Publications by authors named "James A Perry"

38 Publications

Mutagenesis of human genomes by endogenous mobile elements on a population scale.

Genome Res 2021 Nov 12. Epub 2021 Nov 12.

Graduate Program in Molecular Medicine, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.

Several large-scale Illumina whole-genome sequencing (WGS) and whole-exome sequencing (WES) projects have emerged recently that have provided exceptional opportunities to discover mobile element insertions (MEIs) and study the impact of these MEIs on human genomes. However, these projects also have presented major challenges with respect to the scalability and computational costs associated with performing MEI discovery on tens or even hundreds of thousands of samples. To meet these challenges, we have developed a more efficient and scalable version of our mobile element locator tool (MELT) called CloudMELT. We then used MELT and CloudMELT to perform MEI discovery in 57,919 human genomes and exomes, leading to the discovery of 104,350 nonredundant MEIs. We leveraged this collection (1) to examine potentially active L1 source elements that drive the mobilization of new , L1, and SVA MEIs in humans; (2) to examine the population distributions and subfamilies of these MEIs; and (3) to examine the mutagenesis of GENCODE genes, ENCODE-annotated features, and disease genes by these MEIs. Our study provides new insights on the L1 source elements that drive MEI mutagenesis and brings forth a better understanding of how this mutagenesis impacts human genomes.
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http://dx.doi.org/10.1101/gr.275323.121DOI Listing
November 2021

Choledochal stenting for treatment of extrahepatic biliary obstruction in cats.

J Vet Intern Med 2021 Sep 29. Epub 2021 Sep 29.

University of California-Davis, School of Veterinary Medicine, Davis, California, USA.

Background: Limited information currently exists regarding the clinical progression and outcomes of cats that undergo choledochal stenting as a treatment for extrahepatic biliary obstruction (EHBO).

Hypothesis/objectives: Describe clinical characteristics, indications for choledochal stent placement, procedure, and outcomes in a cohort of cats undergoing choledochal stenting and evaluate risk factors associated with survival as well as recurrence of EHBO in affected cats.

Animals: Twenty-three client-owned cats undergoing choledochal stent placement.

Methods: Retrospective study. Medical records from 6 academic institutions were reviewed, and data were extracted and analyzed statistically.

Results: Median age of cats was 10.1 years (range, 2-16), and all cats had at least 2 clinical signs. Most common clinical signs were vomiting in 20/22 (90.9%), inappetence in 19/22 (86.4%), and lethargy in 19/23 (82.6%). Procedural complications were uncommon and rarely related to the stenting procedure. Clinical signs improved postoperatively in 15/20 (75.0%) cats and serum total bilirubin concentration decreased postoperatively in 13/19 (68.4%) cats. Eighteen (78.3%) cats survived to discharge. Recurrence of EHBO was documented in 7/18 (38.9%) cats that survived to discharge. Cholelithiasis was associated with recurrence of EHBO. Median survival time for cats that survived to discharge was 931 days (range, 19-3034). Absence of peritoneal effusion was associated with survival to discharge.

Conclusions And Clinical Importance: Choledochal stenting was an effective treatment modality in cats with EHBO with few procedural complications and potential for prolonged survival, but substantial risk for recurrence of EHBO was identified.
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http://dx.doi.org/10.1111/jvim.16176DOI Listing
September 2021

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Am J Hum Genet 2021 10 27;108(10):1836-1851. Epub 2021 Sep 27.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546043PMC
October 2021

Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort.

PLoS One 2021 1;16(9):e0247287. Epub 2021 Sep 1.

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.

Background: Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.

Methods And Results: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.

Conclusions: Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409653PMC
November 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Baseline cardiometabolic profiles and SARS-CoV-2 infection in the UK Biobank.

PLoS One 2021 1;16(4):e0248602. Epub 2021 Apr 1.

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.

Background: SARS-CoV-2 is a rapidly spreading coronavirus responsible for the Covid-19 pandemic, which is characterized by severe respiratory infection. Many factors have been identified as risk factors for SARS-CoV-2, with much early attention being paid to body mass index (BMI), which is a well-known cardiometabolic risk factor.

Objective: This study seeks to examine the impact of additional baseline cardiometabolic risk factors including high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), Apolipoprotein A-I (ApoA-I), Apolipoprotein B (ApoB), triglycerides, hemoglobin A1c (HbA1c) and diabetes on the odds of testing positive for SARS-CoV-2 in UK Biobank (UKB) study participants.

