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Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10−8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10−4). The top variant in both cohorts was rs1555175145 (discovery β = −0.112 [0.018], P = 2.50 × 10−5; replication β = −0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: “Leukocyte Transendothelial Migration,” “Innate Immune Response,” and “Lyase Activity.” Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

Background: Multiple reports associate the cardiac sodium channel gene ( SCN5A ) variants S1103Y and R1193Q with type 3 congenital long QT syndrome and drug-induced long QT syndrome. These variants are too common in ancestral populations to be highly arrhythmogenic at baseline, however: S1103Y allele frequency is 8.1% in African Americans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current ( I Na-L ) in cardiomyocytes derived from induced pluripotent stem cells but the role of these variants in modulating repolarization remains poorly understood. Methods: We determined the effect of S1103Y on QT intervals among African-American participants in a large electronic health record. Using cardiomyocytes derived from induced pluripotent stem cells carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current ( I Kr ) blocker dofetilide and I Na-L and I Kr at baseline. Results: In 1479 African-American participants with no confounding medications or diagnoses of heart disease, QT intervals in S1103Y carriers was no different from that in noncarriers. Baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared with isogenic cells with the reference allele (SS cells). However, I Na-L was increased in SY and YY cells and the I Na-L blocker GS967 shortened APD in SY/YY but not SS cells ( P I Kr was increased almost 2-fold in SY/YY cells compared with SS cells (tail current: 0.66±0.1 versus 1.2±0.1 pA/pF; P P P Kr and increased dofetilide sensitivity. Conclusions: These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I Na-L . We propose that increased I Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I Kr block in variant carriers. Our findings emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.

OBJECTIVES: Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D). METHODS: We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed. RESULTS: Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (p=0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 [interquartile range (147.6-267.5)] (ng/mL)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), p=0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [(373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes. CONCLUSION: These data indicate that a composite CYP3A phenotype incorporating both increased and decreased variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10−8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10−209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10−9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10−8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.

Background: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. Methods: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. Results: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor–based model were 0.015 (0.004–0.028) and 0.020 (0.001–0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033–0.109) and 0.051 (0.017–0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (−0.006 to 0.054) in CARDIA and 0.039 (0.0005–0.072) in FOS. Conclusions: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.

Importance Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. Objective To examine the results of genetic testing for early-onset AF. Design, Setting, and Participants This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. Exposures Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. Main Outcomes and Measures Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. Results Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes wereTTN(n = 38),MYH7(n = 18),MYH6(n = 10),LMNA(n = 9), andKCNQ1(n = 8). Conclusions and Relevance In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3−/− mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

Background Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell–mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. Objective We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. Methods Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. Results Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10−8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10−16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01–positive group indicated that 19.2% had DRESS and did so within 4 weeks. Conclusions HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P=8.06×10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P=3.22×10-6 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19

Context A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. Objective Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. Methods We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. Results Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from –0.12 (SE 0.02) occurrences of AF per SD change in height to –0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. Conclusion The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone–level elevations in later life.

Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.

Objective To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. Study design In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Results Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time x Genotype interaction P =.005, mean annual z-score change +/- SE -0.20 +/- 0.03 vs -0.09 +/- 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P =.002; -0.20 +/- 0.02 vs -0.07 +/- 0.02; P

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q

IMPORTANCE Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.OBJECTIVE To evaluate the potential direct involvement of thyroid traits on AF.DESIGN, SETTING. AND PARTICIPANTS Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.EXPOSURES Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.MAIN OUTCOMES AND MEASURES Prevalent and incident AF.RESULTS The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I-2= 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I-2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT(4 )by 0.082 SD (standard error, 0.007; P CONCLUSIONS AND RELEVANCE Genetically increased FT3:FT(4 )ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22–1.58]; P P P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99–1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98–1.15]; P =0.13). Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with an increased risk of morbidity and mortality. While DD has been extensively studied in older populations, co-morbidity patterns are less well characterized among middle-aged individuals. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt’s de-identified electronic heath record data resource and identified 6,612 individuals 40–55 years old with LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early stage (grade 1: impaired LV relaxation) DD versus normal function. Among 1,676 subjects with grade 1 DD we identified associations (FDR q

