Publications by authors named "Carl D Langefeld"

445 Publications

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

JAMA Netw Open 2021 Aug 2;4(8):e2121921. Epub 2021 Aug 2.

Henry and Allison McCance Center for Brain Health and Center for Genomic Medicine, Massachusetts General Hospital, Boston.

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations.

Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group.

Design, Setting, And Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020.

Main Outcomes And Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location.

Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals.

Conclusions And Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383133PMC
August 2021

Anesthetic Bladder Capacity is a Clinical Biomarker for Interstitial Cystitis/Bladder Pain Syndrome Subtypes.

Urology 2021 Jul 22. Epub 2021 Jul 22.

Department of Urology/Female Pelvic Health, Wake Forest Baptist Medical Center, Winston-Salem, NC; Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC. Electronic address:

Objective: To further examine anesthetic bladder capacity as a biomarker for interstitial cystitis/bladder pain syndrome (IC/BPS) patient subtypes, we evaluated demographic and clinical characteristics in a large and heterogeneous female patient cohort.

Material And Methods: This is a retrospective review of data from women (n = 257) diagnosed with IC/BPS who were undergoing therapeutic bladder hydrodistention (HOD). Assessments included medical history and physical examination, validated questionnaire scores, and anesthetic BC. Linear regression analyses were computed to model the relationship between anesthetic BC and patient demographic data, symptoms, and diagnoses. Variables exhibiting suggestive correlations (P ≤ .1) were candidates for a multiple linear regression analysis and were retained if significant (P ≤ .05).

Results: Multiple regression analysis identified a positive correlation between BC and endometriosis (P = .028) as well as negative correlations between BC and both ICSI score (P < .001) and the presence of Hunner's lesions (P < .001). There were higher average numbers of pelvic pain syndrome (PPS) diagnoses (P = .006) and neurologic, autoimmune, or systemic pain (NASP) diagnoses (P = .003) in IC/BPS patients with a non-low BC, but no statistical difference in the duration of diagnosis between patients with low and non-low BC (P = .118).

Conclusion: These data, generated from a large IC/BPS patient cohort, provide additional evidence that higher BC correlates with higher numbers of non-bladder-centric syndromes while lower BC correlates more closely with bladder-specific pathology. Taken together, the results support the concept of clinical subgroups in IC/BPS.
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http://dx.doi.org/10.1016/j.urology.2021.07.009DOI Listing
July 2021

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

Circ Genom Precis Med 2021 Aug 9;14(4):e003258. Epub 2021 Jul 9.

Department of Epidemiology (N.F., G.H.), University of North Carolina, Chapel Hill.

Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

Methods: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

Results: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

Conclusions: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435075PMC
August 2021

Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations.

Am J Nephrol 2021 7;52(5):378-387. Epub 2021 Jun 7.

Department of Paediatrics and Inherited Metabolic Disorders, Research Unit of Rare Diseases, First Faculty of Medicine, Charles University, Prague, Czechia.

Introduction: Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1.

Methods: This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals.

Results: Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were <5 U/mL in 22% of ADTKD-MUC1 patients, in 0/249 controls, and in 1% of the reference population. Plasma CA15-3 levels were >20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate.

Discussion/conclusions: Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.
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http://dx.doi.org/10.1159/000515810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315672PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Rare Missense Functional Variants at and in Sporadic Intracerebral Hemorrhage.

Neurology 2021 May 24. Epub 2021 May 24.

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

ObjectiveTo test the genetic contribution of rare missense variants in and in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including and among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1) and rs201716258 (COL4A2), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact ( or ), and modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in / in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.
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http://dx.doi.org/10.1212/WNL.0000000000012227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302151PMC
May 2021

Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.

PLoS One 2021 20;16(5):e0251423. Epub 2021 May 20.

Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136717PMC
May 2021

Genetic landscape of Gullah African Americans.

Am J Phys Anthropol 2021 08 19;175(4):905-919. Epub 2021 May 19.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Objectives: Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah.

Materials And Methods: We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture.

Results: Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations.

