Abstract
BackgroundT1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247.MethodsDNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations.ResultsOur study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247.ConclusionsSeveral risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosomal region in which a novel T1D/AITD susceptibility gene, CD247, is located. The association study showed association between T1D/AITD and several variants in this gene. These results suggests that common susceptibility genes act in concert with variants of CD247 to generate genetic risk for T1D/AITD in this population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0333-z) contains supplementary material, which is available to authorized users.
Highlights
Type 1 diabetes mellitus (T1D) and autoimmune thyroid disease (AITD) are autoimmune disorders commonly occurring in the same family and even in the same individual
We report linkage to T1D/AITD for three chromosomal region and we replicate the previously reported association for T1D/AITD with single nucleotide polymorphisms (SNPs) in PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30 [21, 23, 24, 33, 34]
SNPs chosen for the association study were selected based on the results from our genome-wide linkage scans (GWLS) in combination with SNPs associated to T1D/AITD in previously published Genome-wide association (GWA) studies [19,20,21,22,23]
Summary
T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. Genome-wide association (GWA) studies have revealed several risk factor genes/loci for T1D, AITD and a number of other diseases [19,20,21,22,23,24,25]. These studies have found convincing evidence of associations of several loci with T1D: HLA class II genes on chromosome 6p21, INS on 11p15, CTLA4 on 2q33, PTPN22 on 1p13, the IL2Rα region on 10p15 and the IFIH1 region on 2q24. Several of the identified risk genes are immunoregulatory in nature, and many of these genes and/or associated biological pathways have been observed to overlap with findings from animal models of T1D, notably the nonobese diabetic (NOD) mouse model
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