Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1849, USA.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8134-9. doi: 10.1073/pnas.1306352110. Epub 2013 Apr 30.
Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 × 10(-5)), and one gene involved in innate immunity, TLR4 (P = 8.0 × 10(-4)), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063-0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10(-12)). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.
全基因组关联研究（GWAS）是一种识别与疾病相关常见变异体的基因的有效方法，但不适合检测与疾病相关的罕见和低频变异体的基因。在对通过 GWAS 发现的 10 个基因（IL10、IL23R、CCR1、STAT4、KLRK1、KLRC1、KLRC2、KLRC3、KLRC4 和 ERAP1）和 11 个因先天免疫作用而被选择的基因（IL1B、IL1R1、IL1RN、NLRP3、MEFV、TNFRSF1A、PSTPIP1、CASP1、PYCARD、NOD2 和 TLR4）的深外显子重测序鉴定的非同义变异（NSVs）进行研究的情况下，评估了它们与 Behçet 病（BD）的关联。与 2458 名对照相比，2461 例 BD 病例中基因的罕见和低频 NSVs 的差异分布表明它们与疾病的集体关联。通过严格的标准，需要至少一个具有研究范围显著性的单一负担测试和至少一个具有名义显著性的验证性测试，在一个被 GWAS 识别的基因（IL23R，P=6.9×10（-5））和一个参与先天免疫的基因（TLR4，P=8.0×10（-4））中，罕见和低频 NSVs 与 BD 相关。此外，在应用的所有三种负担测试中，破坏性或罕见的破坏性 NOD2 变体均具有名义显著性（P=0.0063-0.045）。此外，在土耳其人群中，已知导致常染色体隐性遗传家族性地中海热的家族性地中海热基因（MEFV）突变 Met694Val 的携带，赋予了 BD 风险（OR，2.65；P=1.8×10（-12））。在 MEFV 和 TLR4 中与疾病相关的 NSVs 提示先天免疫和细菌感应机制在 BD 发病机制中起作用。
