Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies

Yoshiji Yamada; Jun Sakuma; Ichiro Takeuchi; Yoshiki Yasukochi; Kimihiko Kato; Mitsutoshi Oguri; Tetsuo Fujimaki; Hideki Horibe; Masaaki Muramatsu; Motoji Sawabe; Yoshinori Fujiwara; Yu Taniguchi; Shuichi Obuchi; Hisashi Kawai; Shoji Shinkai; Seijiro Mori; Tomio Arai; Masashi Tanaka

doi:10.18632/oncotarget.17159

Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies

Oncotarget. 2017 Jun 13;8(24):38950-38961. doi: 10.18632/oncotarget.17159.

Authors

Yoshiji Yamada^{1

2}, Jun Sakuma^{2

3

4}, Ichiro Takeuchi^{2

4

5}, Yoshiki Yasukochi^{1

2}, Kimihiko Kato^{1

6}, Mitsutoshi Oguri^{1

7}, Tetsuo Fujimaki⁸, Hideki Horibe⁹, Masaaki Muramatsu¹⁰, Motoji Sawabe¹¹, Yoshinori Fujiwara¹², Yu Taniguchi¹², Shuichi Obuchi¹³, Hisashi Kawai¹³, Shoji Shinkai¹⁴, Seijiro Mori¹⁵, Tomio Arai¹⁶, Masashi Tanaka¹⁷

Affiliations

¹ Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.
² CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
³ Computer Science Department, College of Information Science, University of Tsukuba, Tsukuba, Japan.
⁴ RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.
⁵ Department of Computer Science, Nagoya Institute of Technology, Nagoya, Japan.
⁶ Department of Internal Medicine, Meitoh Hospital, Nagoya, Japan.
⁷ Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Japan.
⁸ Department of Cardiovascular Medicine, Inabe General Hospital, Inabe, Japan.
⁹ Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.
¹⁰ Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
¹¹ Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
¹² Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹³ Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹⁴ Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
¹⁵ Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
¹⁶ Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
¹⁷ Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Abstract

We have performed exome-wide association studies to identify single nucleotide polymorphisms that influence serum concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, or low density lipoprotein (LDL)-cholesterol or confer susceptibility to hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia in Japanese. Exome-wide association studies for serum triglycerides (13,414 subjects), HDL-cholesterol (14,119 subjects), LDL-cholesterol (13,577 subjects), hypertriglyceridemia (4742 cases, 8672 controls), hypo-HDL-cholesterolemia (2646 cases, 11,473 controls), and hyper-LDL-cholesterolemia (4489 cases, 9088 controls) were performed with HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. Twenty-four, 69, or 32 loci were significantly (P < 1.21 × 10-6) associated with serum triglycerides, HDL-cholesterol, or LDL-cholesterol, respectively, with 13, 16, or 9 of these loci having previously been associated with triglyceride-, HDL-cholesterol-, or LDL-cholesterol-related traits, respectively. Two single nucleotide polymorphisms (rs10790162, rs7350481) were significantly related to both serum triglycerides and hypertriglyceridemia; three polymorphisms (rs146515657, rs147317864, rs12229654) were significantly related to both serum HDL-cholesterol and hypo-HDL-cholesterolemia; and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) were significantly related to both serum LDL-cholesterol and hyper-LDL-cholesterolemia. Among polymorphisms identified in the present study, two polymorphisms (rs146515657, rs147317864) may be novel determinants of hypo-HDL-cholesterolemia, and six polymorphisms (rs2853969, rs7771335, rs2071653, rs2269704, rs2269703, rs2269702) may be new determinants of hyper-LDL-cholesterolemia. In addition, 12, 61, 23, or 3 polymorphisms may be new determinants of the serum triglyceride, HDL-cholesterol, or LDL-cholesterol concentrations or of hyper-LDL-cholesterolemia, respectively.

Keywords: HDL-cholesterol; LDL-cholesterol; dyslipidemia; exome-wide association study; triglyceride.

MeSH terms

Asian People / genetics
Dyslipidemias / genetics*
Exome
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide / genetics*