Sanders A E, Jain D, Sofer T, Kerr K F, Laurie C C, Shaffer J R, Marazita M L, Kaste L M, Slade G D, Fillingim R B, Ohrbach R, Maixner W, Kocher T, Bernhardt O, Teumer A, Schwahn C, Sipilä K, Lähdesmäki R, Männikkö M, Pesonen P, Järvelin M, Rizzatti-Barbosa C M, Meloto C B, Ribeiro-Dasilva M, Diatchenko L, Serrano P, Smith S B
1 Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2 Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Dent Res. 2017 Mar;96(3):277-284. doi: 10.1177/0022034516686562. Epub 2017 Jan 12.
Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 10) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.
颞下颌关节紊乱病（TMD）是一种肌肉骨骼疾病，其特征为颞下颌关节和/或相关咀嚼肌出现疼痛和功能减退。在美国，其患病率为5%，女性患病率是男性的两倍。我们在美国西班牙裔社区健康研究/拉丁裔研究（HCHS/SOL）的10153名参与者（769例病例，9384名对照）中开展了一项关于TMD的全基因组关联研究（GWAS）探索性研究。最具潜力的单核苷酸多态性（SNP）在4个独立队列的荟萃分析中进行了检验。一个重复队列来自美国，其他队列分别来自德国、芬兰和巴西，共有1911例TMD病例和6903名对照。在探索性分析中，位于肌聚糖α（SGCA）附近的一个位点rs4794106具有提示意义（P = 2.6×10），并在巴西队列中得到重复验证（即单尾P = 0.016）。在探索性队列中，按性别分层分析在女性中又发现了另外2个全基因组显著位点。一个位于松弛素/胰岛素样家族肽受体2（RXP2）上游（13号染色体，rs60249166，优势比[OR]=0.65，P = 3.6×10），在荟萃分析的女性中得到重复验证（单尾P = 0.052）。另一个（17号染色体，rs1531554，OR = 0.68，P = 2.9×10）在女性中得到重复验证（单尾P = 0.002），并且在两性荟萃分析中也得到重复验证（单尾P = 0.021）。在探索性队列中还发现了一个位于肌营养不良蛋白基因DMD（X染色体）内含子中的全基因组显著水平的新位点（rs73460075，OR = 0.56，P = 3.8×10），以及一个位于Sp4转录因子（SP4）基因上游7号染色体上的提示性位点（rs73271865，P = 2.9×10），但这两个位点均未得到重复验证。SGCA基因编码SGCA，它参与肌纤维的细胞结构，并且与DMD一起构成肌营养不良蛋白 - 糖蛋白复合体的一部分。功能注释表明，这些变异中的几个位于调控与TMD病理生物学过程相关过程的位点。
