- Research article
- Open Access
- Open Peer Review
Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases
BMC Medical Genetics volume 7, Article number: 20 (2006)
The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D.
We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, α = 0.05.
We found no evidence of association with T1D at most of the loci studied 0.02 <P < 1.0. Only a SNP in ADAM33, rs2787094, was any evidence of association obtained, P = 0.0004 in set 1 families (relative risk (RR) = 0.78), but further support was not observed in the 4,326 cases and 4,610 controls, P = 0.57 (OR = 1.02).
Polymorphisms in a variety of genes previously associated with immune-mediated disease susceptibility and/or having effects on gene function and the immune system, are unlikely to be affecting T1D susceptibility in a major way, even though some of the genes tested encode proteins of immune pathways that are believed to be central to the development of T1D. We cannot, however, rule out effect sizes smaller than OR 1.5.
The four susceptibility loci identified so far in T1D, the HLA class II gene complex , INS , CTLA4  and PTPN22 [4, 5] indicate that the regulation of T cell development, activation, expansion and homeostasis is a central component of disease development. A fifth locus, the IL2R2/CD25 region  awaits independent replication and fine mapping of the aetiological variant. With the exception of INS , these genes contain polymorphisms that are associated with susceptibility to other immune-mediated diseases.
Therefore, we hypothesised that further susceptibility variants for T1D may reside in genes previously associated with other immune-mediated diseases, as prior evidence suggests the presence of shared disease susceptibility genes. For example, in families with T1D, other immune-mediated diseases, such as RA and autoimmune thyroid disease (AITD), occur more frequently than expected by chance, indicative of a partly shared genetic basis . This model has gained significant support recently with the association of the Arg620Trp non-synonymous SNP in the PTPN22 gene, encoding the lymphoid specific phosphatase, LYP; not only with T1D  but also with GD, RA and SLE [5, 8, 9]. Likewise CTLA4 has been associated with T1D, AITD, RA and SLE [3, 10].
Furthermore, as susceptibility to T1D and other autoimmune diseases is probably directly related to the homeostatic, regulatory state of the immune system, it is possible that variants in immune response genes influence susceptibility to T1D via alteration of networks of immune regulation. For example, the CARD15 gene product, NOD2, influences the development of the adaptive immune response [11, 12] and functional variants of the gene predispose to the inflammatory bowel disease (IBD), Crohn disease (Table 1). Both the Th1 and mucosal immune system are thought to be important in T1D aetiology .
The aim of this study was to determine whether previously associated polymorphisms of immune-mediated disease also predispose to T1D. We genotyped a total of 41 polymorphisms, including three microsatellite markers, from 16 genes, shown in Table 1, in large T1D collections. For two genes C-reactive protein (CRP), a marker for inflammation and associated with susceptibility to SLE [14, 15], and FCER1B, high-affinity receptor for immunoglobulin E (IgE) (MS4A2), located in the putative T1D locus IDDM4, and associated with atopic illness [16, 17], we also carried out a re-sequencing effort, to gain a more comprehensive profile of allelic variation of the genes and their potential association with T1D. Our sample sizes had good statistical power for ORs greater than 1.5 (Additional File 1) .
T1D families were white European or of white European descent, with two parents and at least one affected child comprising DNA samples from up to 476 multiplex Diabetes UK Warren 1families , 278 multiplex HBDI families , 250 simplex Northern Ireland families , 260 simplex Norwegian families and 233 simplex Romanian families with inclusion criteria as reported in Vella et al. . The T1D cases and the 1958 BBC controls  have been described previously . All DNA samples were collected after approval from the relevant research ethics committees and written informed consent was obtained from the participants. This project has run over a number of years during which samples of cases were still being collected. Consequently, owing to availability of DNA, polymorphisms were genotyped either in "set 1" families (n = 754 UK and USA multiplex families), "set 2" families (n = 743 Norwegian, Romanian and Northern Irish simplex families) and/or a British case-control collection consisting of between approximately 1,500 and 4,400 cases and 1,500 and 4,600 controls.
SNP identification and genotyping
CRP (EMBL Accession number AL445528) and FCER1B (AP001181) were annotated locally, importing Ensembl information into a temporary ACeDB database as described previously . After confirmation of gene structures by BLAST analysis, these were re-extracted in GFF format and submitted to T1Dbase .
