton live births were included in the analysis. Primary outcomes were preterm delivery and LBW. Secondary outcomes were very preterm delivery, preterm LBW, term LBW, and very LBW. Logistic regression models and propensity score matching were used to compare perinatal outcomes between ICSI and IVF cycles. Subset analyses were performed after stratification by sperm source, male factor infertility, and female prognosis.

Results: Of the 90,401 cycles included in the analysis, ICSI was used in 60,719 (67.2%) and conventional IVF was used in 29,682 (32.8%). After propensity score matching and covariate adjustment, the two groups had similar odds of preterm delivery (adjusted odds ratio [OR] 1.02, 95% CI 0.89-1.18) and LBW (adjusted OR 0.92, 95% CI 0.78-1.10). Using the matched data set, subset analyses demonstrated no significant association between the method of fertilization and the examined perinatal outcomes.

Conclusion: Rates of preterm delivery and LBW were similar between pregnancies conceived with ICSI and conventional IVF after propensity score matching and stratifying by baseline patient characteristics. Previously reported differences in these outcomes were likely secondary to patients' inherent risk factors rather than the fertilization procedure itself.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000002423DOI Listing
February 2018

Correlation of Virtual Reality Simulation and Dry Lab Robotic Technical Skills.

J Minim Invasive Gynecol 2018 May - Jun;25(4):689-696. Epub 2017 Nov 14.

Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.

Study Objective: To examine whether a set of virtual reality (VR) surgical simulation drills have correlative validity when compared with the validated Robotic Objective Structured Assessment of Technical Skills (R-OSATS) dry lab drills.

Design: A prospective methods comparison study (Canadian Task Force classification II-2).

Setting: A teaching hospital.

Participants: Thirty current residents, fellows, and faculty from the Departments of Obstetrics and Gynecology, Urology, and General Surgery.

Interventions: Participants completed 5 VR drills on the da Vinci Skills Simulator and 5 dry lab drills. Participants were randomized to the order of completion.

Measurements And Main Results: VR drills were scored automatically by the simulator. Dry lab drills were recorded, reviewed by 3 blinded experts, and scored using the R-OSATS assessment tool. Spearman correlation coefficients were calculated comparing simulator scores and R-OSATS scores for the same surgeon. The correlation for overall summary scores between VR and dry lab drills was strong (r = 0.83; p < .01). Each of the 5 VR drills was also found to have a statistically significant correlation to its corresponding dry lab drill, with correlation coefficients ranging from r = 0.49 to 0.73 (p < .01 for all). The performance on VR drills also confirmed construct validity. Faculty and fellows had consistently higher overall scores than residents (median VR scores: 458 for faculty, 425 for fellows, 339 for residents; p < .01).

Conclusion: We selected a core set of VR drills that reliably correlate with validated dry lab R-OSATS drills. Because dry lab drills require significant time and effort on the part of the trainees and the evaluators, this set of VR drills could serve as an ancillary method of determining trainee competence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmig.2017.11.006DOI Listing
May 2019

Association of IL6ST (gp130) Polymorphism with Functional Outcome Following Spontaneous Intracerebral Hemorrhage.

J Stroke Cerebrovasc Dis 2018 Jan 28;27(1):125-131. Epub 2017 Sep 28.

Department of Neurology, Duke University, Durham, North Carolina; Department of Anesthesiology, Duke University, Durham, North Carolina; Brain Injury Translational Research Center, Duke University, Durham, North Carolina.

Background And Purpose: Genes associated with the inflammatory response and cytostructural integrity may influence recovery following a brain injury. To examine this in the setting of spontaneous intracerebral hemorrhage (ICH), selected single nucleotide polymorphisms (SNPs) were assessed for associations with patient outcome.

Methods: A cohort of 54 patients with supratentorial ICH were enrolled. Based on known involvement with neuroinflammation and cytostructural integrity, 10 preselected SNPs from 6 candidate genes were tested for associations with 6-month functional outcome (modified Rankin Scale [mRS] ≥ 3), mortality, and in-hospital deterioration (Glasgow Coma Scale decrease by >2 within 7 days of admission) following ICH. Fisher's exact test and logistic regression with adjustment for race and ICH score were performed.

Results: SNP rs10940495 (gp130 G/A) within the gp130 gene was the only SNP significantly associated with lower odds of an unfavorable 6-month functional outcome (odds ratio = .16 for mRS ≥ 3; 95% confidence interval, .03-.87, P = .03). Compared with major allele (A) homozygotes, minor allele (G) carriers in the IL6 signal transducer gene (gp130) locus were 84% less likely to have a poor outcome (mRS ≥ 3) at 6 months following spontaneous ICH. The SNP rs10940495 (gp130 G/A) and SNP rs3219119 (PARP-1 A/T) were associated with 6-month mortality (P = .02 and .04, respectively) only on univariate analysis. None of the SNPs examined were associated with in-hospital deterioration.

Conclusion: In this exploratory study, SNP rs10940495 in the gp130 locus was associated with functional outcome at 6 months following spontaneous ICH. These findings, which should be validated through a larger study, suggest that inflammation plays an important role in mediating outcomes after ICH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.08.017DOI Listing
January 2018

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy.

Nat Commun 2017 03 30;8:14898. Epub 2017 Mar 30.

Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA.

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms14898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379100PMC
March 2017