Abstract
The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10−10): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).
Highlights
The presence of circulating antibodies to the body’s own antigens, namely autoantibodies, is the major hallmark of autoimmunity, which can progress to the diagnosis of a variety of autoimmune diseases
Variants in the FCRL3 gene have been previously associated with autoimmune diseases, but such associations have not been reported for ABO blood group genotypes
Outside of the human leukocyte antigen (HLA) region, we discovered the association of several genes with autoantibody positivity, including evidence for association of the ABO blood gene with autoimmunity and surprisingly, a strong association of the known autoimmunity gene, FCRL3, with IA-2A, but not with type 1 diabetes (T1D)
Summary
The presence of circulating antibodies to the body’s own antigens, namely autoantibodies, is the major hallmark of autoimmunity, which can progress to the diagnosis of a variety of autoimmune diseases. The dynamics of T1D-associated autoantibodies in T1D patients are complex. They are detected prior to clinical diagnosis and often persist several years after diagnosis [1], but they can disappear prior to T1D diagnosis [2], and, in general, decline from the time of diagnosis onwards. It is generally accepted that anti-islet antibodies are not pathogenic themselves [5], in contrast, for example, to autoantibodies in systemic erythematosus lupus (SLE) [6]. The report of a T1D patient with a severe hereditary B cell deficiency [7], and the fact that in animal models of T1D the disease is transferable to healthy recipients by T cells but not by serum [8], are consistent with this view
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