Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
Department of Pediatrics, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
HLA. 2016 Nov;88(5):239-244. doi: 10.1111/tan.12907. Epub 2016 Oct 5.
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 B14:02 allele and almost half of them carried the HLA-A33:01-B14:02-DRB101:02 haplotype. Among cadaveric samples 77 out of 96 subjects positive for the B14:02 allele had the p.V282L mutation. Among them, 37 were positive for the HLA-A33:01-B14:02-DRB101:02 haplotype, 23 had the HLA-A33:01-B14:02-DRB103:01 haplotype, 8 had the B14:02-DRB101:02 combination and 5 were carrying the HLA-A68:02-B14:02-DRB113:03 haplotype. Only 4 of these subjects were positive for the B14:02 allele. HLA-B14:02 was the only single allele with association that reached statistically significant P value (RR = 12.00; P = 0.0024). Haplotypes B14:02-DRB101:02 (P < 0.001) and HLA-A68:02-B14:02-DRB113:03 (P < 0.001) as well as HLA-A33:01-B14:02-DRB101:02 and HLA-A33:01-B14:02-DRB103:01 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-A33:01-B14:02-DRB101:02 haplotype with the p.V282L mutation, but also point out a high frequency of the p.V282L mutation among Croatians with HLA-A33:01-B14:02-DRB103:01 and HLA-A68:02-B14:02-DRB113:03 haplotypes.
CYP21A2 基因突变与特定的 HLA-A、-B、-DRB1 等位基因/单倍型呈连锁不平衡，导致 21-羟化酶（21-OHD）缺乏，这占先天性肾上腺皮质增生（CAH）病例的大多数。本研究旨在调查与克罗地亚人中非经典（NC）形式的 CAH 相关的 p.V282L 突变与那些关联。该研究包括 NC 形式 CAH 患者的父母（p.V282L 突变阳性，N = 55）和尸体供体样本（N = 231）。所有受试者均进行 HLA-A、-B 和-DRB1 分型，并检测 p.V282L 突变的存在。在患者父母中，92.73%的受试者为 B14:02 等位基因阳性，其中近一半携带 HLA-A33:01-B14:02-DRB101:02 单倍型。在尸体样本中，96 名 B14:02 等位基因阳性者中有 77 名携带 p.V282L 突变。其中，37 名携带 HLA-A33:01-B14:02-DRB101:02 单倍型，23 名携带 HLA-A33:01-B14:02-DRB103:01 单倍型，8 名携带 B14:02-DRB101:02 组合，5 名携带 HLA-A68:02-B14:02-DRB113:03 单倍型。这些受试者中只有 4 名携带 B14:02 等位基因。HLA-B14:02 是唯一与统计学意义上显著的 P 值相关的单一等位基因（RR = 12.00；P = 0.0024）。单倍型 B14:02-DRB101:02（P < 0.001）和 HLA-A68:02-B14:02-DRB113:03（P < 0.001）以及 HLA-A33:01-B14:02-DRB101:02 和 HLA-A33:01-B14:02-DRB103:01 显示出高相对风险（RR = 45.00、RR = 41.63 和 RR = 36.96）。我们的数据支持先前记录的 HLA-A33:01-B14:02-DRB101:02 单倍型与 p.V282L 突变的关联，但也指出在携带 HLA-A33:01-B14:02-DRB103:01 和 HLA-A68:02-B14:02-DRB113:03 单倍型的克罗地亚人中，p.V282L 突变的发生率很高。