Discussion: This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.
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http://dx.doi.org/10.1002/ajpa.24333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286328PMC
August 2021

Hierarchicell: an R-package for estimating power for tests of differential expression with single-cell data.

BMC Genomics 2021 May 1;22(1):319. Epub 2021 May 1.

Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Study design is a critical aspect of any experiment, and sample size calculations for statistical power that are consistent with that study design are central to robust and reproducible results. However, the existing power calculators for tests of differential expression in single-cell RNA-seq data focus on the total number of cells and not the number of independent experimental units, the true unit of interest for power. Thus, current methods grossly overestimate the power.

Results: Hierarchicell is the first single-cell power calculator to explicitly simulate and account for the hierarchical correlation structure (i.e., within sample correlation) that exists in single-cell RNA-seq data. Hierarchicell, an R-package available on GitHub, estimates the within sample correlation structure from real data to simulate hierarchical single-cell RNA-seq data and estimate power for tests of differential expression. This multi-stage approach models gene dropout rates, intra-individual dispersion, inter-individual variation, variable or fixed number of cells per individual, and the correlation among cells within an individual. Without modeling the within sample correlation structure and without properly accounting for the correlation in downstream analysis, we demonstrate that estimates of power are falsely inflated. Hierarchicell can be used to estimate power for binary and continuous phenotypes based on user-specified number of independent experimental units (e.g., individuals) and cells within the experimental unit.

Conclusions: Hierarchicell is a user-friendly R-package that provides accurate estimates of power for testing hypotheses of differential expression in single-cell RNA-seq data. This R-package represents an important addition to single-cell RNA analytic tools and will help researchers design experiments with appropriate and accurate power, increasing discovery and improving robustness and reproducibility.
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http://dx.doi.org/10.1186/s12864-021-07635-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088563PMC
May 2021

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

Neurology 2021 05 21;96(20):e2469-e2480. Epub 2021 Apr 21.

From the Department of Neurology (J.P.C., J.R.A., A.R.-T., S.M., P.K., A.C., C.K., Z.D., K.S., M.E.G., A.V., C.D.A., S.M.G., J.R., A.B.), Hemorrhagic Stroke Research Program (J.P.C., J.R.A., A.R.-T., S.M., P.K., A.C., C.K, Z.D., K.S., M.E.G., A.V., C.D.A., S.M.G., J.R., A.B.), Henry and Allison McCance Center for Brain Health (J.P.C., J.R.A., P.K., C.K., C.D.A., J.R., A.B.), and Center for Genomic Medicine (J.R.A., S.M., P.K., C.K., C.D.A., J.R., A.B.), Massachusetts General Hospital, Boston; University of Lille (M.P.), Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, France; School of Medicine (A.R.-T.), University of California, Irvine; Department of Neurology and Rehabilitation Medicine (S.D., L.G., M.L.F., D.W.), University of Cincinnati, OH; Department of Biostatistics and Data Sciences (C.D.L.), Wake Forest University, Winston-Salem, NC; Department of Neurology (A.T.), Keck School of Medicine, University of Southern California; and Los Angeles County Department of Health Services (A.T.), CA.

Objective: Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk.

Methods: We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk.

Results: We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD ( = 0.011) and HTNA burden ( = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all < 0.05).

Conclusions: We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.
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http://dx.doi.org/10.1212/WNL.0000000000011932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205476PMC
May 2021

Obstructive Sleep Apnea as a Risk Factor for Intracerebral Hemorrhage.

Stroke 2021 May 8;52(5):1835-1838. Epub 2021 Apr 8.

Department of Neurology (G.J.F., K.N.V., A.C.L., L.H.S., K.N.S.), Yale University, New Haven, CT.

Background And Purpose: To determine whether obstructive sleep apnea (OSA) is associated with intracerebral hemorrhage (ICH) risk, we assessed premorbid OSA exposure of patients with nontraumatic ICH and matched controls.

Methods: Ethnic/Racial Variations of Intracerebral Hemorrhage is a multicenter, case-control study evaluating risk factors for ICH that recruited 3000 cases with ICH and 3000 controls. OSA status was ascertained using the Berlin Questionnaire as a surrogate for premorbid OSA. We performed logistic regression analyses to evaluate the association between OSA and ICH.