IMPORTANCE: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count. OBJECTIVE: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count. DESIGN, SETTING, AND PARTICIPANTS: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children’s Hospital of Philadelphia from January 1, 1998, to December 31, 2020. EXPOSURE: The rs2814778-CC genotype. MAIN OUTCOMES AND MEASURES: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result. RESULTS: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P

Objectives Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin. Variation in human leukocyte antigen (HLA) genes is now used to prevent immune-mediated adverse drug reactions. Combinations of HLA alleles and killer cell immunoglobulin-like receptors (KIR) are associated with multiple autoimmune diseases and infections. The objective of this study is to evaluate the association of HLA alleles and KIR types, alone or in the presence of different HLA ligands, with HIT. Methods HIT cases and heparin-exposed controls were identified in BioVU, an electronic health record coupled to a DNA biobank. HLA sequencing and KIR type imputation using Illumina® OMNI-Quad data were performed. Odds ratios for HLA alleles and KIR types and HLA*KIR interactions using conditional logistic regressions were determined in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. P values for HLA and KIR association were corrected using a false discovery rate (FDR) q

Background Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. Methods We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. Results Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. Conclusion Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

Background: Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. Genome-wide association studies (GWAS) have the potential to identify genetic risk factors and generate insights into biological mechanisms of adverse drug reactions. However, published HIT GWAS are underpowered and do not include confirmation of HIT using functional assays. We aimed to identify genetic associations with HIT using a GWAS approach in two European ancestry populations tested for functional assay and PF4/heparin antibody levels. Methods: We performed a GWAS with positive functional assay as the outcome in a large discovery cohort of patients, including heparin-induced platelet aggregation (HIPA) positive cases (n=1243), antibody positive but functional assay negative controls (n=1091), and antibody negative controls (n=1718). Logistic regressions were adjusted for age, gender, and first two principal components. Significant associations from the discovery cohort (alpha=5.00x10-8) were then investigated in a replication cohort of serotonin-release assay (SRA)-confirmed HIT cases (n=173), antibody positive controls (n=125), and antibody negative controls (n=488). All patients were genotyped with the HumanOmniExpressExome BeadChip, including 9,065,510 variants after imputation and quality control. Genes near significantly associated loci were resequenced. Results: In the discovery cohort, a genome-wide significant association was observed between common variation in the ABO gene and HIPA positive status (rs505922 odds ratio 0.738 [0.668-0.816], p=2.813x10-9). This variant was also significantly associated with SRA-confirmed HIT in the replication cohort (odds ratio 0.392 [0.172-0.891], p=0.025). Meta-analysis indicated strong association of ABO variation with positive functional assay (Figure 1). Sequencing and fine-mapping of the ABO locus indicated this effect was driven by ABO blood groups, with the O blood group being a risk factor for HIT (odds ratio 1.42 [1.25-1.61], p=6.11x10-8). Conclusions: We identify common variation in ABO as a risk factor for platelet reactivity and HIT. Strong association of ABO variation may have important implications for prediction and understanding of HIT pathogenesis. Figure 1 Disclosures No relevant conflicts of interest to declare.

International audience; Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.Aim: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.Methods: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.Results: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P

Background Abiraterone and enzalutamide are recently approved androgen deprivation therapies (ADT) for metastatic prostate cancer. The cardiac safety profile for the two drugs is unknown. Methods Using French and World Health Organization (WHO) pharmacovigilance databases, we performed a disproportionality-analysis of suspected adverse-drug-reactions (ADR) to evaluate the reporting-odds-ratio (ROR) of cardiac ADR associated with abiraterone compared to enzalutamide, other ADT used in prostate cancer, and entire database. Clinical and demographic characterization of patients with ADT-induced cardiac ADR was performed. Results In the 5,759,781 ADR reports in men, 55,070 pertained to ADT. The ROR of AT for abiraterone was of 4.1 [3.1–5.3] vs. enzalutamide, 3.7 [3–4.5] vs. other ADT, and 3.2 [2.7–3.7] vs. entire database. The corresponding ROR for HF were of 2.5 [2–3], 1.5 [1.3–1.7], and 2 [1.7–2.3], respectively. Mean time to AT and HF onset was shorter on abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) vs. other ADT (13.3±3.2 and 9.2±1.1 months; p Table 1 Number (available data) AT HF Hypokalemia Edema Hypertension Age (y) 5989 r: 0.03, p: 0.02 r: 0.05, p≤0.0001 r: 0.06, p≤0.0001 r: 0.04, p≤0.01 ns Dose of hydrocortisone equivalent (mg/day) 3828 ns ns ns r: −0.07, p≤0.001 r: −0.12, p≤0.0001 Dose of abiraterone (mg/day) 6285 ns ns ns ns ns Details concerning correlation (r) between clinical covariates and reporting for AT, HF, hypokalemia, edema and hypertension within overall adverse drug reaction on abiraterone (n: 9203) extracted from VigiBase (through 08/2017). Time to onset Conclusion Compared to other ADT, abiraterone was associated with a higher reporting of AT and HF associated with hypokalemia, hypertension and edema. These findings are consistent with the hyper-mineralocorticism induced by abiraterone and not with other ADT.

Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01–positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics–accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non–HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using “drug allergy” labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center’s BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10−8, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine., Author summary Adverse drug reactions are a considerable burden on the healthcare system. Genetic studies can improve our understanding of the pathophysiological mechanisms of adverse drug reactions but have been hindered by small sample sizes. Drug responses are less often recorded than physiological traits and common diseases. Here, we present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions from electronic health records. We validated our approach by conducting genome-wide association studies for adverse reactions to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Centre’s BioVU DNA Biobank, identifying 7 genetic loci associated with adverse drug reactions. Our high-throughput framework can enable impactful pharmacogenomic research to help develop clinical guidelines for the delivery of the right drug to the right person.

Background— Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. Methods and Results— We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [ r ]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=−0.44, P =0.005), high-density lipoprotein (rG=−0.48, P =0.005), systolic blood pressure (rG=0.44, P =0.02), and triglycerides (rG=0.38, P =0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. Conclusions— The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease.

Introduction African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized. Methods We performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP). Results In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case–control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51–15.20; allele frequencies – cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26–4.10). Conclusions We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.

Publisher's version (útgefin grein), Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44703 GERA participants was 69.7 (8.4) years, and 22019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P =.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P =.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target., This study was supported by grant R01 HL128550 from the NHLBI of the NIH (Dr Thanassoulis); the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs (The Kaiser Permanente Research Program on Genes, Environment and Health); a grant from the NIH (The Genetic Epidemiology Research on Adult Health and Aging cohort); a strategic partnership between the MRC and the University of Oxford (University of Oxford MRC Population Health Research Unit); application 24281 from the UK Biobank Resource; contracts NO1-HC-25195 and HHSN268201500001I, R01 HL 089590, and the SHARe project from the NHLBI (Framingham Heart Study); the NHLBI in collaboration with Multi-Ethnic Study of Atherosclerosis (MESA) investigators (MESA and the MESA SHARe project); contracts HHSN268201500003I from the NIH, contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI, contracts UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, and UL1-TR-001881 from the National Center for Advancing Translational Sciences, and contract DK063491 from the National Institute of Diabetes and Digestive and Kidney Diseases (MESA); contract N02-HL-64278 from the NHLBI (SHARe genotyping); shared instrumentation grant s10rr025141 from the NIH, awards UL1TR002243 and UL1TR000445 from the National Center for Clinical and Translational Science, and award UL1RR024975 from the National Center for Research Resources (Vanderbilt University Medical Center’s Vanderbilt DNA Biobank projects); and investigator-led projects U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, and R01HD07471 from the NIH (genomic data).

IMPORTANCE: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). OBJECTIVE: To determine the association between genetically determined thyrotropin levels and AF. DESIGN, SETTING, AND PARTICIPANTS: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. MAIN OUTCOMES AND MEASURES: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. EXPOSURES: Genetically determined thyrotropin levels. RESULTS: Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10(−11)) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10(−8) for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10(−7)). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10(−6)). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10(−4)). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04). CONCLUSIONS AND RELEVANCE: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.

Importance Polygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening. Objective To determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation. Design, Setting, and Participants A retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations. Exposures Genetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study. Main Outcomes and Measures Prediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI). Results The study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, −0.001; 95% CI, −0.009 to 0.006; MESA, 0.021; 95% CI, −0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, −0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, −0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort. Conclusions and Relevance In this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.