Methods: We examined the effect of BMI, lipid profiles, diabetes and alcohol intake on the odds of testing positive for SARS-Cov-2 among 9,005 UKB participants tested for SARS-CoV-2 from March 16 through July 14, 2020. Odds ratios and 95% confidence intervals were computed using logistic regression adjusted for age, sex and ancestry.

Results: Higher BMI, Type II diabetes and HbA1c were associated with increased SARS-CoV-2 odds (p < 0.05) while HDL-C and ApoA-I were associated with decreased odds (p < 0.001). Though the effect of BMI, Type II diabetes and HbA1c were eliminated when HDL-C was controlled, the effect of HDL-C remained significant when BMI was controlled for. LDL-C, ApoB and triglyceride levels were not found to be significantly associated with increased odds.

Conclusion: Elevated HDL-C and ApoA-I levels were associated with reduced odds of testing positive for SARS-CoV-2, while higher BMI, type II diabetes and HbA1c were associated with increased odds. The effects of BMI, type II diabetes and HbA1c levels were no longer significant after controlling for HDL-C, suggesting that these effects may be mediated in part through regulation of HDL-C levels. In summary, our study suggests that baseline HDL-C level may be useful for stratifying SARS-CoV-2 infection risk and corroborates the emerging picture that HDL-C may confer protection against sepsis in general and SARS-CoV-2 in particular.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016301PMC
April 2021

Survival time of juvenile dogs with oral squamous cell carcinoma treated with surgery alone: A Veterinary Society of Surgical Oncology retrospective study.

Vet Surg 2021 May 27;50(4):740-747. Epub 2021 Mar 27.

Department of clinical studies, VCA Clinical Studies, Los Angeles, California, USA.

Objective: To report the signalment, staging, surgical treatment, and survival time of juvenile dogs treated surgically for oral squamous cell carcinoma (OSCC).

Study Design: Retrospective study.

Animals Or Sample Population: Twenty-five dogs, <2 years of age with OSCC treated with surgery.

Methods: Cases were solicited from the Veterinary Society of Surgical Oncology. Data retrieved included sex, breed, age, weight, clinical signs, tumor location, preoperative diagnostics and staging, histopathological diagnosis with margin evaluation, disease-free interval, and date and cause of death. A minimum follow-up time of 3 months was required for inclusion.

Results: Eighteen dogs were <12 months of age, and seven were <24 months. Various breeds were represented, with a mean body weight of 22.3 ± 14.4 kg. No dogs had evidence of metastatic disease prior to surgery. All dogs underwent partial maxillectomy or mandibulectomy. Histological margins were complete in 24 dogs and incomplete in one. No dogs had evidence of metastatic disease or tumor recurrence. The median follow-up time was 1556 days (92 to 4234 days). All dogs were alive at the last follow-up except for one documented death, due to dilated cardiomyopathy. Median disease-specific survival time was not reached.

Conclusion: The prognosis after wide surgical excision of OSCC in juvenile dogs was excellent.

Clinical Significance: OSCC in juvenile dogs can be effectively treated with surgery alone.
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http://dx.doi.org/10.1111/vsu.13625DOI Listing
May 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

The effect of prednisone on histologic and gross characteristics in canine mast cell tumors.

Can Vet J 2021 01;62(1):45-50

Seattle Veterinary Specialists Blue Pearl, Kirkland, Washington 98034, USA (Linde); Veterinary Referral Center of Central Oregon, 1820 NW Monterey Pines Drive, Bend, Oregon 97703, USA (Stockdale); University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA (Mison); Veterinary Cancer & Surgery Specialists, Portland, Oregon 97222 USA (Perry).

The objective of the study was to determine whether neoadjuvant prednisone therapy affects histological features of cutaneous and subcutaneous mast cell tumors. Twenty-eight dogs with a treatment naïve > 1-cm diameter mast cell tumor (MCT) were randomly assigned (Random number generator; Random.org, Dublin, Ireland) in a blinded fashion to receive either prednisone or placebo (Quality Food Center Pharmacy, Kirkland, Washington, USA). Volumes of mast cell tumors were calculated before incisional and excisional biopsies. Following incisional biopsy, patients received either prednisone (1 mg/kg body weight) daily or a placebo for 7 to 14 days leading up to excisional biopsy. Tumor grade for cutaneous MCT, and mitotic count and atypia for all tumors were reported. Perioperative treatment with prednisone had no significant effect on tumor grade, atypia, or mitotic count. Tumor volume was significantly decreased with prednisone treatment. The use of neoadjuvant prednisone to decrease MCT volume in order to facilitate tumor excision, can be considered without significant concern for change of tumor histologic features in the common population of low- to intermediate-grade MCT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739397PMC
January 2021

and Long QT Syndrome in 1/45 Amish: The Road From Identification to Implementation of Culturally Appropriate Precision Medicine.