Results: Two thousand and sixty-four (71%) cases and 1516 (52%) controls were classified as having OSA by the Berlin Questionnaire. Cases with OSA were significantly more likely to be male and have hypertension, heart disease, hyperlipidemia, and higher body mass index compared with those without OSA. OSA was more common among cases compared with controls (71% versus 52%, odds ratio, 2.28 [95% CI, 2.05-2.55]). In a multivariable logistic regression model, OSA was associated with increased risk for ICH (odds ratio, 1.47 [95% CI, 1.29-1.67]).

Conclusions: OSA is a risk factor for ICH.
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http://dx.doi.org/10.1161/STROKEAHA.120.033342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085039PMC
May 2021

miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model.

J Mol Neurosci 2021 Sep 23;71(9):1802-1814. Epub 2021 Mar 23.

Department of Emergency Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Inflammation after ICH contributes to clinical outcomes, but the relevant molecular mechanisms remain poorly understood. In studies of peripheral leukocyte counts and mRNA-sequencing (mRNA-seq), our group previously reported that monocytes and Interleukin-8 (IL-8) were important contributors to post-ICH inflammation. microRNA (miRNA) are powerful regulators of gene expression and promising therapeutic targets. We now report findings from an integrated analysis of miRNA-seq and mRNA-seq in peripheral blood mononuclear cells (PBMCs) from a swine ICH model. In 10 pigs, one PBMC sample was collected immediately prior to ICH induction and a second 6 h later; miRNA-seq and mRNA-seq were completed for each sample. An aggregate score calculation determined which miRNA regulated the differentially expressed mRNA. Networks of molecular interactions were generated for the combined miRNA/target mRNA. A total of 227 miRNA were identified, and 46 were differentially expressed after ICH (FDR < 0.05). The anti-inflammatory miR-181a was decreased post-ICH, and it was the most highly connected miRNA in the miRNA/mRNA bioinformatic network analysis. miR-181a has interconnected pathophysiology with IL-8 and monocytes; in prior studies, we found that IL-8 and monocytes contributed to post-ICH inflammation and ICH clinical outcome, respectively. miR-181a was a significant mediator of post-ICH inflammation and is promising for further study, including as a potential therapeutic target. This investigation also demonstrated feasible methodology for miRNA-seq/mRNA-seq analysis in swine that is innovative, and with unique challenges, compared with transcriptomics research in more established species.
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http://dx.doi.org/10.1007/s12031-021-01815-9DOI Listing
September 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Admission Hemoglobin Levels Are Associated With Functional Outcome in Spontaneous Intracerebral Hemorrhage.

Crit Care Med 2021 05;49(5):828-837

Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT.

Objectives: To test the hypothesis that admission hemoglobin levels are associated with outcome in primary, nontraumatic intracerebral hemorrhage.

Design: Individual patient data meta-analysis of three studies of intracerebral hemorrhage.

Setting: Two randomized clinical trials and one multiethnic observational study.

Patients: Patients with spontaneous, nontraumatic intracerebral hemorrhage.

Interventions: None.

Measurements And Main Results: Our exposure of interest was admission hemoglobin levels and the primary outcome was 3-month postintracerebral hemorrhage-dichotomized modified Rankin Scale (0-3 vs 4-6). Intermediate outcomes were admission hematoma volume and hematoma expansion defined as 6 mL or 33% increase in hemorrhage size on repeat CT. A total of 4,172 intracerebral hemorrhage patients were included in the study (mean age 63 [sd = 14]; female sex 1,668 [40%]). Each additional g/dL of admission hemoglobin was associated with 14% (odds ratio, 0.86; 95% CI, 0.82-0.91) and 7% (odds ratio, 0.93; 95% CI, 0.88-0.98) reductions in the risk of poor outcome in unadjusted and adjusted analyses, respectively. Dose-response analyses indicated a linear relationship between admission hemoglobin levels and poor outcome across the entire evaluated range (test-for-trend p < 0.001). No consistent associations were found between the admission hemoglobin levels and hematoma volume or hematoma expansion.