Background: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. Methods: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). Results: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate qP =0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94; P =0.008) per 1-SD increment in platelet-derived growth factor receptor-β. Conclusions: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population‐based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma‐related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta‐analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P

Background— Studies in individuals or small kindreds have implicated rare variants in 25 different genes in lone and familial atrial fibrillation (AF) using linkage and segregation analysis, functional characterization, and rarity in public databases. Here, we used a cohort of 20 204 patients of European or African ancestry with electronic medical records and exome chip data to compare the frequency of AF among carriers and noncarriers of these rare variants. Methods and Results— The exome chip included 19 of 115 rare variants, in 9 genes, previously associated with lone or familial AF. Using validated algorithms querying a combination of clinical notes, structured billing codes, ECG reports, and procedure codes, we identified 1056 AF cases (>18 years) and 19 148 non-AF controls (>50 years) with available genotype data on the Illumina HumanExome BeadChip v.1.0 in the Vanderbilt electronic medical record-linked DNA repository, BioVU. Known correlations between AF and common variants at 4q25 were replicated. None of the 19 variants previously associated with AF were over-represented among AF cases ( P >0.1 for all), and the frequency of variant carriers among non-AF controls was >0.1% for 14 of 19. Repeat analyses using non-AF controls aged >60 (n=14 904), >70 (n=9670), and >80 (n=4729) years did not influence these findings. Conclusions— Rare variants previously implicated in lone or familial forms of AF present on the exome chip are detected at low frequencies in a general population but are not associated with AF. These findings emphasize the need for caution when ascribing variants as pathogenic or causative.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Electronic health records (EHRs) linked with biobanks have been recognized as valuable data sources for pharmacogenomic studies, which require identification of patients with certain adverse drug reactions (ADRs) from a large population. Since manual chart review is costly and time-consuming, automatic methods to accurately identify patients with ADRs have been called for. In this study, we developed and compared different informatics approaches to identify ADRs from EHRs, using clopidogrel-induced bleeding as our case study. Three different types of methods were investigated: 1) rule-based methods; 2) machine learning-based methods; and 3) scoring function-based methods. Our results show that both machine learning and scoring methods are effective and the scoring method can achieve a high precision with a reasonable recall. We also analyzed the contributions of different types of features and found that the temporality information between clopidogrel and bleeding events, as well as textual evidence from physicians’ assertion of the adverse events are helpful. We believe that our findings are valuable in advancing EHR-based pharmacogenomic studies.

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery(8).

Although many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8431 European ancestry individuals and tested association of HLA variation with 1368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele phenotype associations were significant in both discovery and replication cohorts, the strongest being HLA-DQB1*03:02 and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two- and four-digit HLA alleles and 10 with nonsynonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly available catalog of clinical phenotypes associated with HLA variation is provided. Examining HLA variant disease associations in this large data set allows comprehensive definition of disease associations to drive further mechanistic insights.

Host response to influenza is highly variable, suggesting a potential role of host genetic variation. To investigate the host genetics of severe influenza in a targeted fashion, 32 single nucleotide polymorphisms (SNPs) within viral immune response genes were evaluated for association with seasonal influenza hospitalization in an adult study population with European ancestry. SNP allele and genotype frequencies were compared between hospitalized influenza patients (cases) and population controls in a case-control study that included a discovery group (26 cases and 993 controls) and two independent, validation groups (one with 84 cases and 4,076 controls; the other with 128 cases and 9,187 controls). Cases and controls had similar allele frequencies for variant rs12252 in interferon-inducible transmembrane protein 3 (IFITM3) (P > 0.05), and the study did not replicate the previously reported association of rs12252 with hospitalized influenza. In the discovery group, the preliminary finding of an association with a nonsense polymorphism (rs8072510) within the schlafen family member 13 (SFLN13) gene (P = 0.0099) was not confirmed in either validation group. Neither rs12252 nor rs8072510 showed an association according to the presence of clinical risk factors for influenza complications (P > 0.05), suggesting that these factors did not modify associations between the SNPs and hospitalized influenza. No other SNPs showed a statistically significant association with hospitalized influenza. Further research is needed to identify genetic factors involved in host response to seasonal influenza infection and to assess whether rs12252, a low-frequency variant in Europeans, contributes to influenza severity in populations with European ancestry.