Meyer J M, Evans T I, Small R E, Redford T W, Han J, Singh R, Moxley G
Millenium Pharmaceuticals, Cambridge, MA, USA.
J Rheumatol. 1999 May;26(5):1024-34.
To examine how HLA-DRB1 genotypes influence rheumatoid arthritis (RA) risk and clinical severity.
We performed polymerase chain reaction based DRB1 and tumor necrosis factor (TNF) genotyping of 309 Caucasian RA and 283 Caucasian control subjects. For risk analyses, we grouped the DRB1 alleles encoding each specific shared epitope: *0401 alone, *0404 with *0102, *0405 with *0408 and *0101, and *1001 alone. For estimates of RA outcome, we retrospectively obtained data regarding ARA classification criteria, age of disease onset and disease duration, number of slow acting antirheumatic drugs (SAARD) used, and rheumatoid factor (RF).
Homozygous shared-epitope DRB1 genotypes, compound heterozygous genotypes, and simple heterozygous genotypes all conferred elevated relative risk (RR) for RA (RR 4.3, 11.7, and 3.5, respectively). However, compound heterozygous genotypes conferred more risk than either simple heterozygous genotype (RR 3.3, p = 0.004) or homozygous genotype (RR 2.8, p = 0.036). There was a trend toward more compound heterozygous genotypes in the male RA group than in the female RA group (p < 0.1), and male sex was associated with higher frequency of rheumatoid nodules (56 vs 35% for female RA). RA outcome was estimated by number of SAARD used; mean SAARD used was higher in male than in female RA (p < 0.01) and higher in genotypes containing one or 2 shared epitope DRB1 alleles than in those negative for shared epitope DRB1 alleles (p < 0.05). Analyses also suggested that shared epitope DRB1 genotype significantly influenced the occurrence of seropositive RA. Seropositive RA fraction was related to either number of shared epitope alleles (0, 1, or 2) represented in the DRB1 genotype, or, alternatively, to the combination of sex with shared epitope DRB1 genotype. The presence of one or 2 shared epitope DRB alleles influenced the occurrence of high titer seropositive RA as defined by sheep cell agglutination test (p < 0.01). TNFab microsatellite markers and TNF promoter polymorphisms did not influence SAARD number, seropositive RA, or high titer seropositive RA.
Not all shared epitope DRB1 genotypes conferred the same relative risk, and the male RA group tended to have more compound heterozygous genotypes and more severe RA as indicated by rheumatoid nodules and SAARD usage. DRB1 genotypes with one or 2 shared epitope DRB1 alleles influenced the RA outcome as estimated by numbers of SAARD used and RF.
研究人类白细胞抗原-DRB1（HLA-DRB1）基因型如何影响类风湿关节炎（RA）的发病风险及临床严重程度。
我们对309名白种人RA患者和283名白种人对照者进行了基于聚合酶链反应的DRB1和肿瘤坏死因子（TNF）基因分型。为进行风险分析，我们将编码各特定共同表位的DRB1等位基因进行分组：单独的0401、0404与0102、0405与0408及0101、单独的*1001。为评估RA的病情转归，我们回顾性获取了关于美国风湿病学会（ARA）分类标准、发病年龄和病程、使用的慢作用抗风湿药（SAARD）数量以及类风湿因子（RF）的数据。
纯合共同表位DRB1基因型、复合杂合基因型和单纯杂合基因型均使RA的相对风险（RR）升高（RR分别为4.3、11.7和3.5）。然而，复合杂合基因型比单纯杂合基因型（RR 3.3，p = 0.004）或纯合基因型（RR 2.8，p = 0.036）带来的风险更高。男性RA组的复合杂合基因型数量有多于女性RA组的趋势（p < 0.1），且男性患类风湿结节的频率更高（女性RA组为35%，男性RA组为56%）。通过使用的SAARD数量评估RA病情转归；男性RA患者使用的平均SAARD数量高于女性RA患者（p < 0.01），且含有1个或2个共同表位DRB1等位基因的基因型高于共同表位DRB1等位基因为阴性的基因型（p < 0.05）。分析还表明，共同表位DRB1基因型显著影响血清阳性RA的发生。血清阳性RA比例与DRB1基因型中代表的共同表位等位基因数量（0、1或2）有关，或者与性别和共同表位DRB1基因型的组合有关。存在1个或2个共同表位DRB等位基因影响了由绵羊细胞凝集试验定义的高滴度血清阳性RA的发生（p < 0.01）。TNFα微卫星标记和TNF启动子多态性不影响SAARD数量、血清阳性RA或高滴度血清阳性RA。
并非所有共同表位DRB1基因型都具有相同的相对风险，男性RA组往往有更多的复合杂合基因型以及更严重的RA，如类风湿结节和SAARD使用情况所示。含有1个或2个共同表位DRB1等位基因的DRB1基因型通过使用的SAARD数量和RF评估影响RA病情转归。