Conclusions: Higher hemoglobin levels are associated with better outcome in intracerebral hemorrhage. Further research is needed to evaluate admission hemoglobin levels as both a therapeutic target and predictor of outcome.
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http://dx.doi.org/10.1097/CCM.0000000000004891DOI Listing
May 2021

Identification of Influential Variants in Significant Aggregate Rare Variant Tests.

Hum Hered 2021 Feb 10:1-13. Epub 2021 Feb 10.

Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA.

Introduction: Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association.

Methods: In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF).

Results: All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF.

Discussion: In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.
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http://dx.doi.org/10.1159/000513290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353006PMC
February 2021

A practical solution to pseudoreplication bias in single-cell studies.

Nat Commun 2021 02 2;12(1):738. Epub 2021 Feb 2.

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Cells from the same individual share common genetic and environmental backgrounds and are not statistically independent; therefore, they are subsamples or pseudoreplicates. Thus, single-cell data have a hierarchical structure that many current single-cell methods do not address, leading to biased inference, highly inflated type 1 error rates, and reduced robustness and reproducibility. This includes methods that use a batch effect correction for individual as a means of accounting for within-sample correlation. Here, we document this dependence across a range of cell types and show that pseudo-bulk aggregation methods are conservative and underpowered relative to mixed models. To compute differential expression within a specific cell type across treatment groups, we propose applying generalized linear mixed models with a random effect for individual, to properly account for both zero inflation and the correlation structure among measures from cells within an individual. Finally, we provide power estimates across a range of experimental conditions to assist researchers in designing appropriately powered studies.
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http://dx.doi.org/10.1038/s41467-021-21038-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854630PMC
February 2021

Arg206Cys substitution in causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus.

Ann Rheum Dis 2021 Jan 17. Epub 2021 Jan 17.

The Institute of Molecular Medicine, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, USA

Objectives: To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the / gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function.

Methods: Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants.

Results: Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced.

Conclusions: SLE risk association in the locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.
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http://dx.doi.org/10.1136/annrheumdis-2020-218810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142439PMC
January 2021

CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance.

Sci Rep 2021 01 14;11(1):1465. Epub 2021 Jan 14.

Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.

Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.
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http://dx.doi.org/10.1038/s41598-021-81126-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809150PMC
January 2021

Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms.

Ann Rheum Dis 2020 Oct 26. Epub 2020 Oct 26.

Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

Objectives: Juvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.

Methods: We performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.

Results: Our analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and as a potential drug target.

Conclusions: In a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.
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http://dx.doi.org/10.1136/annrheumdis-2020-218481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892389PMC
October 2020

Effects of Intensive Systolic Blood Pressure Control on All-Cause Hospitalizations.

Hypertension 2020 12 26;76(6):1717-1724. Epub 2020 Oct 26.

Biostatistics and Data Science (M.E.C., M.C.M., C.D.L.), Wake Forest School of Medicine, Winston-Salem, NC.

Intensive blood pressure control decreases the rate of cardiovascular events by >25% compared with standard blood pressure control. We sought to determine whether the decrease in cardiovascular events seen with intensive blood pressure control is associated with an increased rate of other causes of hospitalization. This is a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial) in 9361 adult participants with hypertension and elevated cardiovascular risk. Participants were randomly assigned to an intensive or standard systolic blood pressure goal (<120 or <140 mm Hg, respectively). The primary outcome was hospitalization rates per 100 person-years for hospitalizations not associated with SPRINT primary events. After excluding hospitalizations linked to SPRINT primary events, there were 4678 participants with a rate of 19.70 hospitalizations per 100 person-years, compared with 4683 participants with a rate of 19.65 (=0.37). Equivalence testing shows that these hospitalization rates were statistically equivalent at the =0.05 level. Of those with hospitalizations, >1 hospitalization was seen in 38.8% of intensive arm participants and 41.9% of standard arm participants (=0.08). The mean cumulative count of nonprimary event hospitalizations was comparable between the two arms. The most common causes of hospitalization were cardiovascular (23.6%) followed by injuries, including bone and joint therapeutic procedures (15.7%), infections (12.0%), and nervous systems disorders (10.7%). No categories of hospitalization were statistically more common in the intensive arm compared with the standard arm. Thus, the decrease in cardiovascular events seen with intensive blood pressure control is not associated with an increased rate of other causes of hospitalization. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666020PMC
December 2020

Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies.

