Tumor necrosis factor markers show sex-influenced association with rheumatoid arthritis

OBJECTIVE: 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). METHODS: DRB1 and TNF microsatellite typing of 297 Caucasian RA patients (132 men, 165 women) and 267 Caucasian controls was performed. RESULTS: 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, DRB1*0401 3.553 in male RA patients and 6.991 in female RA patients). CONCLUSION: Certain TNFab-bearing HLA haplotypes modify RA risk in a manner influenced by sex but independent of DRB1, particularly TNFa2b1 in men.