A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH
April
A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH
Ye Sun 0 1 2
Cheng Wang 0 1 2
Zheng Hao 0 1 2
Jin Dai 0 1 2
Dongyang Chen 0 1 2
Zhihong Xu 0 1 2
Dongquan Shi 0 1 2
Ping Mao 0 1 2
Huajian Teng 0 1 2
Xiang Gao 0 1 2
Zhibin Hu 0 1 2
Hongbing Shen 0 1 2
Qing Jiang 0 1 2
0 1 The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University , Nanjing, Jiangsu 210008, China , 2 Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University , Nanjing, Jiangsu 210061, China , 3 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University , Nanjing, Jiangsu 210061, China , 4 Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing , China
1 Funding: This work was supported by China National Natural Science Funds for Youths (No. 81101338, No. 30901570) and China National Funds for Distinguished Young Scientists (No. 81125013). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
2 Academic Editor: Qingyang Huang, Central China Normal University , CHINA
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Competing Interests: The authors have declared
that no competing interests exist.
Genetic basis of Developmental dysplasia of the hip (DDH) remains largely unknown. To
find new susceptibility genes for DDH, we carried out a genome-wide association study
We enrolled 386 radiology confirmed DDH patients and 558 healthy controls (Set A) to
conduct a genome-wide association study (GWAS). Quality-control was conducted at both the
sample and single nucleotide polymorphism (SNP) levels. We then conducted a
subsequent case-control study to replicate the association between a promising loci, rs6060373
in UQCC gene and DDH in an independent set of 755 cases and 944 controls (set B).
In the DDH GWAS discovering stage, 51 SNPs showed significance of less than 10-4, and
another 577 SNPs showed significance of less than 10-3. In UQCC, all the 12 genotyped
SNPs showed as promising risk loci. Genotyping of rs6060373 in set A showed the minor
alodds ratio of 1.18 for risk allele A. Combining set A and set B, we identified a total p value of
3.63*10-6 with the odds ratio of 1.35 (1.191.53) for allele A.
Our study demonstrates common variants of UQCC, specifically rs6060373, are associated
with DDH in Han Chinese population.
Introduction
Developmental dysplasia of the hip (DDH, OMIM #142700) is one common skeletal disorder,
presenting with shallow acetabulum and decreased coverage of the femoral head. [1] Incidence
of DDH varies from 0.1% to 1.84% in Caucasian population, and 0.1%-0.5% in Chinese
population. [2] Persistent DDH can induce chronic hip pain, dysfunction and increase the hip
osteoarthritis risk. [3]
DDH is a polygenic disease with both environmental and genetic risk factors. [4] Though
Mechanical factors (e.g. breech delivery, high birth weight, primiparity and oligoamnios) are
suggested [5,6], it is accepted that genetic components are a crucial part in the etiology of
DDH. Several DDH susceptibility genes (e.g. GDF5, TBX4, ASPN and PAPPA2) were
discovered by association study in Chinese and Caucasian populations [710]. However, the genetic
basis of DDH remains largely unknown.
Genome-wide association study (GWAS) is a genetic method for explaining complex
human diseases such as osteoarthritis [11,12]. GWAS has the potential to identify new
susceptibility genes with previously unknown function and their relationship to the disorder.
Susceptibility genes for several common skeletal disorders have been identified by using this approach
[1113]. In order to find new susceptibility genes for DDH, we carried out a genome-wide
association study for DDH. Within our GWAS result, we found 12 variants in
Ubiquinol-cytochrome c reductase complex chaperone (UQCC) gene associated with DDH (Table 1).
UQCC encodes a zinc-binding protein, putatively repressed by fibroblast growth factor 2
(FGF2), which functions with several genes in morphogenesis and growth of skeleton. [14,15]
UQCC is expressed in differentiating chondrocytes,[16] and is first expressed at early stages of
mesenchymal cell proliferation in mouse.[17] UQCC has been reported as an important
candidate gene in genome-wide association studies for spine bone size, height and testicular germ
cell tumors.[1820]
Based on the importance of UQCC in chondrogenesis, we thought UQCC could be an
attractive candidate gene of DDH, and then conducted a subsequent case-control study to evaluate the
association between UQCC gene and DDH, and found UQCC was associated with DDH
Test for allele frequency
Population set A was genotyped. Allele 1 and allele 2 indicate the major and minor allele in the DDH population, respectively, and 11, 12 and 22 indicate
homozygote of allele 1 and heterozygote and homozygote of allele 2, respectively. Odds ra (...truncated)