Nucleic Acids Res 2020 11;48(20):11304-11321

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

In genomic fine-mapping studies, some approaches leverage annotation data to prioritize likely functional polymorphisms. However, existing annotation resources can present challenges as many lack information for novel variants and/or may be uninformative for non-coding regions. We propose a novel annotation source, sequence-dependent DNA topology, as a prioritization metric for fine-mapping. DNA topology and function are well-intertwined, and as an intrinsic DNA property, it is readily applicable to any genomic region. Here, we constructed and applied Minor Groove Width (MGW) as a prioritization metric. Using an established MGW-prediction method, we generated a MGW census for 199 038 197 SNPs across the human genome. Summarizing a SNP's change in MGW (ΔMGW) as a Euclidean distance, ΔMGW exhibited a strongly right-skewed distribution, highlighting the infrequency of SNPs that generate dissimilar shape profiles. We hypothesized that phenotypically-associated SNPs can be prioritized by ΔMGW. We tested this hypothesis in 116 regions analyzed by a Massively Parallel Reporter Assay and observed enrichment of large ΔMGW for functional polymorphisms (P = 0.0007). To illustrate application in fine-mapping studies, we applied our MGW-prioritization approach to three non-coding regions associated with systemic lupus erythematosus. Together, this study presents the first usage of sequence-dependent DNA topology as a prioritization metric in genomic association studies.
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http://dx.doi.org/10.1093/nar/gkaa877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672465PMC
November 2020

Platelet Glycoprotein Ib α-Chain as a Putative Therapeutic Target for Juvenile Idiopathic Arthritis: A Mendelian Randomization Study.

Arthritis Rheumatol 2021 04 21;73(4):693-701. Epub 2021 Feb 21.

University of Bristol, Bristol, UK.

Objective: To ascertain the role of platelet glycoprotein Ib α-chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.

Methods: We performed a two-sample Mendelian randomization (MR) study, using both a cis-acting protein quantitative trait locus (cis-pQTL) and trans-pQTL near the GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two-step MR study. Putative associations (GPIbα/platelet count/disease) detected by MR analyses were subsequently assessed using multiple-trait colocalization analyses.

Results: After correction for multiple testing (Bonferroni-corrected threshold P ≤ 2 × 10 ), GPIbα, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)-negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant ≥0.80). GPIbα instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbα trans-pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans-acting instrument operates through other pathways.

Conclusion: The role of platelets in thrombosis is well-established; however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF-negative polyarticular JIA, and indicate that GPIbα may serve as a putative therapeutic target for these JIA subtypes.
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http://dx.doi.org/10.1002/art.41561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048917PMC
April 2021

Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries.

Am J Hum Genet 2020 11 7;107(5):864-881. Epub 2020 Oct 7.

AMPEL BioSolutions LLC, Charlottesville, VA 22902, USA.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675009PMC
November 2020

Impact of rs174537 on Critically Ill Patients with Acute Lung Injury: A Secondary Analysis of the OMEGA Randomized Clinical Trial.

Curr Dev Nutr 2020 Oct 14;4(10):nzaa147. Epub 2020 Sep 14.

Department of Biomedical Engineering, Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC, USA.

Background: Nutrition in the intensive care unit is vital for patient care; however, immunomodulatory diets rich in PUFAs like γ-linolenic acid (GLA), EPA, and DHA remain controversial for patients with acute respiratory distress syndrome. We postulate that genetic variants impacting PUFA metabolism contribute to mixed responses to PUFA-rich diets.

