Hsu Yi-Hsiang, Liu Youfang, Hannan Marian T, Maixner William, Smith Shad B, Diatchenko Luda, Golightly Yvonne M, Menz Hylton B, Kraus Virginia B, Doherty Michael, Wilson A G, Jordan Joanne M
Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, Massachusetts, USA Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina, USA.
J Med Genet. 2015 Nov;52(11):762-9. doi: 10.1136/jmedgenet-2015-103142. Epub 2015 Sep 2.
Hallux valgus (HV) affects ∼36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV.
HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed SNPs. Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327).
The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10(-7)); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10(-7)). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10(-9)). The association signals diminished when combining men and women.
The findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.
拇外翻（HV）影响约36%的白种成年人。尽管被认为具有高度遗传性，但其潜在的遗传决定因素尚不清楚。我们开展了第一项全基因组关联研究（GWAS），旨在识别与HV相关的基因变异。
在三个白种人队列中评估HV（分别有2263名、915名和1231名参与者）。在每个队列中，使用250万个推算的单核苷酸多态性（SNP）进行GWAS。采用加性遗传模型的混合效应回归，并对年龄、性别、体重和家庭内相关性进行调整，用于性别特异性分析和综合分析。为了合并各队列的GWAS结果，采用固定效应逆方差荟萃分析。荟萃分析后，还在一个非裔美国人队列（n = 327）中检查了最相关的研究结果。
全基因组基因分型SNP解释的HV变异比例在男性中为50%，在女性中为48%。HV的遗传决定因素中较高比例是性别特异性的。男性中最显著相关的SNP是位于17号染色体q23-a24上靠近AXIN2基因的rs9675316（p = 0.000000546×10⁻⁷）；女性中最显著相关的SNP是位于13号染色体q14.1-q14.2上靠近ESD基因的rs7996797（p = 0.000000721×10⁻⁷）。在位于11号染色体p15.1上靠近MRGPRX3基因的SNP rs1563374中发现了全基因组显著的SNP-性别相互作用（相互作用p值 = 0.0000000041×10⁻⁹）。合并男性和女性后，关联信号减弱。
研究结果表明，HV的潜在病理生理机制复杂，且受到性别特异性相互作用的强烈影响。所识别的基因变异暗示了骨关节炎中观察到的生物学途径以及影响骨骼发育和炎症的新途径的作用。
