Genome-Wide Association Study Identifies 8 Novel Loci Associated With Blood Pressure Responses to Interventions in Han Chinese (original) (raw)
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Hypertension, 2016
We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions ...
Circulation: Cardiovascular Genetics, 2010
Background— Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity. Methods and Results— A total of 1906 Han Chinese participants took part in a 7-day high-sodium diet followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and after each intervention using a random-zero sphygmomanometer. Significant linkage signals (logarithm of odds [LOD] score, >3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute diastolic BP (DBP) and mean arterial pressure (MAP) responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, an...
Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension
Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 3 10 28) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P 5 1.81 3 10 23 to 5.16 3 10 28. These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.
Genome-Wide Gene–Sodium Interaction Analyses on Blood Pressure
Hypertension, 2016
We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single marker (one and two degree-of-freedom joint tests) and gene-based tests among 1,876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of three urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random-zerosphygmomanometer. A total of 2.05 million SNPs were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P <1.00×10 −4) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-ethnic Study of Atherosclerosis (MESA). SNP and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The one degree-of-freedom tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10 −9). The two degree-of-freedom tests additionally identified associations for CLGN rs2567241 (P=3.90×10 −12) and LOC105369882 rs11104632 (P=4.51×10 −8) with
Circulation. Cardiovascular genetics, 2017
Gene-environmental interaction analysis can identify novel genetic factors for blood pressure (BP). We performed genome-wide analyses to identify genomic loci that interact with potassium to influence BP using single-marker (1 and 2 df joint tests) and gene-based tests among Chinese participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). Among 1876 GenSalt participants, the average of 3 urine samples was used to estimate potassium excretion. Nine BP measurements were taken using a random-zero sphygmomanometer. A total of 2.2 million single nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10-4) from GenSalt were evaluated for replication among 775 Chinese participants of the MESA (Multi-ethnic Study of Atherosclerosis). Single nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studie...
BMC medical genetics, 2014
Genome-wide association studies have identified many genetic loci associated with blood pressure (BP). Genetic effects on BP can be altered by environmental exposures via multiple biological pathways. Especially, obesity is one of important environmental risk factors that can have considerable effect on BP and it may interact with genetic factors. Given that, we aimed to test whether genetic factors and obesity may jointly influence BP. We performed meta-analyses of genome-wide association data for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that included analyses of interaction between single nucleotide polymorphisms (SNPs) and the obesity-related anthropometric measures, body mass index (BMI), height, weight, and waist/hip ratio (WHR) in East-Asians (n = 12,030). We identified that rs13390641 on 2q12.1 demonstrated significant association with SBP when the interaction between SNPs and BMI was considered (P < 5 × 10 -8). The gene located nearest to rs1339064...
Circulation-cardiovascular Genetics, 2010
Background-Genetic determinants of BP response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity. Methods and Results-1,906 Han Chinese participants took part in a 7-day high-sodium followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer. Significant linkage signals (LOD>3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute DBP and MAP responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, and 4.48 at 11q23.3 for percent MAP response were also identified. AGTR1 SNP rs16860760 in the 3q24-q26.1 region was significantly associated with absolute and percent systolic (SBP) responses to potassium (p-values=0.
Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians
Circulation-cardiovascular Genetics, 2017
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 up to 46,629 participants of European ancestry (stage-2). Significant SNPs 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 one 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 SBP (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 trans-ethnically 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.
Blood Pressure in Relation to Three Candidate Genes in a Chinese Population
Journal of Hypertension, 2004
Objective In a prospective analysis of a Caucasian population, we recently found that the genes encoding angiotensin-converting enzyme (ACE, I/D polymorphism), AE-adducin (Gly460Trp) and aldosterone synthase (-344C/ T) jointly influence the incidence of hypertension. We therefore investigated the association between blood pressure and these three genes in a Chinese population.