Genome-Wide Linkage and Positional Candidate Gene Study of Blood Pressure Response to Dietary Potassium Intervention (original) (raw)
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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...
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...
Genome-Wide Gene–Potassium Interaction Analyses on Blood Pressure
Circulation-cardiovascular Genetics, 2017
B lood pressure (BP) is determined by genetic factors, environmental factors, and their interactions. Genome-wide association studies have identified many genetic loci that are robustly associated with BP. 1-5 However, these findings together only explain a small proportion of the interindividual variation of BP. 6 A large number of genetic loci are yet to be identified. 6 It has been proposed that exploring the interaction between genes and environmental risk factors for BP may help to identify novel genetic loci underlying BP regulation. 7-9 In addition, gene-based analysis methods testing the joint contributions of single single nucleotide polymorphisms (SNPs) with modest effect may have higher power to detect BP loci. 10,11 See Clinical Perspective Dietary potassium intake has been demonstrated to decrease BP in clinical trials. 12 Because genetic factors may modify the effects of potassium on BP, examination of gene-dietary potassium intake interactions may help to identify novel genetic variants and genes underlying BP regulation. 13 However, few studies have explored gene-potassium interactions using single variant and gene-based analyses. 14,15 The objective of this analysis was to identify novel genetic variants and genes influencing BP regulation by conducting genome-wide SNPbased and gene-based gene-potassium interaction analyses of systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) phenotypes among 1876 Chinese participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). Methods The data, analytic methods, and study materials will be made available to other researchers for reproducing the results or replicating
Genetic variants in the ADD1 and GNB3 genes and blood pressure response to potassium supplementation
Frontiers of Medicine in China, 2010
Dietary potassium-supplementation has been associated with a decreased risk of hypertension and other cardiovascular outcomes. However, blood pressure (BP) responses to potassium supplementation vary among individuals. This study was designed to examine the association between 12 single nucleotide polymorphisms (SNPs) in the adducin 1 alpha (ADD1) and guanine nucleotide binding protein (G protein) beta polypeptide 3 (GNB3) genes and systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) responses to potassium-supplementation. We conducted a 7-day high-sodium intervention (307.8 mmol sodium/day) followed by a 7-day high-sodium with potassium-supplementation (60 mmol potassium/day) among 1906 Han Chinese participants from rural north China. BP measurements were obtained at the end of each intervention period using a random-zero sphygmomanometer. We identified significant associations between ADD1 variant rs17833172 and SBP, DBP, and MAP responses to potassium-supplementation (all P < 0.0001) that remained significant after adjustment for multiple comparisons. In participants that were heterozygous or homozygous for the G allele of this marker, SBP, DBP, and MAP response to potassium-supplementation were − 3.52 ( − 3.82, − 3.21), − 1.41 ( − 1.66, − 1.15) and − 2.12 ( − 2.37, − 1.87), respectively, as compared to the corresponding responses of 1.99 (0.25, 3.73), − 0.65 ( − 0.10, − 0.21), and − 0.23 ( − 0.37, 0.83), respectively, for those who were homozygous for A allele. In addition, participants with at least one copy of the G allele of rs12503220 of the ADD1 gene had significantly increased DBP and MAP response to potassium-supplementation (P = 0.0041 and 0.01, respectively), which was also significant after correction for multiple testing. DBP and MAP responses to potassium-supplementation were − 1.36 ( − 1.63, − 1.10) and − 2.07 ( − 2.32, − 1.82) for those with at least G allele compared to corresponding responses of 0.86 ( − 0.68, 2.40) and − 0.45 ( − 1.74, 0.84) for those who were homozygous for A allele. In summary, our study identified novel associations between genetic variants of the ADD1 gene and BP response to potassium-supplementation, which could have important clinical and public health implications. Future studies aimed at replicating these novel findings are warranted.
Circulation: Cardiovascular Genetics, 2013
Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; BP responses to dietary intervention and cold pressor test. We conducted a genome-wide association study of BP responses in 1881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/d), a 7-day high-sodium (307.8 mmol/d), and a 7-day high-sodium plus potassium supplementation (60 mmol/d). Nine BP measurements were obtained during baseline observation and each intervention period. The meta-analyses identified 8 novel loci for BP phenotypes, which physically mapped in or near PRMT6 (P=7.29 × 10(-9)), CDCA7 (P=3.57 × 10(-8)), PIBF1 (P=1.78 × 10(-9)), ARL4C (P=1.86 × 10(-8)), IRAK1BP1 (P=1.44 × 10(-10)), SALL1 (P=7.01 × 10(-13)), TRPM8 (P=2.68 × 10(-8)), and FBXL13 (P=3.74 × 10(-9)). There was a strong dose-response relationship between the number of risk alleles of these independent single-nucleotide polymorphisms and the risk of developing hypertension during the 7.5-year follow-up in the study participants. Compared with those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third, and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively (P=0.0003 for trend). Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and cold pressor test. The effect size of these novel loci on BP phenotypes is much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline.
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 ...
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