J Bone Metab.  2016 Nov;23(4):233-242. 10.11005/jbm.2016.23.4.233.

Replication of Caucasian Loci Associated with Osteoporosis-related Traits in East Asians

• Kim BJ
• Ahn SH
• Kim HM
• Ikegawa S
• Yang TL
• Guo Y
• Deng HW
• Koh JM
• Lee SH

• KMID: 2361585
• DOI: http://doi.org/10.11005/jbm.2016.23.4.233

Abstract

BACKGROUND
Most reported genome-wide association studies (GWAS) seeking to identify the loci of osteoporosis-related traits have involved Caucasian populations. We aimed to identify the single nucleotide polymorphisms (SNPs) of osteoporosis-related traits among East Asian populations from the bone mineral density (BMD)-related loci of an earlier GWAS meta-analysis.
METHODS
A total of 95 SNPs, identified at the discovery stage of the largest GWAS meta-analysis of BMD, were tested to determine associations with osteoporosis-related traits (BMD, osteoporosis, or fracture) in Korean subjects (n=1,269). The identified SNPs of osteoporosis-related traits in Korean subjects were included in the replication analysis using Chinese (n=2,327) and Japanese (n=768) cohorts.
RESULTS
A total of 17 SNPs were associated with low BMD in Korean subjects. Specifically, 9, 6, 9, and 5 SNPs were associated with the presence of osteoporosis, non-vertebral fractures, vertebral fractures, and any fracture, respectively. Collectively, 35 of the 95 SNPs (36.8%) were associated with one or more osteoporosis-related trait in Korean subjects. Of the 35 SNPs, 19 SNPs (54.3%) were also associated with one or more osteoporosis-related traits in East Asian populations. Twelve SNPs were associated with low BMD in the Chinese and Japanese cohorts. Specifically, 3, 4, and 2 SNPs were associated with the presence of hip fractures, vertebral fractures, and any fracture, respectively.
CONCLUSIONS
Our results identified the common SNPs of osteoporosis-related traits in both Caucasian and East Asian populations. These SNPs should be further investigated to assess whether they are true genetic markers of osteoporosis.

Keyword

Fractures bone; Genome-wide association study; Osteoporosis; Polymorphism single nucleotide

MeSH Terms

Asian Continental Ancestry Group*
Bone Density
Cohort Studies
Genetic Markers
Genome-Wide Association Study
Hip Fractures
Humans
Osteoporosis
Polymorphism, Single Nucleotide
Genetic Markers

Reference

1. NIH Consensus Development Panel on Osteoporosis, Prevention, Diagnosis and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001; 285:785–795.

2. Choi HJ, Shin CS, Ha YC, et al. Burden of osteoporosis in adults in Korea: a national health insurance database study. J Bone Miner Metab. 2012; 30:54–58.

3. Liu YJ, Zhang L, Papasian CJ, et al. Genome-wide association studies for osteoporosis: a 2013 update. J Bone Metab. 2014; 21:99–116.

4. Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev. 2010; 31:629–662.

5. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997; 7:407–413.

6. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012; 44:491–501.

7. Fu J, Festen EA, Wijmenga C. Multi-ethnic studies in complex traits. Hum Mol Genet. 2011; 20:R206–R213.

8. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007; 448:353–357.

9. Lee SH, Cho EH, Ahn SH, et al. Prediction of future osteoporotic fracture occurrence by genetic profiling: A 6-year follow-up observational study. J Clin Endocrinol Metab. 2016; 101:1215–1224.

10. Nathan M, Pope MH, Grobler LJ. Osteophyte formation in the vertebral column: a review of the etiologic factors--Part II. Contemp Orthop. 1994; 29:113–119.

11. Kanis JA, Melton LJ 3rd, Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res. 1994; 9:1137–1141.

12. Moon DH, Lee HK, Shin JW, et al. Cross-calibration of bone mineral density between two different dual X-ray absorptiometry systems: hologic QDR 4500-A and lunar EXPERT-XL. Korean J Nucl Med. 1999; 33:282–288.

13. Kiel D. Assessing vertebral fractures. National Osteoporosis Foundation Working Group on vertebral fractures. J Bone Miner Res. 1995; 10:518–523.

14. Genant HK, Wu CY, van Kuijk C, et al. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. 1993; 8:1137–1148.

15. Yang TL, Guo Y, Liu YJ, et al. Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations. Osteoporos Int. 2012; 23:781–787.

16. Guo Y, Tan LJ, Lei SF, et al. Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet. 2010; 6:e1000806.

17. Ikeda K, Inoue S, Orimo A, et al. Promoter analysis of mouse estrogen-responsive finger protein (efp) gene: mouse efp promoter contains an E-box that is also conserved in human. Gene. 1998; 216:155–162.

18. Braun A, Roth R, McGinniss MJ. Technology challenges in screening single gene disorders. Eur J Pediatr. 2003; 162:Suppl 1. S13–S16.

19. Mein CA, Barratt BJ, Dunn MG, et al. Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation. Genome Res. 2000; 10:330–343.

20. Styrkarsdottir U, Halldorsson BV, Gudbjartsson DF, et al. European bone mineral density loci are also associated with BMD in East-Asian populations. PLoS One. 2010; 5:e13217.

21. Kim YA, Choi HJ, Lee JY, et al. Replication of Caucasian loci associated with bone mineral density in Koreans. Osteoporos Int. 2013; 24:2603–2610.

22. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002; 359:1761–1767.