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*14:02 allele and almost half of them carried the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype. Among cadaveric samples 77 out of 96 subjects positive for the B*14:02 allele had the p.V282L mutation. Among them, 37 were positive for the HLA-A*33:01-B*14:02-DRB1*01:02 haplotype, 23 had the HLA-A*33:01-B*14:02-DRB1*03:01 haplotype, 8 had the B*14:02-DRB1*01:02 combination and 5 were carrying the HLA-A*68:02-B*14:02-DRB1*13:03 haplotype. Only 4 of these subjects were positive for the B*14:02 allele. HLA-B*14:02 was the only single allele with association that reached statistically significant P value (RR = 12.00; P = 0.0024). Haplotypes B*14:02-DRB1*01:02 (P < 0.001) and HLA-A*68:02-B*14:02-DRB1*13:03 (P < 0.001) as well as HLA-A*33:01-B*14:02-DRB1*01:02 and HLA-A*33:01-B*14:02-DRB1*03:01 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*33:01-B*14:02-DRB1*01:02 haplotype with the p.V282L mutation, but also point out a high frequency of the p.V282L mutation among Croatians with HLA-A*33:01-B*14:02-DRB1*03:01 and HLA-A*68:02-B*14:02-DRB1*13:03 haplotypes.

Study of Human Leukocyte Antigen (HLA) in 13 cases of familial frontal fibrosing alopecia: CYP21A2 gene p.V281L mutation from congenital adrenal hyperplasia linked to HLA class I haplotype HLA‐A*33:01; B*14:02; C*08:02 as a genetic marker

“…The linkage between AH 65.1 and CYP21A2 gene p.V281L, observed in F1 and F2, is included in the conserved extended MHC haplotypes 65.1 described by Dorak and colleagues together with other 36 conserved extended MHC haplotypes. This linkage has been noted in Mediterraneans . In F4‐P1, F16A HLA class I haplotype is linked to CYP21A2 gene p.V281L mutation and also HLA class II haplotype DRB1*03:01‐DQB1*02:01 , which is a MHC extended haplotype recently described for the first time in Croatians .…”

“…This linkage has been noted in Mediterraneans . In F4‐P1, F16A HLA class I haplotype is linked to CYP21A2 gene p.V281L mutation and also HLA class II haplotype DRB1*03:01‐DQB1*02:01 , which is a MHC extended haplotype recently described for the first time in Croatians . No previous data have been found about the linkage of F16A, V281L mutation and HLA‐DRB1*04:02‐DQB1*03:02, which is present in F3.…”

Revisiting the association of HLA alleles and haplotypes with CYP21A2 mutations in a large cohort of patients with congenital adrenal hyperplasia

“…Historically, the HLA-B*14 allele was found to be in genetic linkage disequilibrium with nonclassic CAH in a population of Ashkenazi Jews, Hispanics, and Italians (Speiser et al, 1985). Later studies confirmed an association between p.V281L, and the HLA-B*14 allele in Ashkenazi Jews, non-Ashkenazi Jews, Croatians, and Turks (Yarman et al, 2004; Israel et al, 2006; Grubic et al, 2016). In accordance with these findings, we found an association between p.V281L and the extended haplotype HLA-B*14-C*08 in our ethnically diverse population of CAH patients.…”

“…Following the discovery of the CYP21A2 gene on chromosome 6p21.3 within the HLA complex in 1985, some studies have found associations between specific CYP21A2 mutations and HLA types. The strongest finding to date has been the association between the commonly found p.V281L nonclassic CAH mutation and HLA-B*14 (Speiser et al, 1985; Israel et al, 2006; Grubic et al, 2016).…”

“…The most commonly reported HLA association amongst CAH patients has been the association between the nonclassic CAH mutation, p.V281L, and HLA-B14 in Ashkenazi Jewish, Hispanic, Italian, and Croatian subjects. (Pollack et al, 1981; Speiser et al, 1985; Israel et al, 2006; Grubic et al, 2016).…”