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Male-specific genetic effect on hypertension and metabolic disorders


Genetic risk factors for hypertension may have age or gender specificity and pleiotropic effects. This study aims to measure the risk of genetic and non-genetic factors in the occurrence of hypertension and related diseases, with consideration of potential confounding factors and age-gender stratification. A discovery set of 352,228 genotyped plus 1.8 million imputed single-nucleotide polymorphisms were analyzed for 2,886 hypertensive cases and 3,440 healthy controls obtained from two community-based cohorts in Korea, and selected gene variants were replicated in the Health Examinee cohort (665 cases and 1,285 controls). Genome-wide association analyses were conducted in 12 groups stratified by age and gender after adjusting for potential covariates under three genetic models. Age, rural area residence, body mass index, family history of hypertension, male gender, current alcohol drinking status, and current smoking status were significantly associated with hypertension (P = 4 × 10−151 to 0.011). Five gene variants, rs11066280 (C12orf51), rs12229654 and rs3782889 (MYL2), rs2072134 (OAS3), rs2093395 (TREML2), and rs17249754 (ATP2B1), were found to be associated with hypertension mostly in men (P = 4.76 × 10−14 to 4.46 × 10−7 in the joint analysis); three SNPs (rs11066280, rs12229654, and rs3782889) remained significant after Bonferroni correction in an independent population. Three gene variants, rs12229654, rs17249754, and rs11066280, were significantly associated with metabolic disorders such as hyperlipidemia and diabetes (P = 0.00071 to 0.0097, respectively). Careful consideration of the potential confounding effects in future genome-wide association studies is necessary to uncover the genetic underpinnings of complex diseases.

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Hyung-Lae Kim, MD, Ph.D, of the Ewha School of Medicine at Seoul, and Bok-Ghee Han, Ph.D, of the National Institute of Health at Osong, contributed to direct the development and maintenance of the Korean Genome Epidemiology Study (KoGES). Nam Han Cho, Ph.D, of the Ajou University School of Medicine at Suwon, and Chol Shin, MD, Ph.D, of the Korea University Ansan Hospital at Ansan, created and developed the Ansung and Ansan cohorts, respectively, as part of the Korean Genome Epidemiology Study (KoGES). Daehee Kang, MD, Ph.D, of the Seoul National University College of Medicine at Seoul, developed the HEXA study. Phenotype information was collected by Haesook Min, MS, and Sung Soo Kim, Ph.D, both of the National Institute of Health at Osong. Young Jin Kim, MS, of the National Institute of Health at Osong and Yoon Shin Cho, Ph.D, of Hallym University at Chuncheon, performed genotyping experiments and assured the quality of the genotype data. We thank all who have been involved in the generation of data at each local institute. This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2009-0090837) and Hallym University Research Fund, 2012 (HRF-S-2012-5). The study was performed within the Consortium for Large Scale Genome Wide Association Study III (2011E7300400), which was supported by genotyping data from the Korean Genome Analysis Project (4845-301), phenotypic data from the Korean Genome Epidemiology Study (4851-302) and an intramural grant from the Korea National Institute of Health (2012-N73002-00).

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Correspondence to Ji Wan Park.

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Heo, S.G., Hwang, J., Uhmn, S. et al. Male-specific genetic effect on hypertension and metabolic disorders. Hum Genet 133, 311–319 (2014).

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