title: 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.
authors.affiliation: Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia. zgrubic@kbc-zagreb.hr.
authors.forename: Z
authors.initials: Z
authors.lastname: Grubic
authors.affiliation: Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Maskalan
authors.affiliation: Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: K
authors.initials: K
authors.lastname: Stingl Jankovic
authors.affiliation: Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: S
authors.initials: S
authors.lastname: Zvecic
authors.affiliation: Department of Pediatrics, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: K
authors.initials: K
authors.lastname: Dumic Kubat
authors.affiliation: Department of Pediatrics, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: N
authors.initials: N
authors.lastname: Krnic
authors.affiliation: Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: R
authors.initials: R
authors.lastname: Zunec
authors.affiliation: Department of Pediatrics, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: J
authors.initials: J
authors.lastname: Ille
authors.affiliation: Department of Laboratory Diagnosis, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: V
authors.initials: V
authors.lastname: Kusec
authors.affiliation: Department of Pediatrics, School of Medicine, Zagreb, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Dumic
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D017523:Croatia / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000276:immunology
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase
keywords: alleles and haplotypes; congenital adrenal hyperplasia; human leukocyte antigen; p.V282L mutation