Boerwinkle, Eric

Abstractβ‐Blockers’ heart rate (HR)‐lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β‐blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β‐blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single‐nucleotide polymorphisms (SNPs) previously associated with the HR response to β‐blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β‐blocker used in the PEAR (n = 757), PEAR‐2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR‐2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β‐blockers in whites (rs1042714 C‐allele carriers, meta‐analysis β = –0.95 beats per minute [bpm], meta‐analysis P = 3×10–4; rs1042713 A‐allele carriers, meta‐analysis β = –1.15 bpm, meta‐analysis P = 2×10–3). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β‐blockade in hypertensive patient cohorts.

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and Results Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR ‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P <5×10 −8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS 2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P =4.17×10 −8 ). G‐allele carriers of HMGCS 2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P =0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10 −8 . HMGCS 2 , a part of the HMG ‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. Conclusions These results suggest that HMGCS 2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00246519 and NCT 01203852.

Background For many indications, the negative chronotropic effect of β‐blockers is important to their efficacy, yet the heart rate ( HR ) response to β‐blockers varies. Herein, we sought to use a genome‐wide association approach to identify novel single nucleotide polymorphisms ( SNP s) associated with HR response to β‐blockers. Methods and Results We first performed 4 genome‐wide association analyses for HR response to atenolol (a β1‐adrenergic receptor blocker) as: (1) monotherapy or (2) add‐on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta‐analysis was then performed between the genome‐wide association analysis performed in PEAR atenolol monotherapy and add‐on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNP s associated with HR response to atenolol at a P <1E‐05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1‐adrenergic receptor blocker). From the genome‐wide association meta‐analyses, SNP rs17117817 near olfactory receptor family10 subfamily‐p‐member1 ( OR 10P1 ), and SNP rs2364349 in sorting nexin‐9 ( SNX 9 ) replicated in blacks. The combined studies meta‐analysis P values for the rs17117817 and rs2364349 reached genome‐wide significance (rs17117817G‐allele; Meta‐β=5.53 beats per minute, Meta‐ P =2E‐09 and rs2364349 A‐allele; Meta‐β=3.5 beats per minute, Meta‐ P =1E‐08). Additionally, SNP s in the OR 10P1 and SNX 9 gene regions were also associated with HR response in whites. Conclusions This study highlights OR 10P1 and SNX 9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Background Although hydrochlorothiazide ( HCTZ ) is a well‐established first‐line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure ( BP ) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. Methods and Results First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway ( P =5.8E‐05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC 3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C‐allele carriers had a better BP response to HCTZ versus noncarriers (∆ SBP /∆ DBP : −11.4/−6.9 versus −6.8/−3.5 mm Hg; ∆ SBP P =6.7E‐04; ∆ DBP P =4.8E‐04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC 3 genomic region significantly associated with the BP response to HCTZ ( P <0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP ‐response ( r =−0.42; P =7E‐03) and SBP ‐response ( r =−0.36; P =2E‐02). Conclusions This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC 3 is a potential determinant of the BP response to HCTZ . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Background The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure ( BP ) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker. Methods and Results A genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance ( P <1.0E‐05) were tested for replication in an external cohort, INVEST (International Verapamil‐ SR Trandolapril study). We also examined genome‐wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69–3.88, P =8.64E‐06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35–2.57, P =0.001) and approached genome‐wide significance in the meta‐analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63–2.86, P =8.60E‐08). Other genes in the region surrounding rs261316 ( ALDH1A2) include AQP9 and LIPC . Conclusions A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β‐blocker combination. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

AbstractIntroductionThe objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African‐American cohort.MethodsWe repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004–2006 and 2011–2013.ResultsAfter a mean follow‐up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow‐up visit.ConclusionA panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.