A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

Abstract

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.

Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus

“…2,6,8,11 The most significantly associated SNP, rs12923849 has previously showed some degree of association with T1D. 1 The other three top hits in our screening phase; rs9934231, rs6498168 and rs7206912 have not previously been reported to be associated in MS or other autoimmune diseases. Because of failure of genotyping rs6498168 in the replication phase, it was replaced by a SNP in complete LD (r 2 ¼ 1), rs8060411, and this SNP was for completeness, also tested in the screening panel.…”

“…Thus, they cluster in some proximity to regions where differences are seen in the transcripts. Hakonarson et al 1 have previously studied CLEC16A expression in NK cells in view of the T1D-associated SNP rs2903692 and found that homozygotes for the A allele showed a trend towards increased CLEC16A mRNA expression (KIAA0350/CLEC16A Affymetrix probe set 231221 (Affymetrix, Santa Clara, CA, USA) ). Interestingly, this SNP rs2903692 is in strong LD (r 2 ¼ 0.88) with rs12708716.…”

“…[1][2][3] Multiple replication and candidate gene studies have verified this region as being disease associated in T1D and MS, and association with CLEC16A has also been found in anti-cyclic citrullinated peptide (CCP) negative rheumatoid arthritis, juvenile idiopathic arthritis, Addison's disease and NOD2-negative Crohn's disease. [4][5][6][7][8][9] The association of CLEC16A SNPs across multiple immune-mediated diseases and the observation that the gene is almost uniquely expressed on immune cells, make a common effect on autoimmunity likely.…”

“…2 This SNP association has been replicated and confirmed at genomewide significance level in MS (Po5 Â 10 À7 ). 6,11 In T1D, the strongest association so far has been found for four SNPs situated in intron 19 and 22; rs12708716, 9 rs725613, rs2903692 and rs17673553, 1 which are all in fairly strong linkage disequilibrium (LD) (r 2 ¼ 0.66-1.00; haploview v 4.1, hapmap release 21, CEU sample set (Utah residents with Northern and Western European ancestry from the Centre de'Etude du Polymorphism Human (CEPH) collection). 12,13 The LD between the MSassociated rs6498169 and the T1D SNPs is modest (r 2 ¼ 0.18-0.26), 12,13 and association with rs6498169 has not been found in T1D.…”

The association between type 1 diabetes and the ITPR3 gene polymorphism due to linkage disequilibrium with HLA class II

“…The genotypes in the parents were in Hardy-Weinberg equilibrium with P ¼ 0.410. The remaining SNPs in the panel were chosen to follow-up the first stage of a genome-wide association study 4 . The transmission disequilibrium test (TDT) and the conditional logistic regression analysis were done using the TDTPHASE program in the UNPHASED software (http://www.hgmp.mrc.ac.uk/Bfdudbrid/ software/unphased/).…”