Meyer J M, Han J, Moxley G
McGuire Veterans Administration Medical Center and Medical College of Virginia of Virginia Commonwealth University, Richmond 23249, USA.
Arthritis Rheum. 2001 Feb;44(2):286-95. doi: 10.1002/1529-0131(200102)44:2<286::AID-ANR45>3.0.CO;2-4.
The observation that not all shared-epitope genotypes confer the same risk suggests that a second HLA-region locus may confer risk. Tumor necrosis factor alpha (TNFgamma) is a possible candidate. We examined TNFalpha for sex influences on HLA-associated risk for rheumatoid arthritis (RA).
DRB1 and TNF microsatellite typing of 297 Caucasian RA patients (132 men, 165 women) and 267 Caucasian controls was performed.
The TNFab microsatellite haplotype distribution differed among the male RA, female RA, and control groups (P < 0.01); the difference was largely an excess of TNFa2b1 haplotypes in the male RA group. However, this did not simply reflect an excess of shared-epitope haplotypes bearing TNFa2b1. In RA, not all shared-epitope-bearing haplotypes had the same TNFab. The *0401-bearing haplotypes commonly had TNFa6b5, TNFa2b1, TNFa10b4, and TNFa11b4, while the *0404-bearing haplotypes had TNFa11b4. In the female RA group, TNFa2b1 was most often on 0401-bearing haplotypes. In the male RA group, there was a surprise: TNFa2b1 was often on HLA haplotypes without shared-epitope DRB1 alleles. To estimate the relative strength of associated HLA markers, we performed logistic regression analyses stratified by sex and controlling for a potential confounder, age at disease onset. Among women, TNFa2b3 favored RA (odds ratio 1.932, P < 0.05) while TNFa6b5 was protective (odds ratio 0.522, P < 0.05). Among males, TNFa2b1 and TNFa11b4 conferred elevated odds ratios (2.58 and 1.681, respectively, P < 0.05). However, the odds ratios for TNFa2b1 in men and TNFa2b3 in women were generally well below those for RA-associated DRB1 markers (for example, DRB10401 3.553 in male RA patients and 6.991 in female RA patients).
Certain TNFab-bearing HLA haplotypes modify RA risk in a manner influenced by sex but independent of DRB1, particularly TNFa2b1 in men.
并非所有共享表位基因型都具有相同风险这一观察结果表明，第二个HLA区域基因座可能会带来风险。肿瘤坏死因子α（TNFγ）是一个可能的候选基因。我们研究了TNFα在HLA相关的类风湿关节炎（RA）风险中是否存在性别影响。
对297例白种人RA患者（132例男性，165例女性）和267例白种人对照进行了DRB1和TNF微卫星分型。
TNFab微卫星单倍型分布在男性RA组、女性RA组和对照组之间存在差异（P < 0.01）；差异主要表现为男性RA组中TNFa2b1单倍型过多。然而，这并非简单地反映了携带TNFa2b1的共享表位单倍型过多。在RA中，并非所有携带共享表位的单倍型都具有相同的TNFab。携带0401的单倍型通常具有TNFa6b5、TNFa2b1、TNFa10b4和TNFa11b4，而携带0404的单倍型具有TNFa11b4。在女性RA组中，TNFa2b1最常出现在携带0401的单倍型上。在男性RA组中，有一个意外发现：TNFa2b1经常出现在没有共享表位DRB1等位基因的HLA单倍型上。为了估计相关HLA标记的相对强度，我们进行了按性别分层并控制潜在混杂因素（发病年龄）的逻辑回归分析。在女性中，TNFa2b3有利于RA（优势比1.932，P < 0.05），而TNFa6b5具有保护作用（优势比0.5俯2，P < 0.05）。在男性中，TNFa2b1和TNFa11b4的优势比升高（分别为2.58和1.681，P < 0.05）。然而，男性中TNFa2b1和女性中TNFa2b3的优势比通常远低于与RA相关的DRB1标记（例如，男性RA患者中DRB10401为3.553，女性RA患者中为6.991）。
某些携带TNFab的HLA单倍型以受性别影响但独立于DRB1的方式改变RA风险，尤其是男性中的TNFa2b1。
