van Gerven N M F, de Boer Y S, Zwiers A, Verwer B J, Drenth J P H, van Hoek B, van Erpecum K J, Beuers U, van Buuren H R, den Ouden J W, Verdonk R C, Koek G H, Brouwer J T, Guichelaar M M J, Vrolijk J M, Coenraad M J, Kraal G, Mulder C J J, van Nieuwkerk C M J, Bloemena E, Verspaget H W, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
1] Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Genes Immun. 2015 Jun;16(4):247-52. doi: 10.1038/gene.2014.82. Epub 2015 Jan 22.
The classical human leukocyte antigen (HLA)-DRB103:01 and HLA-DRB104:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB103:01/HLA-DRB104:01 positive. HLA-DRB103:01/HLA-DRB104:01-positive patients had a higher median IAIHG score than HLA-DRB103:01/HLA-DRB104:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB103:01: P=0.2; HLA-DRB104:01; P=0.5); however, HLA-DRB103:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB104:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB103:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB103:01 and HLA-DRB104:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB103:01 is the strongest genetic modifier of disease severity in AIH.
经典的人类白细胞抗原（HLA）-DRB103:01和HLA-DRB104:01等位基因是已确定的自身免疫性肝炎（AIH）风险等位基因。为研究这些等位基因的免疫调节作用，我们从649例荷兰1型AIH患者的全基因组关联数据中推算出基因型。因此，我们比较了这些HLA等位基因阳性和阴性患者的国际自身免疫性肝炎小组（IAIHG）诊断评分以及潜在的临床特征。75%的AIH患者HLA-DRB103:01/HLA-DRB104:01呈阳性。HLA-DRB103:01/HLA-DRB104:01阳性患者的IAIHG评分中位数高于HLA-DRB103:01/HLA-DRB104:01阴性患者（P<0.001）。我们未观察到HLA等位基因与丙氨酸转氨酶水平之间存在关联（HLA-DRB103:01：P=0.2；HLA-DRB104:01；P=0.5）；然而，HLA-DRB103:01与较高的免疫球蛋白G水平独立相关（P=0.04）。HLA-DRB104:01等位基因与老年发病（P=0.03）和女性占优势独立相关（P=0.04）。HLA-DRB103:01阳性患者接受了免疫抑制药物治疗和肝移植。总之，HLA-DRB103:01和HLA-DRB104:01等位基因均与1型AIH患者的综合诊断IAIHG评分独立相关，但对AIH的发生并非必不可少。HLA-DRB103:01是AIH疾病严重程度最强的遗传修饰因子。
