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Genetic Variants of the HLA-A, HLA-B and AIF1 Loci Show Independent Associations with Type 1 Diabetes in Norwegian Families

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Genetic Variants of the HLA-A, HLA-B and AIF1 Loci Show Independent Associations with Type 1 Diabetes in Norwegian Families Genes and Immunity (2009) 10, 141–150 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families MC Eike1,2, M Olsson3, DE Undlien4,5, K Dahl-Jørgensen6,7, G Joner6,8, KS Rønningen9, E Thorsby1,2 and BA Lie1 1Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway; 2Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway; 3Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden; 4Institute of Medical Genetics, Faculty Division Ulleva˚l University Hospital, University of Oslo, Oslo, Norway; 5Department of Medical Genetics, Ulleva˚l University Hospital, Oslo, Norway; 6Department of Paediatrics, Ulleva˚l University Hospital, Oslo, Norway; 7Faculty of Medicine, University of Oslo, Oslo, Norway; 8Institute of Health Management and Health Economics, University of Oslo, Oslo, Norway and 9Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex. Genes and Immunity (2009) 10, 141–150; doi:10.1038/gene.2008.88; published online 6 November 2008 Keywords: type 1 diabetes; autoimmune disease; major histocompatibility complex; human leukocyte antigen; genetic predisposition; conditional analysis Introduction AIDs, including ankylosing spondylitis, celiac disease, Graves’ disease, juvenile idiopathic arthritis, multiple Type 1 diabetes (T1D) is an autoimmune disease (AID) sclerosis, rheumatoid arthritis, sarcoidosis, systemic characterized by the destruction of insulin-producing lupus erythematosus and ulcerative colitis (cf. Supple- b-cells of the pancreas, causing irreversible insulin mentary Table 1). This commonality between AIDs is deficiency and a number of serious clinical complica- also reflected in genome-wide linkage scans14 and/or tions. The most important susceptibility factors reside association studies revealing shared genetic factors within the major histocompatibility complex (MHC) elsewhere in the genome, most notably variants of the where particular human leukocyte antigen (HLA) class CTLA4 and PTPN22 genes.15 This has led to the belief II DRB1-DQA1-DQB1 haplotypes confer high disease that, despite a wide variety of clinical manifestations, risk.1,2 However, numerous studies have strongly AIDs share certain biological features that are common to implicated additional T1D risk loci within the MHC.3–12 the autoimmune process. Genetic mapping of the MHC This complex contains an unusually high density of in a particular AID, such as T1D, therefore represents genes involved in immunological responses,13 of which potential value not only for the disease under study, but many are good candidates for involvement in auto- also for mapping of this region in other AIDs. However, immune processes. The observation of multiple suscept- association studies in the MHC are subject to severe ibility loci in the MHC is shared with a number of other confounding due to strong, variable and extensive linkage disequilibrium (LD), which has substantially complicated such efforts. Consequently, other than in Correspondence: MC Eike, Institute of Immunology, Rikshospitalet cases of strong primary associations (frequently for University Hospital, Sognsvannsveien 20, N-0027 Oslo, Norway. E-mail: [email protected] antigen-presenting HLA class II molecules, such as in Received 31 July 2008; revised 2 September 2008; accepted 8 October T1D), evidence for disease associations has often been 2008; published online 6 November 2008 conflicting. In an effort to resolve some of these conflicts, Conditional MHC screen of T1D candidate loci MC Eike et al 142 we used a candidate gene approach, examining pre- LD with the known class II risk variants (using single- viously suggested susceptibility loci from various AIDs, point main effects tests adjusted for DRB1-DQA1-DQB1 to identify additional risk variants for T1D within the genotypes), only five markers remained with significant MHC. results (Po0.05), that is, HLA-A, HLA-B and the single- nucleotide polymorphisms (SNPs) rs1800750 (tumor necrosis factor (TNF) À376), rs3132451 and rs2259571 Results (in the allograft inflammatory factor 1 (AIF1) gene), respectively (Figure 1b and Table 1; cf. Supplementary Polymorphisms were selected on the basis of