Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population

Baek,Seung‑Hoon; Kim,Kang‑Il; Yoon,Kyung‑Sik; Kim,Tae‑Ho; Kim,Shin‑Yoon

doi:10.3892/mmr.2016.6036

Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population

Authors:
- Seung‑Hoon Baek
- Kang‑Il Kim
- Kyung‑Sik Yoon
- Tae‑Ho Kim
- Shin‑Yoon Kim
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Affiliations: Department of Orthopedic Surgery, Graduate School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea, Department of Orthopedic Surgery, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Biomedical Research Institute, Kyungpook National University Hospital, Daegu 41940, Republic of Korea
Published online on: December 14, 2016 https://doi.org/10.3892/mmr.2016.6036
Pages: 750-758
Copyright: © Baek et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease and is associated with genetic predisposition, and exposure to certain risk factors. In particular, idiopathic ONFH in twins and the clustering of cases in families have indicated that genetic factors are involved. However, the majority of cases of ONFH are sporadic and various studies have demonstrated that differences in the study design and/or the ethnic groups analyzed leads to different results. The present study performed one of the first genome‑wide association studies to identify genetic loci that may increase the risk of idiopathic ONFH. In total, 217 patients with idiopathic ONFH and 217 control samples, without ONFH, were genotyped using Axiom™ chips. Following quality control, 509,886 single‑nucleotide polymorphisms (SNPs) were included in the association analysis to identify genetic variants that may influence susceptibility to idiopathic ONFH. The lowest P‑value identified by the current study was for an association with rs220324 (P=3.57x10‑7), an SNP that is located near to the uromodulin‑like 1 gene region on chromosome 21q22.3, although none of the SNPs reached the traditional genome‑wide significance level of 5x10‑8. However, the DnaJ heat shock protein family (Hsp40) member C6 (DNAJC6) locus, a region between 65.37 and 65.67 Mb located on chromosome 1p31.3, harbored a cluster of SNPs that were associated with idiopathic ONFH at a significance level of P<1x10‑5. Four variants, rs10493374, rs12032616, rs17127529 and rs6679032, with marginal associations were located in and around the DNAJC6 locus and were in strong linkage disequilibrium with each other. In conclusion, the current study did not identify any SNPs that were associated with idiopathic ONFH at a genome‑wide significance level, however, the results suggest that future studies should investigate the effects of SNPs in the DNAJC6 gene on the idiopathic ONFH risk.