Circ Genom Precis Med 2020 12 3;13(6):e003133. Epub 2020 Nov 3.

Regeneron Genetics Center LLC, Tarrytown, NY (C.V.H., N.G., C.G.-J., A.E., A.R.S.).

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health.

Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting.

Results: A missense variant was identified in (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram (=5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, =0.0006), greater history of syncope (32% versus 17%, =0.020), and higher rate of sudden cardiac death in first degree relatives
Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.
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http://dx.doi.org/10.1161/CIRCGEN.120.003133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748050PMC
December 2020

Baseline Cardiometabolic Profiles and SARS-CoV-2 Infection in the UK Biobank.

medRxiv 2020 Nov 20. Epub 2020 Nov 20.

Background: SARS-CoV-2 is a rapidly spreading coronavirus with a high incidence of severe upper respiratory infection that first presented in Wuhan, China in December 2019. Many factors have been identified as risk factors for SARS-CoV-2, with much attention being paid to body mass index (BMI). Little investigation has been done to investigate dysregulation of lipid profiles and diabetes, which are often comorbid in high BMI patients.

Objective: This study seeks to describe the impact of BMI, HDL, LDL, ApoA, ApoB, triglycerides, hemoglobin A1c (HbA1c), diabetes, alcohol and red wine intake on the odds of testing positive for SARS-CoV-2 in UK Biobank (UKB) study participants.

Methods: We examined the effect of BMI, lipid profiles, diabetes and alcohol intake on the odds of testing positive for SARS-Cov-2 among 9,005 UKB participants tested for SARS-CoV-2 from March 16 through July 14, 2020. Odds ratios and 95% confidence intervals were computed using logistic regression adjusted for age, sex and ancestry.

Results: Higher BMI, Type II diabetes and HbA1c were associated with increased SARS-CoV-2 odds (p < 0.05) while HDL and ApoA were associated with decreased odds (p < 0.001). Though the effect of BMI, Type II diabetes and HbA1c were eliminated when HDL was controlled, the effect of HDL remained significant when BMI was controlled for. Additionally, red wine intake was associated with reduced odds of testing positive for SARS-CoV-2 (p < 0.05). LDL, ApoB and triglyceride levels were not found to be significantly associated with increased odds.

Conclusion: Elevated HDL and ApoA levels and alcohol intake, specifically red wine intake, were associated with reduced odds of testing positive for SARS-CoV-2, while higher BMI, type II diabetes and HbA1c were associated with increased odds. The effects of alcohol, BMI, type II diabetes and HbA1c levels were no longer significant after controlling for HDL, suggesting that these effects may be mediated in part through regulation of HDL levels. In summary, our study corroborates the emerging picture that high HDL levels may confer protection against SARS-CoV-2.

Highlights: Higher baseline HDL levels were associated with reduced odds of testing positive for SARS-CoV-2.BMI, Type II diabetes and hemoglobin A1C levels were associated with elevated odds of testing positive for SARS-CoV-2, but this effect was abrogated when controlling for HDL.Red wine intake was associated with reduced odds of testing positive for SARS-CoV-2, although this effect may in part be moderated by HDL.Baseline LDL and Triglyceride levels were not associated with increased odds of testing positive for SARS-CoV-2.
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http://dx.doi.org/10.1101/2020.07.25.20161091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402045PMC
November 2020

De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population.

Proc Natl Acad Sci U S A 2020 02 21;117(5):2560-2569. Epub 2020 Jan 21.

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201;

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
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http://dx.doi.org/10.1073/pnas.1902766117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007577PMC
February 2020

Lower urinary tract transitional cell carcinoma in cats: Clinical findings, treatments, and outcomes in 118 cases.

J Vet Intern Med 2020 Jan 13;34(1):274-282. Epub 2019 Nov 13.

School of Veterinary Medicine, University of California-Davis, Davis, California.

