Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis.
Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis.
复制标题
DOI：
10.1002/art.39228
复制
发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Karlson EW
中科院分区：
文献类型：
--
作者：
Kim K;Jiang X;Cui J;Lu B;Costenbader KH;Sparks JA;Bang SY;Lee HS;Okada Y;Raychaudhuri S;Alfredsson L;Bae SC;Klareskog L;Karlson EW
本研究的目的是完善吸烟和人类白细胞抗原（HLA）多态性之间的相互作用，在血清阳性类风湿关节炎（RA），在最近的氨基酸为基础的RA易感性的HLA模型的背景下。我们从3，588名瑞典风湿性关节炎流行病学调查（EIRA;病例/对照=1654/1934）、589名护士健康研究（NHS; 229/360）和2，125名韩国（1390/735）受试者的病例对照免疫芯片阵列数据中估算HLA氨基酸和经典等位基因。我们使用加性相互作用模型研究了重度吸烟（>10包-年）与RA相关氨基酸位点（HLA-DRβ1中的11、13、71和74; HLA-B中的9; HLA-DPβ1中的9）和HLA-DRβ1四种氨基酸单倍型的遗传风险评分（GRS）之间的相互作用效应，其中归因于相互作用的比例（AP）。重度吸烟和所有调查的HLA氨基酸位置和单倍型与RA易感性在所有三个人群。在交互作用分析中，我们发现在所有三项研究中，重度吸烟与HLA-DRβ1氨基酸单倍型之间的预期加性联合效应均存在显著偏离（0.416≤AP≤0.796）。我们进一步确定了关键的相互作用变体位于HLA-DRβ1的氨基酸位置11和13，而不是所有人群中的其他RA风险氨基酸位置。在第11和13位，有类似的模式之间的RA风险效应和残基的相互作用效应。我们的研究结果表明，吸烟产生的瓜氨酸化自身抗原与HLA-DR分子之间的物理相互作用以HLA-DRβ1四氨基酸单倍型为特征，主要是位置11和13。
This study aimed to refine the interaction between cigarette smoking and human leukocyte antigen (HLA) polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recent amino-acid based HLA model for RA susceptibility. We imputed HLA amino acids and classical alleles from case-control Immunochip array data of 3,588 Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA; case/control=1654/1934), 589 Nurses’ Health Study (NHS; 229/360) and 2,125 Korean (1390/735) subjects. We examined interaction effects between heavy smoking (>10 pack-years) and genetic risk score (GRS) from RA-associated amino-acid positions (11, 13, 71 and 74 in HLA-DRβ1; 9 in HLA-B; and 9 in HLA-DPβ1) and from HLA-DRβ1 four-amino-acid haplotypes with an attributable proportion due to interaction (AP) using the additive interaction model. Heavy smoking and all investigated HLA amino-acid positions and haplotypes were associated with RA susceptibility in all three populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA-DRβ1 amino-acid haplotype in all three studies (0.416≤AP≤0.796). We further identified the key interacting variants as being located at amino-acid positions 11 and 13 of HLA-DRβ1 but not the other RA-risk amino-acid positions in all populations. At the positions 11 and 13, there were similar patterns between RA-risk effects and interaction effects of residues. Our findings of significant gene-environment interaction effects implicate that a physical interaction between citrullinated auto-antigens produced by smoking and HLA-DR molecules is characterized by the HLA-DRβ1 four-amino-acid haplotype, primarily by the positions 11 and 13.