A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH

PLOS ONE, Dec 2019

Purpose 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 (GWAS) for DDH. Methods 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). Results 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 allele A as a promising risk allele (p = 4.82*10-7). In set A, the odds ratio of allele A was 1.77. Genotyping of rs6060373 in Set B produced another significant result (p = 0.0338) with an odds 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 (1.19–1.53) for allele A. Conclusion Our study demonstrates common variants of UQCC, specifically rs6060373, are associated with DDH in Han Chinese population.

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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 - 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)


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Ye Sun, Cheng Wang, Zheng Hao, Jin Dai, Dongyang Chen, Zhihong Xu, Dongquan Shi, Ping Mao, Huajian Teng, Xiang Gao, Zhibin Hu, Hongbing Shen, Qing Jiang. A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH, PLOS ONE, 2015, Volume 10, Issue 4, DOI: 10.1371/journal.pone.0120212