Rolim Inês, Duarte Nádia, Barata Gabriela, Costa João, Gardete-Correia Luís, Boavida José, Duarte Rui, Raposo João, Peerally Zulmira, Catarino Manuela, Penha-Gonçalves Carlos
Instituto Gulbenkian de Ciência, Apartado 14, P-2781-901, Oeiras, Portugal.
Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal.
Immunogenetics. 2017 Jul;69(7):429-437. doi: 10.1007/s00251-017-0999-1. Epub 2017 May 22.
Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain (IGH) locus are genetic determinants of AutoAbs against pancreatic antigens and contribute to T1D susceptibility. With this aim, two independent study designs were used: a case-control study and a family-based cohort comprising a total of 240 T1D patients, 172 first-degree relatives (mother and/or father), and 130 unrelated healthy controls living in Portugal. We found that three SNPs in the IGH locus show suggestive association with T1D with the highest nominal association at rs1950942 (in the IGHM-IGHJ gene region) in both the case-control study (P = 9.35E-03) and the family-based cohort (P = 3.08E-03). These SNPs were also associated with IgG AutoAbs against pancreatic antigens and with AutoAb multi-reactivity in T1D patients. Notably, we found that the SNP with the highest association with T1D susceptibility and IgG autoantibody reactivity (rs1950942) was also associated with anti-GAD IgM reactivity in T1D patients (P = 5.98E-03) and in non-affected parents (P = 4.17E-03). This finding implies that IGH association with autoreactive IgM is detectable irrespective of disease status.These results suggest that genetic variants at the IgM gene region of the IGH locus contribute to antibody autoreactivity and are associated with T1D. We propose that the control of autoantibody generation by IGH polymorphisms is a component of the complex architecture of T1D genetic susceptibility.
多项证据表明，1型糖尿病（T1D）患者中逐渐形成的自身免疫反应包括多反应性自身抗体（AutoAb）库的产生，但其在T1D发病机制中的作用仍不清楚。我们检验了以下假设：免疫球蛋白重链（IGH）基因座的变异是针对胰腺抗原的自身抗体的遗传决定因素，并导致T1D易感性。为此，我们采用了两种独立的研究设计：一项病例对照研究和一个基于家系的队列研究，该队列共纳入了240名T1D患者、172名一级亲属（母亲和/或父亲）以及130名居住在葡萄牙的无血缘关系的健康对照。我们发现，IGH基因座中的三个单核苷酸多态性（SNP）与T1D存在提示性关联，在病例对照研究（P = 9.35E-03）和基于家系的队列研究（P = 3.08E-03）中，rs1950942（位于IGHM-IGHJ基因区域）的名义关联最高。这些SNP还与T1D患者中针对胰腺抗原的IgG自身抗体以及自身抗体的多反应性相关。值得注意的是，我们发现与T1D易感性和IgG自身抗体反应性关联最高的SNP（rs1950942）也与T1D患者（P = 5.98E-03）和未患病父母（P = 4.17E-03）中的抗GAD IgM反应性相关。这一发现意味着，无论疾病状态如何，均可检测到IGH与自身反应性IgM的关联。这些结果表明，IGH基因座的IgM基因区域的遗传变异导致抗体自身反应性，并与T1D相关。我们提出，IGH多态性对自身抗体产生的控制是T1D遗传易感性复杂结构的一个组成部分。
