HLA-DR4 genotype frequency and gender effect in familial rheumatoid arthritis

We have studied HLA-A, B, C, and DR antigens in 75 unrelated white families, each with multiple cases of adult-onset definite or classical rheumatoid arthritis (RA) (by ARA criteria). There was no difference in age of onset or serological features of RA between males and females. HLA-DR4 phenotype frequency among female (68%) and male (71%) patients also did not differ significantly. The observed frequencies of HLA-DR4 genotypes (homozygous, heterozygous, and those lacking it) differed significantly (p less than 0.005) between affected and unaffected individuals. However, the observed genotype distribution did not differ from what is expected given the Hardy-Weinburg equilibrium. There is a direct correlation between the number of DR4 allele(s) carried (two, one, or zero) and the percent affected (p less than 0.026 for females and p less than 0.052 for males). These findings highlight the importance of discerning the additional genetic determinants, including those that are gender-associated, which influence susceptibility to RA.