An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies

Youichi Sato; Atsushi Tajima; Motoki Katsurayama; Shiari Nozawa; Miki Yoshiike; Eitetsue Koh; Jiro Kanaya; Mikio Namiki; Kiyomi Matsumiya; Akira Tsujimura; Kiyoshi Komatsu; Naoki Itoh; Jiro Eguchi; Issei Imoto; Aiko Yamauchi; Teruaki Iwamoto

doi:10.1093/hropen/hox002

An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies

Hum Reprod Open. 2017 Jun 14;2017(1):hox002. doi: 10.1093/hropen/hox002. eCollection 2017.

Authors

Youichi Sato¹, Atsushi Tajima^{2

3}, Motoki Katsurayama¹, Shiari Nozawa⁴, Miki Yoshiike⁴, Eitetsue Koh⁵, Jiro Kanaya⁵, Mikio Namiki⁵, Kiyomi Matsumiya⁶, Akira Tsujimura⁷, Kiyoshi Komatsu⁸, Naoki Itoh⁹, Jiro Eguchi¹⁰, Issei Imoto², Aiko Yamauchi¹, Teruaki Iwamoto^{4

11}

Affiliations

¹ Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School, 1-78-1 Sho-machi, Tokushima 770-8505, Japan.
² Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
³ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
⁴ Department of Urology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
⁵ Department of Urology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
⁶ Department of Urology, Suita Tokushukai Hospital, 1-21 Senriokanishi, Suita 565-0814, Japan.
⁷ Department of Urology, Graduate School of Medicine, Faculty of Medicine, Osaka University, 2-15 Yamadaoka, Suita 565-0871, Japan.
⁸ Department of Urology, Harasanshinkai Hospital, 1-8 Taihaku-machi, Hakata-ku, Fukuoka 812-0033, Japan.
⁹ Department of Urology, Sapporo Medical University S1 W17, Chuo-ku, Sapporo 060-8543, Japan.
¹⁰ Department of Urology, School of Medical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
¹¹ Center for Infertility and IVF, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara 329-2763, Japan.

Abstract

Study question: Are the single nucleotide polymorphisms (SNPs) rs2075230, rs6259 and rs727428 at the sex hormone-binding globulin (SHBG) locus, which were identified by genome-wide association studies (GWASs) for testosterone levels, associated with testosterone levels in Japanese men?

Summary answer: The SNP rs2075230, but not rs6259 and rs727428, is significantly associated with testosterone levels in Japanese men.

What is already known: Previous GWASs have revealed that rs2075230 is associated with serum testosterone levels in 3495 Chinese men and rs6259 and rs727428 are associated with serum testosterone levels in 3225 men of European ancestry.

Study design size and duration: This is an independent validation study of 1687 Japanese men (901 in Cohort 1 and 786 in Cohort 2).

Participants/materials setting and method: Cohort 1 (20.7 ± 1.7 years old, mean ± SD) and Cohort 2 (31.2 ± 4.8 years) included samples obtained from university students and partners of pregnant women, respectively. The three SNPs were genotyped using either TaqMan probes or restriction fragment length polymorphism PCR. Blood samples were drawn from the cubital vein of the study participants in the morning, and total testosterone and SHBG levels were measured using a time-resolved immunofluorometric assay. Association between each SNP and testosterone levels was evaluated by meta-analysis of the two Japanese male cohorts.

Main results and the role of chance: The age of the two cohorts was significantly different (P < 0.0001). We found that rs2075230 was significantly associated with serum testosterone levels (β _STD = 0.15, P = 7.2 × 10^-6); however, rs6259 and rs727428 were not (β _STD = 0.17, P = 0.071; β _STD = 0.082, P = 0.017, respectively), after adjusting for multiple testing in a combined analysis of two Japanese male cohorts. Moreover, rs2075230, rs6259 and rs727428 were significantly associated with high SHBG levels (β _STD = 0.22, P = 3.4 × 10^-12; β _STD = 0.23, P = 6.5 × 10^-6 and β _STD = 0.21, P = 3.4 × 10^-10, respectively).

Large scale data: Not applicable.

Limitations reasons for caution: This study had differences in the age and background parameters of participants compared to those observed in previous GWASs. In addition, the average age of participants in the two cohorts in our study also differed from one another. Therefore, the average testosterone levels, which decrease with age, between studies or the two cohorts were different.

Wider implications of the findings: The three SNPs have a considerable effect on SHBG levels and hence may indirectly affect testosterone levels.

Study funding/competing interests: This study was supported partly by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (26462461) (to Y.S.) and (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.) and the Takeda Science Foundation (to A.Ta.). There are no conflicts of interest to declare.

Keywords: Japanese men; genome-wide association studies; independent validation study; sex hormone-binding globulin; single nucleotide polymorphism; testosterone.