Genetic association study of common variants in TGFB1 and IL-6 with developmental dysplasia of the hip in Han Chinese population

Wenlong Ma,Jianbing Ma,Liqiang Zhi,Shuxin Yao,Sixiang Zeng,Honggan Chen,Yixin Wu,Zhuqing Zha,Ke Chen

doi:10.1038/s41598-017-11185-1

Abstract

Developmental dysplasia of the hip (DDH) is a congenital or developmental deformation or misalignment of the hip joint that is affected by environmental and genetic factors. Recently, polymorphisms in both TGFB1 and IL-6 have been identified as being significantly associated with hip osteoarthritis in Caucasians. In this study, we conducted a case-control study involving 4,206 Han Chinese individuals to investigate the effects of TGFB1 and IL-6 on the disease status and severity of DDH. A total of 32 single-nucleotide polymorphisms (SNPs) were selected to ensure coverage of the two genetic loci. We found SNP rs1800470 in TGFB1 (OR = 1.255, P = 0.0004) and rs1800796 (OR = 0.84, P = 0.0228) in IL-6 to be significantly associated with DDH in this cohort. Further haplotype-based analysis replicated this significant result. Another SNP in IL-6, rs1800796, showed a marginally significant association with DDH. As a non-synonymous SNP, rs1800470 alters the amino acid sequence of the polypeptide encoded by TGFB1; however, bioinformatics analyses revealed that this SNP has limited functional significance. No significant results were obtained in an association study focusing on the severity of DDH and epistasis analysis. Our findings support an important role for TGFB1 in the risk of DDH. Further research is needed to validate the weak association between rs1800796 in IL-6 and DDH.

Highlights

Developmental dysplasia of the hip (DDH) is a congenital or developmental deformation or misalignment of the hip joint that endangers skeletal development in children[1]
DDH patients Healthy controls DDH patients Healthy controls can act as both a pro-inflammatory cytokine and an anti-inflammatory myokine[16]. Both TGF-β1 and IL-6 are pro-inflammatory cytokines involved in the pathogenesis of hip osteoarthritis[17], which is a major consequence of DDH in adulthood, and both proteins are involved in the bone remodelling process[18]
Analyses based on the combined sample from both the discovery and validation stages showed that two single-nucleotide polymorphisms (SNPs), rs1800470 (OR = 1.255, P = 0.0004) and rs1800796 (OR = 0.84, P = 0.0228), were significantly associated with the disease status of DDH

Summary

Introduction

Developmental dysplasia of the hip (DDH) is a congenital or developmental deformation or misalignment of the hip joint that endangers skeletal development in children[1]. Gene-association mapping studies have identified several susceptibility loci for DDH. Polymorphisms in TGFB1 and IL-6 have been identified as significantly associated with hip osteoarthritis in studies based on Caucasian populations[20, 21]. Most of these early studies suffered from the lacks of replication and insufficient statistical power which may be due to the sample size and small effect size or a combination of both. We conducted a case-control study based on 4,206 Han Chinese subjects to investigate the potential effects of TGFB1 and IL-6 on the disease status and severity of DDH in this population. Our study explored specific linkage disequilibrium (LD) structure of Han Chinese population on TGFB1 and IL-6, and identified Han Chinese specific connection between the polymorphisms within TGFB1 and IL-6 and DDH

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