Background: Lower urinary tract transitional cell carcinoma (TCC) is an important but rarely described disease of cats.

Objectives: To report the clinical characteristics, treatments, and outcomes in a cohort of cats with lower urinary tract TCC and to test identified variables for prognostic relevance.

Animals: One-hundred eighteen client-owned cats with lower urinary tract carcinoma.

Methods: Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed statistically.

Results: Median age of affected cats was 15 years (range, 5.0-20.8 years) and median duration of clinical signs was 30 days (range, 0-730 days). The trigone was the most common tumor location (32/118; 27.1%) as assessed by ultrasound examination, cystoscopy, or both. Treatment was carried out in 73 of 118 (61.9%) cats. Metastatic disease was documented in 25 of 118 (21.2%) cats. Median progression-free survival and survival time for all cats were 113 days (95% confidence interval [CI], 69-153) and 155 days (95% CI, 110-222), respectively. Survival increased significantly (P < .001) when comparing cats across the ordered treatment groups: no treatment, treatment without partial cystectomy, and treatment with partial cystectomy. Partial cystectomy (hazard ratio [HR], 0.31; 95% CI, 0.17-0.87) and treatment with nonsteroidal anti-inflammatory drugs (HR, 0.55; 95% CI, 0.33-0.93) were significantly associated with longer survival times.

Conclusions And Clinical Importance: The results support treatment using partial cystectomy and NSAIDs in cats with TCC.
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http://dx.doi.org/10.1111/jvim.15656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979092PMC
January 2020

Immunomodulatory Effects of Surgery, Pain, and Opioids in Cancer Patients.

Vet Clin North Am Small Anim Pract 2019 Nov;49(6):981-991

University of Pennsylvania, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, 3900 Delancey Street, Philadelphia, PA 19104, USA.

Surgery is the mainstay of therapy for canine and human solid cancers. Alarmingly, evidence suggests that the process of surgery may exacerbate metastasis and accelerate the kinetics of cancer progression. Understanding the mechanisms by which cancer progression is accelerated as a result of surgery may provide pharmacologic interventions. This review discusses surgery-induced cancer progression. It focuses on immunomodulatory properties of anesthesia and opioids and evidence that studies evaluating the role of opioids in tumor progression are indicated. It concludes by discussing why companion animals with spontaneously arising cancer are an ideal model for clinical trials to investigate this phenomenon.
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http://dx.doi.org/10.1016/j.cvsm.2019.07.008DOI Listing
November 2019

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Am J Hum Genet 2019 10 26;105(4):706-718. Epub 2019 Sep 26.

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817529PMC
October 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019

Apocrine gland anal sac adenocarcinoma with perineural metastasis in a cat.

JFMS Open Rep 2018 Jul-Dec;4(2):2055116918815323. Epub 2018 Dec 3.

Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA.

Case Summary: A 15-year-old female spayed domestic shorthair cat was presented for hyporexia and acute development of L4-Cd myelopathy (urinary incontinence, pelvic limb paresis with hyporeflexia and absent tail tone). Humane euthanasia was elected owing to the rapid neurological deterioration and necropsy was performed. Post-mortem examination identified a right-sided anal sac mass and medial iliac lymphadenopathy. No gross lesions were evident in the cauda equina or peripheral nerves. Histopathology and immunohistochemistry utilizing wide-spectrum cytokeratin confirmed apocrine gland carcinoma of the anal sac with lymph node, peripheral nerve and cauda equina metastasis.

Relevance And Novel Information: This is the first report of feline anal sac adenocarcinoma metastasizing to perineural tissue. In addition, it provides a novel differential diagnosis for L4-Cd myelopathy and urinary incontinence in a cat.
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http://dx.doi.org/10.1177/2055116918815323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287314PMC
December 2018

Biological implant-associated granulomatous inflammation resulting in secondary hypercalcemia and azotemia in a dog.

Clin Case Rep 2018 Sep 25;6(9):1801-1806. Epub 2018 Jul 25.

University of Pennsylvania Philadelphia PA USA.

Implant associated granulomatous inflammation causing hypercalcemia can occur following use of commercial xenogeneic pericardial tissue patches in dogs. Removal of the implant can result in resolution of the hypercalcemia, suggesting a causal relationship between the tissue reaction to a xenogeneic implant and development of hypercalcemia.
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http://dx.doi.org/10.1002/ccr3.1661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132143PMC
September 2018

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Nat Commun 2018 08 23;9(1):3391. Epub 2018 Aug 23.

