Human Genetics Group, The University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Ann Rheum Dis. 2011 Oct;70(10):1793-7. doi: 10.1136/ard.2010.144576. Epub 2011 Jul 21.
The genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations.
To investigate these associations in the Han Chinese population.
Haplotypes from the HapMap database Chinese population were used to select tag-single-nucleotide polymorphisms (SNPs) (r(2)=0.8) across 19 distinct RA genomic regions. A two phase case-control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving p<0.2 in the first phase being genotyped in phase II (n=464 cases, n=822 controls). Association statistics were calculated using permutation tests both unadjusted and adjusted for the number of markers studied.
Robust association was detected for MMEL1 and CTLA4, and modest association was identified for another six loci: PADI4, STAT4, PRDM1, CDK6, TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6 × 10(-5) unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4, significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3 × 10(-5) unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed.
This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis.
全基因组关联研究在白种欧洲人群中已极大地推动了对类风湿关节炎（RA）易感基因和遗传位点的鉴定。然而，很少有研究尝试解析其他种族人群中的疾病发病机制。
在中国汉族人群中调查这些关联。
使用 HapMap 数据库中的汉族人群单体型选择标签单核苷酸多态性（SNP）（r²=0.8），跨越 19 个不同的 RA 基因组区域。进行了两阶段病例对照关联研究，在第一阶段（n=571 例，n=880 例对照）中对 169 个 SNP 进行了基因分型，在第一阶段达到 p<0.2 的 64 个 SNP 在第二阶段（n=464 例，n=822 例对照）中进行了基因分型。使用置换检验计算了未调整和调整所研究标记数量的关联统计数据。
在 MMEL1 和 CTLA4 中检测到了稳健的关联，在另外六个位点中检测到了适度的关联：PADI4、STAT4、PRDM1、CDK6、TRAF1-C5 和 KIF5A-PIP4K2C。在 MMEL1 中对三个标记物进行基因分型，均显示出关联，其中 rs3890745 的信号最强（p=2.6×10⁻⁵未调整，p=0.003 调整，OR=0.79）。对于 CTLA4，在显示关联的五个变体中有三个显示出关联，其中标记物 rs12992492 的关联最强（p=4.3×10⁻⁵未调整，p=0.0021 调整，OR=0.77）。在汉族人群中，PTPN22 中的常见变体与 RA 缺乏关联得到了证实。
本研究鉴定出 MMEL1 和 CTLA4 为 RA 易感基因，在汉族人群中提供了进一步六个位点的关联证据，并证实了 PTPN22 在亚洲人群中缺乏关联。它还证实了多民族人群研究有助于解析疾病发病机制的价值。
