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As a result of genome-wide association studies in larger sample sets, there has been an increase in identifying genes that influence susceptibility to individual immune-mediated diseases, as well as evidence that some genes are associated with more than one disease. In this study, we tested 17 single nucleotide polymorphisms (SNP) from 16 gene regions that have been reported in several autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ankylosing spondylitis (AS) and Crohn's disease (CD) to determine whether the variants are also associated with type 1 diabetes (T1D). In up to 8010 cases and 9733 controls we found some evidence for an association with T1D in the regions containing genes: 2q32/ STAT4, 17q21 /STAT3, 5p15 /ERAP1 (ARTS1) , 6q23/ TNFAIP3 and 12q13/ KIF5A/PIP4K2C with allelic P -values ranging from 3.70 × 10 −3 to 3.20 × 10 −5 . These findings extend our knowledge of susceptibility locus sharing across different autoimmune diseases, and provide convincing evidence that the RA/SLE locus 6q23/ TNFAIP3 is a newly identified T1D locus.

Aims/hypothesis Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. Methods The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. Results Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region ( p  = 1.13 × 10 −16 ). The association was confirmed in the family dataset ( p  ≤ 9.20 × 10 −4 ). rs9258750A>G was the most associated variant in the HLA region ( p  = 2.06 × 10 −9 and p  = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1 , HLA-DQB1 , HLA-A , HLA-B or HLA-C ( p  > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. Conclusions/interpretation ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.

Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser 307 association with T1D ( P =3.46 × 10 −9 ) and continued potential evidence for AITD ( P =0.0345), we provide evidence for association of Gly307Ser with MS ( P =4.20 × 10 −4 ) and rheumatoid arthritis (RA) ( P =0.017). The Ser 307 allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.

Aims/hypothesis We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. Methods The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. Results Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p combined = 1.0 x 10⁻⁴). No SNPs showed evidence of interaction with any covariate (p > 0.05). Conclusions/interpretation We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.

Aims/hypothesis Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. Methods We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent–child trios for analysis. We tested for association using the transmission disequilibrium test. Results Seventeen of the 18 susceptibility loci reached nominal levels of significance ( p  < 0.05) in the expanded family collection, with 14q24.1 just falling short ( p  = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance ( p  < 2.8 × 10 −3 ). All susceptibility loci had consistent direction of effects with the original study. Conclusions/interpretation The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.

In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes ( INS , PTPN22 , IL2RA , CTLA4 , IFIH1 , SUMO4 , VDR , PAX4 , OAS1 , IRS1 , IL4 , IL4R , IL13 , IL12B , CEACAM21 , CAPSL , Q7Z4c4(5Q) , FOXP3 , EFHB ) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortium's candidate gene study. The study had approximately 80% power at α =0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (−23 Hph I) was the most associated SNP ( P =3.8 × 10 −31 ), with the estimated RR=0.57 (95% confidence interval, 0.52–0.63). In addition, rs689 was associated with age-at-diagnosis of T1D ( P =0.001), with homozygosity for the T1D protective T allele, delaying the onset of T1D by approximately 2 years in these families. At PTPN22 , rs2476601 (R620W), in agreement with previous reports, was the most significantly associated SNP ( P =6.9 × 10 −17 ), with RR=1.55 (1.40–1.72). Evidence for association with T1D was observed for the IFIH1 SNP, rs1990760 ( P =7.0 × 10 −4 ), with RR=0.88 (0.82–0.95) and the CTLA4 SNP rs1427676 ( P =0.0005), with RR=1.14 (1.06–1.23). In contrast, no convincing evidence of association was obtained for SUMO4 , VDR , PAX4 , OAS1 , IRS1 , IL4 , IL4R , IL13 , IL12B , CEACAM21 or CAPSL gene regions ( http://www.T1DBase.org ).

Aims/hypothesis HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without. Materials and methods TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1. Results TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR] = 1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI = 1.29-1.72) than did the TPOAbs-negative patients (p = 0.0004; OR = 1.16; 95% CI = 1.10-1.24) or type 1 diabetes patients overall (OR = 1.20; 95% CI = 1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p = 1.86 x 10-¹⁵). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601). Conclusions/interpretation Our results identify a subgroup of type 1 diabetic patients that is sensitive to allelic variation of the negative regulatory molecule CTLA-4 and indicate that TPOAbs testing could be used to subclassify type 1 diabetes patients for inclusion in genetic, biological or clinical studies.

Longitudinal studies in Sudan show ethnic differences in incidence and clinical phenotypes associated with Leishmania donovani . Immunologically, bias in type 1 vs type 2 cytokine responses is important. To determine whether polymorphisms at IL4/IL9 or IFNGR1 contribute to susceptibility, we examined 59 multicase families of visceral leishmaniasis (VL) with/without post Kala-azar dermal leishmaniasis (PKDL). Multipoint nonparametric analysis (Allegro) linked IL4/IL9 to VL per se ( P =0.002). Transmission disequilibrium testing with robust variance estimates confirmed association in the presence of linkage between VL per se and IL4 ( P =0.008) but not IL9 . Stepwise logistic regression analysis showed both IL4RP2 and IL4RP1 markers contributed significantly to the association, suggesting a common disease-associated haplotype. In contrast, IFNGR1 was linked ( P =0.031) and associated ( P =0.007) to PKDL but not VL or VL per se . Hence, polymorphism in a type 2 cytokine gene influences underlying susceptibility to VL, whereas IFNGR1 is specifically related to susceptibility to PKDL.