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. Author manuscript; available in PMC: 2010 Jan 12.
Published in final edited form as: Genes Immun. 2009 Dec;10(Suppl 1):S95–120. doi: 10.1038/gene.2009.98

Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as type I diabetes loci, and support for a new locus, 12q13.3–q14.1

JD Cooper 1, NM Walker 1, BC Healy 1, DJ Smyth 1, K Downes 1, JA Todd 1, the Type I Diabetes Genetics Consortium
PMCID: PMC2805450  NIHMSID: NIHMS163344  PMID: 19956108

Abstract

A candidate gene study was conducted on 10 established type II diabetes genes and 45 genes associated with autoimmune diseases, including type I diabetes (T1D), in a maximum of 1410 affected sib-pair families assembled by the Type I Diabetes Genetics Consortium. Associations at P values < 10−3 were found for three known T1D regions at chromosomes 4q27, 12q13.2 and 12q24.13 (http://www.T1DBase.org). Support was obtained for a newly identified T1D candidate locus on chromosome 12q13.3–12q14.1 (rs1678536/KIF5A: P=8.1 × 10−3; relative risk (RR) for minor allele=0.89, 95% CI=0.82–0.97), which has a separate association from the previously reported T1D candidate locus ERBB3/12q13.2–q13.3. Our new evidence adds to that previously published for the same gene region in a T1D case–control study (rs1678542; P=3.0 × 10−4; odds ratio (OR)=0.92, 95% CI=0.88–0.96). This region, which contains many genes, has also been associated with rheumatoid arthritis.

Keywords: autoimmune disease, type I diabetes, type II diabetes, SNPs, T1DGC

Introduction

The advent of genome-wide association studies has highlighted the commonality and differences between diseases. Genes found to be associated in one disease are now routinely genotyped in related diseases, providing a more focused and often more informative candidate gene approach.1,2 A candidate gene study was performed using a panel of 216 SNPs from 10 known T2D loci (including HHEX and SLC30A8), 126 SNPs from 5 known T1D regions (including CTLA4 and IL2) and 239 SNPs from 40 known other autoimmune disease regions (including IL23R and PADI4). Although T1D and T2D are considered etiologically distinct, characterized by autoimmune destruction of the pancreatic β cells and by impaired β cell function, respectively, T2D loci were included in the study as they may share a common pathophysiological etiology, suggested by the similarities in their clinical manifestation.3 The five known T1D loci were included for further confirmation. All SNPs were genotyped in a maximum of 1410 T1D affected sib-pair families assembled by the Type I Diabetes Genetics Consortium (T1DGC), providing 2198 parent–child trios. A complete list of SNPs, genes and regions is provided in Supplementary Table 1.

Results

A total of 581 SNPs was selected from T2D genes related to β-cell function, T1D and other autoimmune candidate genes and genotyped at the Broad Institute of Harvard/MIT in Cambridge, MA, USA (http://www.broad.mit.edu/) using the Illumina Golden Gate platform. In addition to the standard sample and SNP quality control, we visually inspected the SNP signal intensity plots for each of the family groups (see accompanying paper4), resulting in 334 SNPs that passed quality control (Supplementary Table 1).8

Fifty-one SNPs exhibited some evidence (P < 0.05) of association with T1D (Table 1),8 16 of which were from known T1D regions. Only four SNPs reached the required level of significance for this study (P<0.001) and these SNPs were all from known T1D regions: rs11171747 on chromosome 12q13.2 (P=7.1 × 10−6), located 21 kb telomeric of ERBB3;5 rs4767364 (P=1.6 × 10−4) and rs17696736 (P=6.2 × 10−4) on 12q24.13 in the C12orf30 region, located 597 kb telomeric of SH2B3;5 and rs12510683 (P=7.1 × 10−4) on 4q27 in the KIAA1109 region, located 393 kb centromeric of IL2-IL21.

Table 1.

SNPs from known T1D, T2D and autoimmune disease regions with evidence of T1D association, P<0.05, ordered by genomic position

