The results presented here and reported recently elsewhere1, 10, 14, 15
indicate that one may be confident in 21 non-HLA loci in T1D and 11 in celiac disease (), of which four are newly identified loci in T1D (1q31/RGS1
Tables and ) and of which two are new for celiac disease, 3p21/CCR5
. Further, the results provide convincing confirmation of the importance of the 2q33/CTLA4
region (). Seven of these chromosome regions are shared between the two diseases, suggesting that for an investigation of shared loci in two diseases that are known to co-segregate, the prior odds of 1000:1 against there being a true association at any locus tested 20
is too conservative.
Four alleles, 1q31/RGS1
, show the same direction of association in the two diseases, constituting evidence for shared causal variants. We know that this is not due to bias in ascertainment of the cases (Supplementary Appendix
); nor is the use of a common set of controls a problem since we have consistent results from families (Supplementary Appendix
The minor alleles of the SNPs 2q12/IL18RAP
rs917997 and 6q25/TAGAP
rs1738074 were negatively associated with T1D (),with the effects in the opposite direction to the previous celiac disease findings ().10
These results may be interpreted in two ways: the causal variants in these two regions have opposite biological effects in T1D and celiac disease, or that there are different causal variants for each disease in each region with the typed marker SNPs tagging these causal variants. For the 2q12/IL18RAP
regions we have found no evidence so far in T1D GWA studies13, 15
for a second loci within these regions (data not shown). Moreover, there is precedent for a causal variant having opposing effects in different diseases. For example, the minor allele of 1p13/PTPN22
variant Arg620Trp predisposes a person to many immune-mediated diseases but is protective for Crohn's disease.30
Hence, we favor the possibility that the causal variants have opposite effects in the T1D and celiac disease patients. In contrast, for 4q27 our current data indicate that different causal variants are involved, perhaps affecting different genes, in T1D and celiac disease. The important immune response genes, IL-2 31
and IL-21 are strong functional candidates. Before we can draw further conclusions, all the regions discussed here must be thoroughly resequenced from multiple persons to ascertain a complete catalogue of polymorphisms, followed by further genotyping in order to identify all of the most associated variants.
Nevertheless, the 32 base pair insertion/deletion in CCR5
(rs333), which causes loss of expression of the receptor,22
could well be the actual functional, causal variant involved. The disease associations of the two chemokine receptor genes, CCR3
() and CCR5
(), suggest the central importance of lymphocyte trafficking in these organ specific diseases. The development and anatomy of the small intestine and pancreas are close, and the gut immune system shares close connections with the pancreatic lymph nodes, which have been linked to insulitis and β-cell destruction.32
In recent-onset T1D patients alterations in the levels of CCR5 ligands, CCL3 (MIP-1α) and CCL4 (MIP-1β) have been reported.33
In the NOD mouse model of T1D, CCR5 and its ligand CCL4 have multiple reported significant roles in the disease development. 34
There are, however, distinct differences in genetic susceptibility between the two diseases, including at 1p13/PTPN22
(), and although there are shared T1D and celiac disease predisposing alleles at the HLA-DQB1 gene, there are distinguishing HLA-DQB1
genotype differences (Supplementary Appendix
). One possibility is that there is a common autoimmunity-inflammatory genetic background, and that further combinations of more disease-specific variation at HLA and non-HLA genes, in interaction with epigenetic and environmental factors, determine the final clinical outcomes.
Our results support further evaluation of the hypothesis that cereal and gluten consumption might be an environmental factor in T1D leading to the alteration of the function of the gut immune system and its relationship with the pancreatic immune system.6, 12, 32, 35
Furthermore, insulin and its precursors are major targets of the T and B lymphocyte autoreactive response in T1D; thus, one might speculate that bovine insulin in infant feeds could enhance anti-insulin responses,3
particularly if there are genetically-determined defects in oral tolerance predisposing to T1D. Conversely, genes classified as autoimmunity genes, because they are associated with T1D, contribute to celiac disease.