School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.
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http://dx.doi.org/10.1038/s41467-018-05747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107638PMC
August 2018

An APOO Pseudogene on Chromosome 5q Is Associated With Low-Density Lipoprotein Cholesterol Levels.

Circulation 2018 09;138(13):1343-1355

Division of Endocrinology, Diabetes and Nutrition (M.E.M., E.A.O., X.W., A.D.H., R.M., J.A.P., K.A.R., A.R.S., B.D.M., N.A.Z., Y.-P.C.C.), Department of Medicine, University of Maryland School of Medicine, Baltimore.

Background: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels.

Methods: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association.

Results: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation.

Conclusions: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162188PMC
September 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 01 22;50(1):26-41. Epub 2017 Dec 22.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41588-017-0011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945951PMC
January 2018

Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation.

Cancer Res 2017 06 31;77(11):2869-2880. Epub 2017 Mar 31.

Presage Biosciences, Inc., Seattle, Washington.

The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546104PMC
June 2017

Sex-specific effects of serum sulfate level and nonsense variants on DHEA homeostasis.

Mol Genet Metab Rep 2017 Mar 27;10:84-91. Epub 2017 Jan 27.

Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, United States.

Context: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, , encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in (R12X and W48X) associated with hyposulfatemia ( = 9 × 10).

Objective: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.

Design: Retrospective cohort study.

Setting: Academic research.

Patients: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.

Main Outcome Measures: DHEA, DHEA-S, and DHEA-S/DHEA ratio.

Results: Increased serum sulfate was associated with decreased DHEA-S ( = 0.03) and DHEA-S/DHEA ratio ( = 0.06) in males but not females. Female nonsense variant carriers, who had lower serum sulfate ( = 9 × 10 ), exhibited 14% lower DHEA levels ( = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers ( = 0.002). Consistent with this finding, female nonsense variant carriers also had lower total testosterone levels compared to non-carrier females ( = 0.03).

Conclusions: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.
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http://dx.doi.org/10.1016/j.ymgmr.2017.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278115PMC
March 2017

Rare and low-frequency coding variants alter human adult height.

Nature 2017 02 1;542(7640):186-190. Epub 2017 Feb 1.

Netherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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http://dx.doi.org/10.1038/nature21039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302847PMC
February 2017

Clopidogrel Improves Skin Microcirculatory Endothelial Function in Persons With Heightened Platelet Aggregation.

J Am Heart Assoc 2016 10 31;5(11). Epub 2016 Oct 31.

Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Background: Platelet activation can lead to enhanced oxidative stress, inflammatory response, and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy persons before and after clopidogrel administration and evaluated its effects on endothelial function. We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function.

Methods And Results: Microcirculatory endothelial function was quantified by laser Doppler flowmetry (LDF) mediated by thermal hyperemia (TH) and postocclusive reactive hyperemia, respectively, in 287 and 241 relatively healthy and homogenous Old Order Amish persons. LDF and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percentage change in post- versus preclopidogrel LDF measures. Preclopidogrel TH-LDF and platelet aggregation were higher in women than in men (P<0.001). Clopidogrel administration was associated with ≈2-fold higher percentage change in TH-LDF in participants with high versus low baseline platelet aggregation (39.4±10.1% versus 17.4±5.6%, P=0.03). Clopidogrel also increased absolute TH-LDF measures in persons with high platelet aggregation (1757±766 to 2154±1055, P=0.03), with a more prominent effect in women (1909±846 to 2518±1048, P=0.001). There was no evidence that clopidogrel influenced postocclusive reactive hyperemia LDF measures.

Conclusions: The administration of clopidogrel in healthy persons with high baseline platelet aggregation results in improved TH-induced microcirculatory endothelial function. These data suggest that clopidogrel may have a beneficial effect on microcirculatory endothelial function, presumably through antiplatelet activity, and may confer additional vascular benefits.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799396.
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http://dx.doi.org/10.1161/JAHA.116.003751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210318PMC
October 2016

From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases.

G3 (Bethesda) 2016 09 8;6(9):2909-18. Epub 2016 Sep 8.

Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10(-8)) and 27.3% (P = 6.9 × 10(-14)) decrease in serum sulfate, respectively (P = 8.8 × 10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.
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http://dx.doi.org/10.1534/g3.116.032979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015947PMC
September 2016
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