Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
PLoS Genet. 2018 Dec 3;14(12):e1007833. doi: 10.1371/journal.pgen.1007833. eCollection 2018 Dec.
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.
原发性胆汁性胆管炎（PBC）是一种慢性自身免疫性肝病，其特征是肝内胆管进行性破坏。最强的遗传相关性与 HLA-DQA1*04:01 相关，但至少有三个额外的独立 HLA 单倍型与易感性相关。我们使用 2861 例 PBC 病例和 8514 例对照的密集单核苷酸多态性 (SNP) 数据，使用最先进的方法学来推断经典 HLA 等位基因和氨基酸多态性。然后，我们通过逐步回归证明，HLA 区域的关联可以很大程度上用五个独立的氨基酸位置的变异来解释。对涉及的 HLA 等位基因/氨基酸取代进行蛋白质结构的三维建模和静电势计算表明，HLA-DP 分子中口袋 P6 的静电势与赋予 PBC 易感性/保护的 HLA-DPB1 等位基因/氨基酸取代之间存在相关性，突出了未来功能研究的潜在新途径。
