Genetic risk score based on the prevalence of vertebral fracture in Japanese women with osteoporosis

Heying Zhou; Seijiro Mori; Tatsuro Ishizaki; Atsushi Takahashi; Koichi Matsuda; Yukihiro Koretsune; Shiro Minami; Masahiko Higashiyama; Shinji Imai; Kozo Yoshimori; Minoru Doita; Akira Yamada; Satoshi Nagayama; Kazuo Kaneko; Satoshi Asai; Masaki Shiono; Michiaki Kubo; Hideki Ito

doi:10.1016/j.bonr.2016.07.001

Genetic risk score based on the prevalence of vertebral fracture in Japanese women with osteoporosis

Bone Rep. 2016 Jul 12:5:168-172. doi: 10.1016/j.bonr.2016.07.001. eCollection 2016 Dec.

Authors

Heying Zhou¹, Seijiro Mori¹, Tatsuro Ishizaki², Atsushi Takahashi^{3

4}, Koichi Matsuda⁵, Yukihiro Koretsune⁶, Shiro Minami⁷, Masahiko Higashiyama⁸, Shinji Imai⁹, Kozo Yoshimori¹⁰, Minoru Doita¹¹, Akira Yamada¹², Satoshi Nagayama¹³, Kazuo Kaneko¹⁴, Satoshi Asai¹⁵, Masaki Shiono¹⁶, Michiaki Kubo¹⁷, Hideki Ito¹⁸

Affiliations

¹ Center for the Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
² Research Team for Human Care, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
³ Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁴ Laboratory for Omics Informatics, Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁵ Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶ National Hospital Organization, Osaka National Hospital, Osaka, Japan.
⁷ Department of Bioregulation, Institute for Advanced Medical Research, Nippon Medical School, Kawasaki, Japan.
⁸ Osaka Medical Center for Cancer & Cardiovascular Diseases, Osaka, Japan.
⁹ Department of Orthopaedic Surgery, Shiga University of Medical Science, Shiga, Japan.
¹⁰ Japan Anti-Tuberculosis Association, Fukujuji Hospital, Tokyo, Japan.
¹¹ Department of Orthopedic Surgery, School of Medicine, Iwate Medical University, Morioka, Japan.
¹² Clinical Trial Promotion Headquarters, Aso Iizuka Hospital, Tokyo, Japan.
¹³ Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan.
¹⁴ Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
¹⁵ Division of Pharmacology, Nihon University School of Medicine, Tokyo, Japan.
¹⁶ Tokushukai Medical Corporation, Kanagawa, Japan.
¹⁷ Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
¹⁸ Local Independent Administrative Agency, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.

Abstract

A genetic risk score (GRS) was developed for predicting fracture risk based on the prevalence of vertebral fractures in 441 Japanese females with osteoporosis. A total of 979 (858 nonsynonymous and 121 silent) single-nucleotide polymorphisms (SNPs) located in 74 osteoporosis-susceptibility genes were genotyped and evaluated for their association with fracture prevalence. Four SNPs (protein kinase domain containing, cytoplasmic [PKDCC; rs4952590], CDK5-regulatory subunit-associated protein 1-like 1 [CDKAL1; rs4712556], wingless-type MMTV-integration site family member 16 [WNT16; rs2707466], and G-patch domain-containing gene 1 [GPATCH1; rs10416265]) showed a significant association (p < 0.05) with the fracture, in which the minor allele of the former two SNPs was the protective allele and that of the latter two SNPs was the risk allele. Applying a dominant-genetic model, we allotted - 1 point each to the protective-allele carriers and 1 point each to the risk-allele carriers, and GRS values were calculated as the sum of the points. The receiver-operating characteristic curves showed that GRS adequately predicted vertebral fracture. For the model predicted by the GRS with and without the effect of age, areas under the curves were 0.788 (95% confidence interval [CI]: 0.736-0.840) and 0.667 (95% CI: 0.599-0.735), respectively. Multiple logistic regression analysis revealed that the odds ratio for the association between fracture prevalence and GRS was 3.27 (95% CI: 1.36-7.87, p = 0.008) for scores of - 1 to 0 (n = 303) and 12.12 (95% CI: 4.19-35.07, p < 0.001) for scores of 1 to 2 (n = 35) relative to a score of - 2 (n = 103). The GRS based on the four SNPs could help identify at-risk individuals and enable implementation of preventive measures for vertebral fracture.

Keywords: AUC, area under the curve; BMD, bone mineral density; CDKAL1, CDK5-regulatory subunit-associated protein 1-like 1; CI, confidence interval; GPATCH1, G-patch domain-containing gene 1; GRS, genetic risk score; GWAS, genome-wide association studies; Genetic risk score; OR, odds ratio; Osteoporosis; PKDCC, protein kinase domain containing, cytoplasmic; ROC, receiver-operating characteristics; SNP, single-nucleotide polymorphism; Single-nucleotide polymorphism; Vertebral fracture; WNT16, wingless-type MMTV-integration site family member 16.