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Premature ovarian failure (POF) has an autoimmune pathogenesis in a significant proportion of cases. Autoantibodies to the steroid cell enzyme, 3beta-hydroxysteroid dehydrogenase (3betaHSD) are present in one fifth of patients and may identify an autoimmune subgroup. As autoimmune diseases are associated with alleles of the human leukocyte antigen (HLA) genes, we examined the distribution of HLA-DRB1 and -DQB1 genotypes in 118 women with POF, of whom 21% had 3betaHSD autoantibodies, and 134 racially matched control subjects. Two HLA-DQB1 alleles, 0301 and 0603, were associated with 3betaHSD autoantibody positivity (P = 0.04 and P = 0.006, respectively). As the DQB1*0301 and -0603 genes share an identical codon at position 57 (aspartate, Asp), we analyzed the frequency of DQbeta-Asp57 encoding DQB1 genes in our series. Eighteen of 21 POF patients with 3betaHSD autoantibodies had DQbeta-Asp57-encoding genotypes (haplotype frequency, 27 of 42; 64%) compared with 92 of 134 control subjects (haplotype frequency, 109 of 268; 41%; P = 0.004), and 9 of 21 (43%) cases were homozygous for codon 57 genotypes compared with 17 of 134 (13%) control subjects (P = 0.0006). These probability values were not significant after correction for multiple testing, and these trends will therefore require confirmation in larger cohorts. HLA class II molecules present antigenic peptides to CD4+ T lymphocytes. DQbeta57 occupies a key site at the boundary of the peptide binding groove, with a major impact on peptide binding. Our preliminary demonstration of an association between POF, 3betaHSD autoimmunity, and a distinctive HLA-DQ molecule supports the hypothesis that autoantibodies to this steroid cell enzyme may be markers of autoimmune ovarian failure and suggests that presentation of autoantigenic or external peptides to T lymphocytes by HLA-DQ molecules with Asp57-beta-chains is important in the pathogenesis of this disease.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Human Leukocyte Antigen-<i>DQB1*</i>Genotypes Encoding Aspartate at Position 57 Are Associated with 3β-Hydroxysteroid Dehydrogenase Autoimmunity in Premature Ovarian Failure

Human Leukocyte Antigen-DQB1*Genotypes Encoding Aspartate at Position 57 Are Associated with 3β-Hydroxysteroid Dehydrogenase Autoimmunity in Premature Ovarian Failure