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1	Nishimura T, Matsumoto T, Nishino M and Tomita K: Histopathologic study of veins in steroid treated rabbits. Clin Orthop Relat Res. 334:37–42. 1997. View Article : Google Scholar
2	Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y and Gershwin ME: Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 32:94–124. 2002. View Article : Google Scholar : PubMed/NCBI
3	Orlić D, Jovanović S, Anticević D and Zecević J: Frequency of idiopathic aseptic necrosis in medically treated alcoholics. Int Orthop. 14:383–386. 1990. View Article : Google Scholar : PubMed/NCBI
4	Jones LC and Hungerford DS: The pathogenesis of osteonecrosis. Instr Course Lect. 56:179–196. 2007.PubMed/NCBI
5	Kim SY and Rubash HE: Avascular necrosis of the femoral head: the Korean experienceThe adult hip. 2. 2nd edition. Lippincott Williams & Wilkins; Philadelphia, PA: pp. 1078–1086. 2006
6	Glueck CJ, Glueck HI, Welch M, Freiberg R, Tracy T, Hamer T and Stroop D: Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thromb Haemost. 71:195–198. 1994.PubMed/NCBI
7	Nobillot R, Le Parc JM, Benoit J and Paolaggi JB: Idiopathic osteonecrosis of the hip in twins. Ann Rheum Dis. 53:7021994. View Article : Google Scholar : PubMed/NCBI
8	Ferrari P, Schroeder V, Anderson S, Kocovic L, Vogt B, Schiesser D, Marti HP, Ganz R, Frey FJ and Kohler HP: Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients. Transplantation. 74:1147–1152. 2002. View Article : Google Scholar : PubMed/NCBI
9	Zalavras CG, Vartholomatos G, Dokou E and Malizos KN: Factor V Leiden and prothrombin gene mutations in femoral head osteonecrosis. Thromb Haemost. 87:1079–1080. 2002.PubMed/NCBI
10	Zalavras CG, Malizos KN, Dokou E and Vartholomatos G: The 677C->T mutation of the methylene-tetrahydrofolate reductase gene in the pathogenesis of osteonecrosis of the femoral head. Haematologica. 87:111–112. 2002.PubMed/NCBI
11	Kim SY, Suh JS, Park EK, Jung WB, Kim JW, Koo KH and Kim CY: Factor V Leiden gene mutation in femoral head osteonecrosis. J Korean Ortho Res Soc. 6:259–264. 2003.
12	Chang JD, Hur M, Lee SS, Yoo JH and Lee KM: Genetic background of nontraumatic osteonecrosis of the femoral head in the Korean population. Clin Orthop Relat Res. 466:1041–1046. 2008. View Article : Google Scholar : PubMed/NCBI
13	Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, Su JS, et al: Type II collagen gene variants and inherited osteonecrosis of the femoral head. N Engl J Med. 352:2294–2301. 2005. View Article : Google Scholar : PubMed/NCBI
14	Gordon H, Moller F Trier, Andersen V and Harbord M: Heritability in inflammatory bowel disease: From the first twin study to genome-wide association studies. Inflamm Bowel Dis. 21:1428–1434. 2015.PubMed/NCBI
15	Veron A, Blein S and Cox DG: Genome-wide association studies and the clinic: A focus on breast cancer. Biomark Med. 8:287–296. 2014. View Article : Google Scholar : PubMed/NCBI
16	Grarup N, Sandholt CH, Hansen T and Pedersen O: Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia. 57:1528–1541. 2014. View Article : Google Scholar : PubMed/NCBI
17	Gardeniers JWM: The Arco Perspective for Reaching One Uniform Staging System of OsteonecrosisBone Circulation and Vascularization in Normal and Pathological Conditions. Scoutens A, Arlet J, Gardeniers JWM and Hughes SPF: 247. Plenum Press; New York, NY: pp. 375–380. 1993, View Article : Google Scholar
18	Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, De Bakker PI, Daly MJ and Sham PC: PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 81:559–575. 2007. View Article : Google Scholar : PubMed/NCBI
19	Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, et al: Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet. 37:1243–1246. 2005. View Article : Google Scholar : PubMed/NCBI
20	Barrett JC, Fry B, Maller J and Daly MJ: Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics. 21:263–265. 2005. View Article : Google Scholar : PubMed/NCBI
21	Glimcher MJ and Kenzora JE: The biology of osteonecrosis of the human femoral head and its clinical implications. III. Discussion of the etiology and genesis of the pathological sequelae; commments on treatment. Clin Orthop Relat Res. 140:273–312. 1979.
22	Kang JS, Park S, Song JH, Jung YY, Cho MR and Rhyu KH: Prevalence of osteonecrosis of the femoral head: A nationwide epidemiologic analysis in Korea. J Arthroplasty. 24:1178–1183. 2009. View Article : Google Scholar : PubMed/NCBI
23	Koo KH, Jeong ST and Jones JP Jr: Borderline necrosis of the femoral head. Clin Orthop Relat Res. 358:158–165. 1999. View Article : Google Scholar
24	Jones LC, Mont MA, Le TB, Petri M, Hungerford DS, Wang P and Glueck CJ: Procoagulants and osteonecrosis. J Rheumatol. 30:783–791. 2003.PubMed/NCBI
25	Kerachian MA, Harvey EJ, Cournoyer D, Chow TY and Séguin C: Avascular necrosis of the femoral head: Vascular hypotheses. Endothelium. 13:237–244. 2006. View Article : Google Scholar : PubMed/NCBI
26	Sag D, Cekic C, Wu R, Linden J and Hedrick CC: The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. Nat Commun. 6:63542015. View Article : Google Scholar : PubMed/NCBI
27	Athanasiadis G, Buil A, Souto JC, Borrell M, López S, Martinez-Perez A, Lathrop M, Fontcuberta J, Almasy L and Soria JM: A genome-wide association study of the Protein C anticoagulant pathway. PLoS One. 6:e291682011. View Article : Google Scholar : PubMed/NCBI
28	Camire RM and Bos MH: The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost. 7:1951–1961. 2009. View Article : Google Scholar : PubMed/NCBI