Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

Lu, Xiangfeng; Wang, Laiyuan; Lin, Xu; Huang, Jianfeng; Gu, C. Charles; He, Meian; Shen, Hongbing; He, Jiang; Zhu, Jingwen; Li, Huaixing; Hixson, James E.; Wu, Tangchun; Dai, Juncheng; Lu, Ling; Shen, Chong; Chen, Shufeng; He, Lin; Mo, Zengnan; Hao, Yongchen; Mo, Xing‐Bo; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Fan, Zhongjie; Liu, Ying; Zhao, Liancheng; Li, Hongfan; Lu, Fanghong; Yao, Cailiang; Yu, Lin; Xu, Lizhen; Mu, Jianjun; Wu, Xianping; Deng, Ying; Hu, Dongsheng; Zhang, Weidong; Xu, Jun‐Fa; Guo, Dongshuang; Guo, Zhirong; Zhou, Zhengyuan; Yang, Zidong; Wang, Renping; Yang, Jun; Zhou, Xiaoyang; Yan, Weili; Sun, Ning; Gao, Pingjin; Gu, Dongfeng

doi:10.1093/hmg/ddu478

Cited by 167 publications

(130 citation statements)

References 35 publications

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“…Ten SNPs have been associated with SBP or DBP with GWAS significance in East Asian, 4 and we also identified and replicated 19 BP loci in Chinese population. 12 We pruned these SNPs and identified 22 uncorrelated (r 2 <0.5) SNPs. Of these SNPs, 2 (rs10745332 and rs17030613) were in MOV10 but showed weak linkage disequilibrium (r 2 =0.19 HapMap CHB+CEU).…”

Section: Snps Selection Genotyping and Grsmentioning

confidence: 99%

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Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

Huang

Wang

et al. 2015

Hypertension

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Recently, GWAS in East Asian and Chinese not only replicated previously reported BP loci in European populations but also identified several East Asian-specific variants for BP, 4,12 which suggested that both shared and population-specific BP susceptibility were commonly present. Moreover, besides genetic heterogeneity, there are marked differences between Chinese and Europeans in environmental exposure factors, including weight, diet, physical activity, obesity, alcohol drinking, and Abstract-Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease (P range from 4.57×10 -3 to 3.10×10 -6 ). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure-related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18-66) and 26% (6-45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the P<0.05). Our data indicate that genetic predisposition to higher blood pressure is an independent risk factor for blood pressure increase and incident hypertension and cardiovascular disease and provides modest incremental information to cardiovascular disease risk prediction. The potential clinical use of this panel of blood pressure-associated polymorphisms remains to be determined. (Hypertension. 2015;66:786-792.

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Section: Snps Selection Genotyping and Grsmentioning

confidence: 99%

“…For example, at least 6 common variants identified in Europeans were monomorphic or had low minor allele frequency (<0.05) in the Chinese population, 12 suggesting genetic heterogeneity between different ethnic populations. Kato et al 4 published the first large-scale GWAS meta-analysis for BP in East Asians.…”

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Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

Huang

Wang

et al. 2015

Hypertension

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“…The evolutionary role of Casz1 in heart development is further emphasized by genome-wide association studies showing genetic association of the CASZ1 locus with blood pressure and hypertension (Levy et al, 2009;Takeuchi et al, 2010;Lu et al, 2015). Consistently, it has been demonstrated that CASZ1 has an essential role in blood vessel assembly and lumen formation (Charpentier et al, 2013a,b).…”

Section: Introductionmentioning

confidence: 94%

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development

Dorr

Amin

et al. 2015

Development

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Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. Genetic fate mapping with an inducible Casz1 allele demonstrates that CASZ1-expressing cells give rise to cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to a decrease in cardiomyocyte cell number. We further report that the loss of Casz1 leads to a prolonged or arrested S phase, a decrease in DNA synthesis, an increase in phospho-RB and a concomitant decrease in the cardiac mitotic index. Taken together, these studies establish a role for CASZ1 in mammalian cardiomyocyte cell cycle progression in both the first and second heart fields.

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“…Unfortunately, the genotyped individuals in original GWAS of Chinese hypertensive populations 38,39 were relatively small, which may not be sufficient to discover the association of LPAR1 with hypertension when P value cutoff was set as GWAS significance (<10 -7 ). Although some meta-analysis 35,40,41 in East Asian increased sample size by combining various experiments, it can be strongly disturbed by the experimental similarity and validity. These disturbances, together with strict P cutoff, may lead to ignorance of those who have mild effects on trait.…”

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confidence: 99%

“…[32][33][34][35][36][37][38][39][40][41] However, LPAR1 has not been reported by these GWAS. It was probably because the results of GWAS can be affected by several factors, such as population size, stratification, conservative statistic cutoff, and chip density.…”

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Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

et al. 2015

Hypertension

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Abstract-Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3′-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10 -5 , odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10 -5 , odds ratio [95% confidence interval]=1. 75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. Results Characteristics of PopulationsTwo thousand six hundred thirty patients with EH and 3171 controls of Han Chinese were recruited from 3 geographically independent medical centers in total. The characteristics of these populations are shown in Table 1. In addition to the prevalence of coronary artery disease and diabetes mellitus, the biochemical parameters were significantly different between case and control groups at each center. Although most of the hypertensive patients were treated with antihypertensive drugs, the SBP and diastolic blood pressure remained higher compared with their counterparts (Table 1). Single-Nucleotide Polymorphism Association TestTwenty-nine single-nucleotide polymorphisms (SNPs) from the LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 genes and their flanking sequences were first genotyped in population 1 by multiplex ligation-dependent probe amplification. Twenty-eight SNPs were genotyped successfully. The 28 SNPs are shown in Table S5. The primers used for multiplex ligation-dependent probe amplification and sequencing are listed in Tables S2 and S3. The consistency between 2 genotyping methods was generally >99%. All SNPs passed the Hardy-Weinberg equilibrium test (Table S5). In allelic association analysis, 2 SNPs in the LPAR1 gene, rs2766997 (P=0.037) and rs531003 (P=0.006), exhibited positive signals (P<0.05) associated with EH in population 1 in the regression test adjusted risk factors, including sex, age, body mass index, and diabetes mellitus (Tabl...

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Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

Cited by 167 publications

References 35 publications

Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

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