Objectives: In this study, we aimed to test the effects of single nucleotide polymorphism (SNP) rs174537 on differential responses to PUFA-rich diets.

Methods: We performed a secondary analysis of the OMEGA trial (NCT00609180) where 129 subjects received placebo control diets and 143 received omega-oil. DNA was extracted from buffy coats and used to genotype rs174537; plasma was used to quantitate PUFAs. We tested for SNP-diet interactions on PUFA concentrations, inflammatory biomarkers, and patient outcomes.

Results: We observed that all individuals receiving omega-oil displayed significantly higher concentrations of GLA, EPA, and DHA (all < 0.0001), but they did not vary by genotype at rs174537. Statistically significant SNP-diet interactions were observed on circulating DHA concentrations in African Americans. Specifically, African American T-allele carriers on placebo illustrated elevated DHA concentrations. Additionally, all individuals receiving omega-oil had higher concentrations of EPA-derived urinary F3-isoprostane (Caucasians:  = 0.0011; African Americans:  = 0.0002). Despite these findings, we did not detect any significant SNP-diet interactions on pulmonary functional metrics, clinical outcomes, and mortality.

Conclusions: This study highlights the importance of genetic and racial contributions to PUFA metabolism and inflammation. In particular, rs174537 had a significant impact on circulating DHA and urinary isoprostane concentrations. Given our relatively small sample size, further investigations in larger multiethnic cohorts are needed to evaluate the impact of rs174537 on fatty acid metabolism and downstream inflammation.
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http://dx.doi.org/10.1093/cdn/nzaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524639PMC
October 2020

Epigenetic methylation in Eosinophilic Esophagitis: Molecular ageing and novel biomarkers for treatment response.

Clin Exp Allergy 2020 12 6;50(12):1372-1380. Epub 2020 Nov 6.

Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Background: Treatment failure in eosinophilic esophagitis (EoE) is common. We hypothesize that DNA methylation differs between patients by treatment response to topical steroids (oral viscous budesonide), thus offering the potential to inform targeting therapies.

Objective: We sought to identify differentially methylated sites and affiliated genes in pre-treatment oesophageal cells between responders and non-responders and test for accelerated epigenetic ageing in oesophageal cells of EoE patients.

Methods: DNA was extracted from prospectively collected and biobanked oesophageal biopsies from 36 Caucasian treatment naïve EoE patients at diagnosis. Methylation assays were completed using the Infinium HumanMethylation450 BeadChip. Normalized β values for each CpG site were tested (t test) for differential methylation. Further, 353 CpG probes were used to estimate epigenetic age for each patient and a linear regression model tested whether chronologic age and epigenetic age differed. Epigenetic age results were confirmed in an independent cohort of healthy controls.

Results: Eighteen CpG sites were differentially methylated by treatment response (P < .00001). The mean epigenetic age and chronological age were 56.1 ± 11.1 and 36.7 ± 12.3 years, a mean age difference of 19.3 ± 5.2 years (P < .0001); accelerated ageing was not observed in the oesophageal cells of healthy controls.

Conclusions And Clinical Relevance: EoE patients that respond versus do not respond to treatment have differences in their methylation profile, including enrichment of genes in pathways consistent with cellular injury and repair due to environmental stress and cell adhesion and barrier integrity. EoE also appears to accelerate cellular ageing. Whether treatment can arrest or reverse accelerated epigenetic ageing and the implications for long-term disease progression is important areas for future research.
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http://dx.doi.org/10.1111/cea.13748DOI Listing
December 2020

Sex differences in human adipose tissue gene expression and genetic regulation involve adipogenesis.

Genome Res 2020 10 23;30(10):1379-1392. Epub 2020 Sep 23.

Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.

