Fine Mapping and Functional Studies of Risk Variants for Type 1 Diabetes at Chromosome 16p13.13

Abstract

Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, identifying 93 novel variants. A panel of 939 SNPs that included 46 of these novel variants was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 × 10−5) with disease, with rs34306440 being most significantly associated (P = 5.74 × 10−6). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to the risk for type 1 diabetes is through reduced expression of DEXI.

Dexidisruption depletes gut microbial metabolites and accelerates autoimmune diabetes

“…We have also demonstrated that increased T1D risk mediated through 16p13.13 is associated with decreased DEXI expression, implying that wild-type or normal DEXI function has a protective function in autoimmune disease (25). Our eQTL result has since been replicated by other groups (24,26), but in the absence of a Dexi knockout mouse model, definitive studies to extend evidence in support of DEXI's preventive role in T1D have not been possible. Furthermore, there are so far no known rare variants of DEXI in humans with informative phenotypes.…”

“…Within the complex 16p13.13 region, most studies have focussed upon the function of CLEC16A itself because the most associated SNPs are located in intron 19 of the gene (18)(19)(20)(21)(22)(23)(24). However, we have identified DEXI as a causal candidate gene in the 16p13.13 region our previous work, using expression quantitative trait locus (eQTL) mapping and chromosome confirmation capture (3C) in human monocytes.…”

Progress in Understanding Type 1 Diabetes Through Its Genetic Overlap with Other Autoimmune Diseases

“…Recent work has focused on pathway analysis as well as functional studies of the variants identified [35, 11••, 36, 10, 37, 38•]. Most of the variants identified to date are non-coding SNPs.…”

“…It is important to note, in the context of complex and not-entirely understood regulation of gene expression, that the genes implicated are not necessarily the most proximal gene to each SNP In addition to GWAS, several techniques have been used implicate specific genes; e.g., survey of expression quantitative trait loci or interrogation of chromatin state. Within immune-related genes, the function of the variants is mostly still not entirely understood, but the genes implicated can be broadly divided into (a) genes involved in innate immunity (e.g., IFIH1 and CLEC16A ), (b) genes altering the strength of receptor signaling (e.g., PTPN22, PTPN2 and SH2B3 ), (c) genes altering the balance between immunity and tolerance, often via alteration of IL-2 signaling (e.g., IL-2, IL2RA , and PTPN2 ) and (d) other genes [10, 39, 29, 40–42]. …”

“…T1DM remains an active focus of research, but clinical progress aside from the development of new insulins (with longer or shorter half-lives) has been scant. Recent work has focused on three areas: (1) the construction of an artificial external pancreas [2, 3], (2) the use of stem cells to generate a new pancreas and/or pancreas transplant [4–8] and (3) genomic dissection of the genetic determinants of T1DM [9, 10, 11••, 12]. This first area is beginning to yield its first fruit, with recent publications on the use of an artificial pancreas showing improved HbA1c without increased hypoglycemia.…”