Association of HLA alleles and haplotypes with CYP21A2 gene p. V282L mutation in the Croatian population.

ABSTRACT

The CYP21A2 mutations that are in linkage disequilibrium with particular HLA-A, -B, -DRB1 alleles/haplotypes, cause deficiency of the 21-hydroxylase enzyme (21-OHD) and account for the majority of congenital adrenal hyperplasia (CAH) cases. The aim of this study was to investigate those associations with the p.V282L mutation linked to the non-classical (NC) form of CAH among Croatians. The study included parents of patients with the NC form of CAH, positive for the p.V282L mutation (N = 55) and cadaveric donor samples (N = 231). All subjects were HLA-A, -B, and -DRB1 typed and tested for the presence of the p.V282L mutation. Among parents of patients, 92.73% of subjects were positive for the B*1402 allele and almost half of them carried the HLA-A*3301-B*1402-DRB1*0102 haplotype. Among cadaveric samples 77 out of 96 subjects positive for the B*1402 allele had the p.V282L mutation. Among them, 37 were positive for the HLA-A*3301-B*1402-DRB1*0102 haplotype, 23 had the HLA-A*3301-B*1402-DRB1*0301 haplotype, 8 had the B*1402-DRB1*0102 combination and 5 were carrying the HLA-A*6802-B*1402-DRB1*1303 haplotype. Only 4 of these subjects were positive for the B*1402 allele. HLA-B*1402 was the only single allele with association that reached statistically significant P value (RR = 12.00; P = 0.0024). Haplotypes B*1402-DRB1*0102 (P < 0.001) and HLA-A*6802-B*1402-DRB1*1303 (P < 0.001) as well as HLA-A*3301-B*1402-DRB1*0102 and HLA-A*3301-B*1402-DRB1*0301 showed high relative risks (RR = 45.00, RR = 41.63 and RR = 36.96, respectively). Our data support the previously documented association of the HLA-A*3301-B*1402-DRB1*0102 haplotype with the p.V282L mutation, but also point out a high frequency of the p.V282L mutation among Croatians with HLA-A*3301-B*1402-DRB1*0301 and HLA-A*6802-B*1402-DRB1*1303 haplotypes.