Sex differences in adipose tissue distribution and function are associated with sex differences in cardiometabolic disease. While many studies have revealed sex differences in adipocyte cell signaling and physiology, there is a relative dearth of information regarding sex differences in transcript abundance and regulation. We investigated sex differences in subcutaneous adipose tissue transcriptional regulation using omic-scale data from ∼3000 geographically and ethnically diverse human samples. We identified 162 genes with robust sex differences in expression. Differentially expressed genes were implicated in oxidative phosphorylation and adipogenesis. We further determined that sex differences in gene expression levels could be related to sex differences in the genetics of gene expression regulation. Our analyses revealed sex-specific genetic associations, and this finding was replicated in a study of 98 inbred mouse strains. The genes under genetic regulation in human and mouse were enriched for oxidative phosphorylation and adipogenesis. Enrichment analysis showed that the associated genetic loci resided within binding motifs for adipogenic transcription factors (e.g., PPARG and EGR1). We demonstrated that sex differences in gene expression could be influenced by sex differences in genetic regulation for six genes (e.g., and ). These genes exhibited dynamic expression patterns during adipogenesis and robust expression in mature human adipocytes. Our results support a role for adipogenesis-related genes in subcutaneous adipose tissue sex differences in the genetic and environmental regulation of gene expression.
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http://dx.doi.org/10.1101/gr.264614.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605264PMC
October 2020

Integrative Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation, and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans.

Diabetes 2020 12 14;69(12):2779-2793. Epub 2020 Sep 14.

Department of Internal Medicine, Section of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed -expression quantitative trait methylation (-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]- < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (; = -0.632, = 4.70 × 10) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR- < 0.05) with the Matsuda index, S, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, S, and/or BMI in EWAS. These associated genes include , , , and In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.
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http://dx.doi.org/10.2337/db20-0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679782PMC
December 2020

Comparative Study of Prostate Cancer Biophysical and Migratory Characteristics via Iterative Mechanoelectrical Properties (iMEP) and Standard Migration Assays.

Sens Actuators B Chem 2020 Oct 27;321. Epub 2020 Jun 27.

The Bradley Department of Electrical and Computer Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States.

This study reveals a new microfluidic biosensor consisting of a multi-constriction microfluidic device with embedded electrodes for measuring the biophysical attributes of single cells. The biosensing platform called the iterative mechano-electrical properties (iMEP) analyzer captures electronic records of biomechanical and bioelectrical properties of cells. The iMEP assay is used in conjunction with standard migration assays, such as chemotaxis-based Boyden chamber and scratch wound healing assays, to evaluate the migratory behavior and biophysical properties of prostate cancer cells. The three cell lines evaluated in the study each represent a stage in the standard progression of prostate cancer, while the fourth cell line serves as a normal/healthy counterpart. Neither the scratch assay nor the chemotaxis assay could fully differentiate the four cell lines. Furthermore, there was not a direct correlation between wound healing rate or the migratory rate with the cells' metastatic potential. However, the iMEP assay, through its multiparametric dataset, could distinguish between all four cell line populations with p-value < 0.05. Further studies are needed to determine if iMEP signatures can be used for a wider range of human cells to assess the tumorigenicity of a cell population or the metastatic potential of cancer cells.
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http://dx.doi.org/10.1016/j.snb.2020.128522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455013PMC
October 2020

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Stroke 2020 08 22;51(8):2454-2463. Epub 2020 Jul 22.

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).

Background And Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.

Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.

Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the gene that reached genome-wide significance (=4.62×10) and an additional 29 variants with suggestive evidence of association (<1×10), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction value of 2.08×10 (0.05/24 unique loci), we were able to validate associations at the locus in both SiGN (=8.18×10) and METASTROKE (=1.72×10) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the and genes represent potential novel ischemic stroke loci.

Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
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http://dx.doi.org/10.1161/STROKEAHA.120.029123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387190PMC
August 2020

Kidney-Risk Variants Induce Mitochondrial Fission.

Kidney Int Rep 2020 Jun 30;5(6):891-904. Epub 2020 Mar 30.

Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of and elucidate potential mechanisms in -nephropathy.

Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.

Results: genotypes did not alter expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to was a eQTL for and a eQTL for ; and were co-expressed in cells. knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various genotypes. Mitochondria in wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.

Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in -nephropathy.
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http://dx.doi.org/10.1016/j.ekir.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271005PMC
June 2020
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