Abstract：
OBJECTIVE: To investigate genetic interactions between mitochondrial deoxyribonucleic acid (mtDNA) haplogroups and nuclear single nucleotide polymorphisms (nSNPs) to analyze their impact on the development of the rapid progression of knee osteoarthritis (OA).
METHODS: A total of 1095 subjects from the Osteoarthritis Initiative, with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index, contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies.
RESULTS: The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (odds ratio = 1.670; 95% confidence interval [CI]: 1.031-2.706; adjusted p-value = 0.027). The assessment of the population attributable fraction showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23.4%) (95%CI: 7.89-38.9; p-value < 0.05). The area under the curve of the cross-validation model (0.730) was very similar to the obtained for the predictive model (0.735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies.
CONCLUSIONS: This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes.
METHODS: A total of 1095 subjects from the Osteoarthritis Initiative, with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index, contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies.
RESULTS: The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (odds ratio = 1.670; 95% confidence interval [CI]: 1.031-2.706; adjusted p-value = 0.027). The assessment of the population attributable fraction showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23.4%) (95%CI: 7.89-38.9; p-value < 0.05). The area under the curve of the cross-validation model (0.730) was very similar to the obtained for the predictive model (0.735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies.
CONCLUSIONS: This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes.
摘要：
目的：研究mtDNA单倍群和核单核苷酸多态性（nSNPs）之间的遗传相互作用，以分析它们对膝骨关节炎（OA）快速进展的影响。
方法：来自骨关节炎倡议（OAI）的1095名受试者，随访时间至少为48个月，包括在内。进行了适当的统计方法，包括根据年龄调整的广义估计方程，性别,体重指数（BMI），对侧膝关节OA,西安大略省和麦克马斯特大学骨关节炎指数（WOMAC）疼痛，目标膝盖的先前损伤和mtDNA变体m.16519C的存在。其他基因组数据包括高加索人mtDNA单倍群的基因分型和8个以前在健壮的全基因组关联研究（GWAS）中与膝关节OA风险相关的nSNP。
结果：在TP63和单倍群Uk同时存在rs12107036的G等位基因显着增加了膝关节OA快速进展的风险（OR=1,670；95CI：1,031-2,706；调整后的p值=0,027）。对群体归因分数（PAF）的评估表明，快速进展者的最高比例是在rs12107036的G等位基因和单倍群Uk（23,4％）的同时存在下（95CI：7,89-38,9；p值<0.05）。交叉验证模型(0,730)的曲线下面积(AUC)与预测模型(0,735)获得的非常相似。建立列线图以帮助临床医生进行临床试验或流行病学研究。
结论：这项研究表明，在OA中存在线粒体上位症，提供了核和线粒体变异影响不同OA表型易感性的新机制。
方法：来自骨关节炎倡议（OAI）的1095名受试者，随访时间至少为48个月，包括在内。进行了适当的统计方法，包括根据年龄调整的广义估计方程，性别,体重指数（BMI），对侧膝关节OA,西安大略省和麦克马斯特大学骨关节炎指数（WOMAC）疼痛，目标膝盖的先前损伤和mtDNA变体m.16519C的存在。其他基因组数据包括高加索人mtDNA单倍群的基因分型和8个以前在健壮的全基因组关联研究（GWAS）中与膝关节OA风险相关的nSNP。
结果：在TP63和单倍群Uk同时存在rs12107036的G等位基因显着增加了膝关节OA快速进展的风险（OR=1,670；95CI：1,031-2,706；调整后的p值=0,027）。对群体归因分数（PAF）的评估表明，快速进展者的最高比例是在rs12107036的G等位基因和单倍群Uk（23,4％）的同时存在下（95CI：7,89-38,9；p值<0.05）。交叉验证模型(0,730)的曲线下面积(AUC)与预测模型(0,735)获得的非常相似。建立列线图以帮助临床医生进行临床试验或流行病学研究。
结论：这项研究表明，在OA中存在线粒体上位症，提供了核和线粒体变异影响不同OA表型易感性的新机制。
