Journal
HYPERTENSION
Volume 56, Issue 5, Pages 973-U533Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.110.153429
Keywords
hypertension; genetic variation; ATP2B1; Millennium Genome Project; Global BPgen
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [20390185, 21390099, 19659163, 16790336, 12204008, 15790293, 16590433, 17790381, 18390192, 18590265, 18590587, 18590811, 19590929, 19650188, 19790423, 17390186, 20390184, 21390223]
- Ministry of Health, Labor and Welfare, Health and Labor Sciences, Japan [H15-longevity-005, H17-longevity-003, H16-kenko-001, H18-longevity (kokusai), H11-longevity-020, H17-kenkou-007, H17-pharmaco-common-003, H18-Junkankitou[Seishuu]-Ippan-012, H20-Junkankitou[Seishuu]-Ippan-009, 013]
- Japan Science and Technology Agency
- National Institute of Biomedical Innovation
- Japan Society for the Promotion of Science, Tokyo, Japan [16.54041, 18.54042, 19.7152, 20.7198, 20.7477, 20.54043]
- Ministry of Health, Labor and Welfare, Japan
- Japan Atherosclerosis Prevention Fund
- Uehara Memorial Foundation
- Takeda Medical Research Foundation
- National Cardiovascular Research grants
- Biomedical Innovation grants
- Japan Research Foundation for Clinical Pharmacology
- Grants-in-Aid for Scientific Research [21390223, 16790336, 20390184, 17390186, 18590811, 21390099, 19650188, 12204008, 18590265, 19659163, 20390185] Funding Source: KAKEN
- MRC [G0801056, MC_U105630924, G0400874, MC_UP_A100_1003] Funding Source: UKRI
- Medical Research Council [MC_U105630924, G0801056, G0400874, MC_UP_A100_1003, G0801056B, G0401527] Funding Source: researchfish
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Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3x10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1x10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9x10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4x10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6x10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. (Hypertension. 2010;56:973-980.)
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