rs number Chromosome Gene region Parent–child trios MAF 1-df P T1D, T2D or autoimmune
rs6745050 2q33 2764 0.392 0.023 T1D
rs12990970 2q33 2750 0.394 0.045 T1D
rs231727 2q33 CTLA4 2763 0.359 0.00122 T1D
rs10197319 2q33 2644 0.469 0.0378 T1D
rs17268364 2q33 2756 0.459 0.0268 T1D
rs4294983 2q33 2500 0.072 0.0278 T1D
rs12640179 4q13 GC 886 0.078 0.0167 Autoimmune
rs16847054 4q13 GC 1657 0.062 0.0129 Autoimmune
rs12510683 4q27 2774 0.225 0.000713 T1D
rs6827444 4q27 KIAA1109 2726 0.181 0.0199 T1D
rs12511287 4q27 2767 0.307 0.0349 T1D
rs11567751 5p13 IL7R 2704 0.297 0.0147 Autoimmune
rs6897932 5p13 IL7R 2674 0.247 0.0424 Autoimmune
rs3194051 5p13 IL7R 2736 0.298 0.0196 Autoimmune
rs10214237 5p13 2751 0.246 0.0338 Autoimmune
rs700162 5p13 UGT3A1 2563 0.402 0.0436 Autoimmune
rs2447876 5p13 UGT3A1 241 0.188 0.0302 Autoimmune
rs3792876 5q31 SLC22A4 2762 0.073 0.0157 Autoimmune
rs2073838 5q31 SLC22A4 2778 0.073 0.0196 Autoimmune
rs7739974 6p22 CDKAL1 2709 0.206 0.0195 T2D
rs1569699 6p22 CDKAL1 2750 0.325 0.0195 T2D
rs2206736 6p22 CDKAL1 2784 0.172 0.0174 T2D
rs9356747 6p22 CDKAL1 2768 0.234 0.0356 T2D
rs7741604 6p22 CDKAL1 2782 0.141 0.0208 T2D
rs9465873 6p22 CDKAL1 2749 0.386 0.032 T2D
rs12211466 6p22 CDKAL1 557 0.062 0.00157 T2D
rs7738382 6p22 CDKAL1 2752 0.281 0.0433 T2D
rs11970030 6p22 CDKAL1 2765 0.124 0.04 T2D
rs4712569 6p22 CDKAL1 2756 0.163 0.00371 T2D
rs201351 6p22 CDKAL1 2739 0.119 0.00874 T2D
rs201300 6p22 CDKAL1 2765 0.387 0.0422 T2D
rs4389757 6p22 CDKAL1 2763 0.125 0.00234 T2D
rs9465994 6p22 CDKAL1 2764 0.473 0.0402 T2D
rs4710965 6p22 CDKAL1 2690 0.462 0.0422 T2D
rs6942273 6p22 CDKAL1 2755 0.44 0.0213 T2D
rs4876369 8q24 SLC30A8 1646 0.153 0.00162 T2D
rs10811661 9p21 CDKN2B 2750 0.171 0.0182 T2D
rs10876864 12q13 2691 0.449 0.00109 T1D
rs2271194 12q13 ERBB3 2653 0.447 0.00892 T1D
rs705708 12q13 ERBB3 2763 0.488 0.000125 T1D
rs11171747 12q13 2744 0.356 7.12E-06 T1D
rs1678536 12q13 KIF5A 2756 0.278 0.00811 Autoimmune
rs2640629 12q14 2705 0.331 0.0439 Autoimmune
rs701008 12q14 AGAP2 2742 0.353 0.00252 Autoimmune
rs2301551 12q14 AGAP2 2651 0.295 0.0253 Autoimmune
rs11172349 12q14 2722 0.307 0.0172 Autoimmune
rs12298022 12q24 C12orf30 2759 0.077 0.00102 T1D
rs17696736 12q24 C12orf30 2742 0.468 0.000618 T1D
rs4767364 12q24 C12orf30 2745 0.273 0.000164 T1D
rs6110460 20p13 DEFB129 2669 0.47 0.0302 Autoimmune
rs729749 22Q12 NCF4 2658 0.248 0.049 Autoimmune
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MAF, minor allele frequency in unaffected parents; T1D, type I diabetes; T2D, type II diabetes.

Gene regions showing some evidence of association (0.05> P> 0.001) with T1D included SNPs in two T2D genes thought to be involved with β-cell function (Table 1): CDKAL1 on chromosome 6p22.3 (P=1.6 × 10−3) and SLC30A8 on 8q24.11 (P=1.6 × 10−3). Recent studies of SLC30A8 have identified an association of T2D with the non-synonymous SNP, rs13266634 (Arg325Trp), an SNP also genotyped in this study. This SNP has also been reported to determine ZnT8 autoantibody specificity in T1D;6 however, no association with T1D was found with this SNP in this study of T1D affected sib-pair families (data not shown) in agreement with an earlier study of 7680 British T1D cases and 7200 controls.7 Similarly, the most strongly associated CDKAL1 SNP with T2D was not associated with T1D in this large British case–control study.7