earlier Table 2 for further details). reports of involvement in T1D and/or other AIDs, either directly (association reported for the marker) or indir- ectly (association or functional evidence reported for the gene in which the marker is located). In an effort to break Tests of independence between significant markers up the strong LD pattern, we also included additional To test whether these five T1D-associated genetic polymorphisms to maximize the number of haplotypes variants were independent of LD also with each other, picked up by the sum of markers, based on the work of, we repeated the main effects tests, still adjusting for among others, Allcock et al. (2004).16 Supplementary DRB1-DQA1-DQB1 genotypes, but with the additional Table 1 summarizes the most important earlier references inclusion of each of the other significant markers in the (reviews where appropriate), with direct affirmative model, one at a time (Table 1). None of the markers evidence reported for the polymorphisms investigated remained significant across all tests, although HLA-B here (Supplementary Table 2), and at least some form of only had one insignificant, but borderline, P-value. Note, adjustment for LD effects with known associated however, that the number of pseudo-cases/controls variants of other MHC loci. varies between the tests due to slight differences in genotyping success rates and inclusion of more markers Association tests in the model, and that some of the variation in Unconditional transmission-disequilibrium tests of all significance therefore may be attributed to variable loss markers showed the lowest P-value for the DRB1-DQA1- of statistical power. Nonetheless, all markers appeared to DQB1 haplotypes (P ¼ 5.8 Â 10À101), as expected, and influence the results of some of the other markers to significant P-values (at a ¼ 0.05) for 39 of the 53 some extent. The greatest impact appeared to be investigated markers (Figure 1a and Supplementary conferred by HLA-B, which reduced the P-values of both Table 2). Twenty seven of these were still significant HLA-A and the TNF SNP rs1800750 to nonsignificant after Bonferroni correction for multiple markers levels, but HLA-A also appeared to have some effect on (Po9.4 Â 10À4). However, after adjusting for effects of HLA-B. Also, the associations of the AIF1 SNPs rs3132451 Unconditional TDT 1E-27 1E-21 1E-15 -value P 1E-09 1E-03 0.05 corr Conditioned on DRDQ 1E-03 HLA-B rs3132451 1E-02 HLA-A rs1800750 rs2259571 -value 0.05 P 1E-01 pos (kb) 30020 3056731500 31750 32000 32250 32500 32750 IIIIIIregions genes TNF HLA-A HLA-E HLA-B MICA MICB BAT1 NFKBIL1 LTA AIF1 HSPA1L HSPA1B CFB AGER BTNL2 DRDQ C2 Figure 1 Results of association tests. (a) Unconditional transmission-disequilibrium tests. (b) Main effects tests adjusted for DRB1-DQA1- DQB1 (DRDQ) genotypes. P-values for DRDQ are not shown. Significance levels at a ¼ 0.05, Bonferroni-corrected for multiple markers À4 (0.05corr ¼ 9.4 Â 10 ) and uncorrected, respectively, are marked with dashed lines. Positions of the classical MHC regions and genes with genotyped markers are included for reference. Positions are along chromosome 6, genome build 36. Complete association results and further details are available in Supplementary Table 2. Genes and Immunity Conditional MHC screen of T1D candidate loci MC Eike et al 143 Table 1 Regression modelling of associated markers to reveal associations independent of each other in Norwegian families Test marker Markers adjusted for (included in model) DRDQ DRDQ and HLA-A DRDQ and HLA-B DRDQ and rs1800750 DRDQ and rs3132451 DRDQ and rs2259571 nP-value nP-value nP-value nP-value nP-value nP-value HLA-A 1414 0.012 — — 1226 0.12 1318 0.077 1036 0.031 1206 0.0073 HLA-B 1284 0.0052 1226 0.055 — — 1196 0.030 942 0.0015 1090 0.011 rs1800750 1460 0.023 1318 0.094 1196 0.69 — — 1042 0.071 1214 0.068 rs3132451 1102 0.0046 1036 0.0068 942 0.016 1042 0.0030 — — 988 0.086 rs2259571 1306 0.034 1206 0.027 1090 0.0058 1214 0.058 988 0.33 — — Tests were adjusted for DRB1-DQA1-DQB1 (DRDQ) genotypes and additionally for genotypes of other markers with significant independent effects (Po0.05) of DRDQ (cf. Figure 1b). n: number of pseudo-cases and -controls. P-values are for a likelihood ratio test (uncorrected). Degrees of freedom were 1 for tests of SNPs, 23 for HLA-B, 14 for HLA-A adjusted for DRDQ genotypes and 13 for HLA-A adjusted for DRDQ genotypes and additional markers.
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