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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.
Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, et al
Nature genetics. 2020;(12):1314-1332
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Abstract
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.
Li, C, Kim, YK, Dorajoo, R, Li, H, Lee, IT, Cheng, CY, He, M, Sheu, WH, Guo, X, Ganesh, SK, et al
Circulation. Cardiovascular genetics. 2017;(2):e001527
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Abstract
BACKGROUND Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. METHODS AND RESULTS We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively). CONCLUSIONS We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
Richard, MA, Huan, T, Ligthart, S, Gondalia, R, Jhun, MA, Brody, JA, Irvin, MR, Marioni, R, Shen, J, Tsai, PC, et al
American journal of human genetics. 2017;(6):888-902
Abstract
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
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The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.
Ehret, GB, Ferreira, T, Chasman, DI, Jackson, AU, Schmidt, EM, Johnson, T, Thorleifsson, G, Luan, J, Donnelly, LA, Kanoni, S, et al
Nature genetics. 2016;(10):1171-1184
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Abstract
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
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Effectiveness of Valsartan/Amlodipine Single-pill Combination in Hypertensive Patients With Excess Body Weight: Subanalysis of China Status II.
Ge, B, Peng, W, Zhang, Y, Wen, Y, Liu, C, Guo, X
Journal of cardiovascular pharmacology. 2015;(5):497-503
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Abstract
Obesity is a major global health concern and is associated with hypertension. However, there is a lack of studies evaluating the effectiveness of valsartan/amlodipine single-pill combination in Chinese hypertensive patients with excess body weight uncontrolled by monotherapy. To evaluate this effectiveness and its association with obese categories, we performed a prespecified subanalysis and a post hoc analysis of patients from China status II study. In this subanalysis, 11,289 and 11,182 patients stratified by body mass index (BMI) and waist circumference (WC), respectively, were included. Significant mean sitting systolic and diastolic blood pressure (BP) reductions from baseline were observed at week 8 across all BMI and WC subgroups (P < 0.001). The percentages of patients achieving BP control were 65.2%, 62.8%, and 64.5% (men 64.5% and women 64.4%) in the overweight, obesity, and abdominal obesity subgroups, respectively. The positive association between BP control and obese categories could only be found in subgroups stratified by BMI other than WC. Our study demonstrated the effectiveness of valsartan/amlodipine single-pill combination in Chinese hypertensive patients with excess body weight uncontrolled by monotherapy, and its effectiveness was better associated with BMI than WC.