In addition, some evidence of association with T1D (Table 1) was found for rs231727 in CTLA4 on chromosome 2q33.2 (P=1.2 × 10−3), a known T1D region;7 rs1678536 in KIF5A on 12q13.3 (P=8.11 × 10−3) and rs701008 in AGAP2 on 12q14.1 (P=2.5 × 10−3). The KIF5A and AGAP2 SNPs are not independently associated with T1D: using logistic regression, adding rs1678536/KIF5A to rs701008/AGAP2 gave P=0.37 and rs701008/AGAP2 to rs1678536/KIF5A gave P=0.08. The two SNPs are 138 kb apart and in the same linkage disequilibrium block (D′ =0.78 and r2=0.42 in parents).7 The associated 12q13.3–q14.1 region is approximately 1.6Mb. Nevertheless, the association of the rs1678536/KIF5A and rs701008/AGAP2 SNPs is independent of the established ERBB3/12q13.2–q13.3 region:8 using logistic regression, adding rs11171747/ERBB3 (most associated SNP found in this study) to rs1678536/KIF5A gave P=1.4 × 10−3 and adding rs1678536/KIF5A to rs11171747/ERBB3 gave P=7.3 × 10−3. KIF5A is about 2Mb centromeric of ERBB3 with a single recombination hotspot between these genes.

Discussion

In addition to the previously reported T1D-associated ERBB3/12q13.2–q13.3 region,5 we provide evidence of an independent T1D locus within the 12q13.3–q14.1 region, which contains 47 protein-coding genes, including KIF5A, AGAP2, PIP4K2C and also the vitamin D-associated gene CYP27B1, which has been reported to show some evidence of an association with T1D.9 However, rs1678542/KIF5A (an SNP associated with rheumatoid arthritis)10 and rs10877012/CYP27B1 are not independently associated with T1D in 7455 cases and 9089 controls: using logistic regression, adding rs1678542/KIF5A to rs10877012/CYP27B1 gave P=0.018 and rs10877012/CYP27B1 to rs1678542/KIF5A gave P=0.10. The 12q13.3–q14.1 region has been earlier associated with rheumatoid arthritis (rs1678542/KIF5A)10 and most recently with T1D in 8010 cases and 9733 controls (rs1678542/KIF5A, P=3.0 × 10−4; OR=0.92, 95% CI=0.88–0.96).2 Hence, we have obtained further support for the 12q13.3–q14.1 region in T1D affected sib-pair families. As this region contains 47 protein-coding genes, further sequencing and genotyping will be required to ascertain the contribution of these genes to T1D. We found no convincing evidence of commonality between type I and type II diabetes.

Materials and methods

Subjects

The DNA samples were genotyped at the Broad Institute of Harvard/MIT in Cambridge, MA, USA (http://www.broad.mit.edu/). The samples were assembled by the T1DGC and consist of affected sib-pair families of two parents and two affected offspring. The families were obtained from nine cohorts: Diabetes UK (DUK), Human Biological Data Interchange (HBDI), T1DGC Asia Pacific (AP) Network, T1DGC European (EUR) Network, T1DGC United Kingdom (UK) Network, T1DGC North America (NA) Network, Joslin (JOS) Diabetes Center, Sardinia (SAR) and Denmark (DAN). The AP, EUR, NA and UK collections were newly recruited by the T1DGC, whereas the remainder where part of established collections; 2074 families had at least 1 member who passed sample quality control, 1410 families provided 2798 parent–child trios.

SNP selection

A total of 581 SNPs were selected from T2D genes related to β-cell function, recent T1D and other autoimmune candidate genes (Table 1; www.T1DBase.org). SNPs were genotyped using the Illumina Golden Gate platform at the Broad Institute of Harvard/MIT in Cambridge, MA, USA (http://www.broad.mit.edu/). In addition to standard sample and SNP quality control, SNP signal intensity plots for each of the family groups were visually inspected (see accompanying paper4). This process provided 334 SNPs with well-separated signal clouds—148 of 239 SNPs from autoimmune disease regions, 114 of 216 SNPs from T2D regions and 72 of 126 SNPs from T1D regions. Genotype signal intensity cluster plots are available in T1DBase.8

Statistics

All analyses were carried out in the R statistical environment using the snpMatrix package from the bioConductor project.11 Family groups were analyzed using the transmission/disequilibrium test configured as a score test. The scores and their variances were summed over family groups and genotyping centers to pool information.

Supplementary Material

01

Acknowledgements

The Type I Diabetes Genetics Consortium is a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and supported by U01 DK062418. JDC, NMW, DJS, KD, BCH and JAT are funded by the Juvenile Diabetes Research Foundation International (JDRF), the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.

Footnotes

Conflict of interest

The authors declare no conflict of interest.

References

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Supplementary Materials

01
NIHMS163344-supplement-01.pdf (3.2MB, pdf)

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