Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.
Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.
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全基因组关联揭示了 MRAS 对男性疼痛性颞下颌疾病的影响。
DOI：
10.1097/j.pain.0000000000001438
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发表时间：
2019
期刊：
影响因子：
7.4
通讯作者：
Järve
中科院分区：
文献类型：
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作者：
Smith,ShadB;Parisien,Marc;Bair,Eric;Belfer,Inna;Chabot-Doré,Anne-Julie;Gris,Pavel;Khoury,Samar;Tansley,Shannon;Torosyan,Yelizaveta;Zaykin,DmitriV;Bernhardt,Olaf;deOliveiraSerrano,Priscila;Gracely,RichardH;Jain,Deepti;Järve
疼痛性颞下颌关节紊乱病（TMDs）是导致慢性口面部疼痛的主要原因，但其潜在的分子机制仍不清楚。虽然许多环境因素与患上疼痛性TMD的风险较高有关，但家庭和双胞胎研究也支持遗传遗传成分。我们进行了一项全基因组关联研究，假设TMD的加性遗传模型在一个发现队列中的999例和2031例无TMD对照的口面疼痛：前瞻性评价和风险评估（OPPERA）研究。使用logistic模型调整性别，年龄，入组地点，和种族，我们确定了3个不同的基因座，是显着的组合或性别分离的分析。3号染色体上的单核苷酸多态性（rs 13078961）与TMD仅在男性中显著相关（比值比5 2.9，95%置信区间：2.02-4.27，P 5 2.2 3 10 28）。在对7个独立的口面疼痛队列（包括160，194名参与者）进行的荟萃分析中，名义上复制了这种关联（比值比5 1.16，95%置信区间：1.0-1.35，P 5 2.3 3 10 22）。在人背根神经节和血液中的功能分析表明，该变体是一个表达数量性状基因座，次要等位基因与附近肌肉RAS癌基因同源物（MRAS）基因（β 5 20.51，P 5 2.43 3 10 25）的表达降低相关。Mras基因无效突变的雄性小鼠在炎症性疼痛模型中表现出持续的机械性异常性疼痛，而雌性小鼠则没有。遗传和行为证据支持一种新的机制，通过该机制，遗传决定的MRAS表达调节对慢性疼痛的弹性。这种效应是男性特有的，可能有助于男性疼痛性TMD的发生率较低。
Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio 5 2.9, 95% confidence interval: 2.02-4.27, P 5 2.2 3 10 28). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio 5 1.16, 95% confidence interval: 1.0-1.35, P 5 2.3 3 10 22). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta 5 20.51, P 5 2.43 3 10 25). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.