Direct sequencing of nested PCR products from 32 T1D individuals was carried out for all exons of CRP and 3 kb 5' and 3' of the gene, using Applied Biosystems 3700 capillary sequencer. Polymorphisms were identified using the Staden Package and loaded into T1Dbase. FCER1B was also sequenced, as for CRP, in 96 T1D individuals for 2 kb 5' and 3 kb 3' of the gene and all exons, except exon 6, were successfully sequenced.
SNPs were genotyped using either TaqMan MGB chemistry (Applied Biosystems), Invader Biplex assay (Third Wave Technologies, Madison)  or PCR RFLP. The microsatellites were genotyped on an ABI3700 using fluorescent primers. All genotyping data were double scored to minimize error.
Family studies of variants with a MAF less than 5% may be compromised by apparent under transmission of alleles resulting from undetected genotyping errors . To evaluate potential genotyping errors we genotyped a large selection of samples from three SNPs: SNP8 (rs2066844), SNP12 (rs2066845), SNP13 (ss28514842), twice, using two different methods, either TaqMan, Invader or PCR RFLP. The concordance rate between the methods was >99.2%.
All statistical analyses were performed within STATA  making specific use of the Genassoc and htSNP2 packages for association and tag SNP selection, available from . All genotyping data of unaffected parents and controls were assessed for, and found to be in Hardy-Weinberg equilibrium (P > 0.05). Associations of the SNPs and microsatellites were tested by the Transmission/disequilibrium test in the families. Allelic and genotypic relative risks were calculated using pseudo-controls and cases with conditional logistic regression . In order to minimise any confounding due to variation in allele frequencies across Great Britain , case-control data were stratified by broad geographical region within the logistic regression model used to calculate ORs and test associations. Both genotypic and allelic effects were allowed for by modelling loci as three-level, 2 degrees of freedom (2 df), categorical variables corresponding to a model assuming no particular mode of inheritance and continuous (1 df) variables equating to a multiplicative model. Where a difference was found, by a likelihood ratio test, between the multiplicative model and a model assuming no particular mode of inheritance, the 2 df P-value is reported. The tag SNPs were analysed by use of a multivariate test statistic [6, 32].
For CRP and FCER1B, we resequenced and followed a tag selection approach, selecting tags that capture the variation of the remaining common SNPs (MAF ≥ 0.05) with a minimum R 2 of 0.8 . Nineteen SNPs were identified in CRP, five of which were novel (Additional File 2)  and seven tag SNPs were selected and genotyped in set 1 families (multilocus P = 0.49). We also genotyped the tag SNPs in the case-control collection (1,607 cases and 1,636 controls) and found no support for association (multilocus P = 0.42), indicating that common variants of CRP are unlikely to influence T1D susceptibility in a major way. The CRP intronic microsatellite (GT)n polymorphism (ss28514831) (Table 1 and Additional file 2) was also genotyped in set 1 and 2 families but showed no association with T1D (P = 0.90).
On resequencing FCER1B, which is located in the putative diabetes-susceptibility region IDDM4 , we identified 34 SNPs, 17 of which were novel, and selected five tag SNPs (Additional File 3) . We were unable to detect the non-synonymous SNP in exon 7, Gly237Glu, in 96 DNA samples, that has previously been associated with atopic asthma . We initially genotyped the five tag SNPs in set 1 families (multilocus P = 0.085), and then followed this result up in set 2 families giving a combined multilocus P = 0.070 (adjusted for two-stage design). In 1,600 cases and 1,636 controls we obtained P = 0.24, and the combination of the multilocus family and case-control results indicated that variants of FCER1B are unlikely to play a major role in T1D susceptibility (P = 0.23). The FCER1B intronic microsatellite polymorphism (ss28514807) also showed no evidence of association with T1D in set 1 and 2 families (P = 0.65).
Five SNPs from FCRL3, CFH, SLC9A3R1, PADI4, RUNX1 and six SNPs from SPINK5 were genotyped in set 1 families and a minimum of 1,500 cases and 1,500 controls (Table 2). All except FCRL3 (TDT P = 0.04) and one locus in SPINK5 (P = 0.03), showed a P value of > 0.05. However, we did not obtain any further evidence of association of FCRL3 in 1,896 cases and 2,020 controls (Table 2). IL1RN, IL1RA, IGR2198 and the CARD15 SNPs 8, 12 and 13 were genotyped in sets 1 and 2 families, and all showed P > 0.10 (Table 3). The two SLC22A4 SNPs and the single LAG3 SNP were genotyped in a minimum of 3,290 cases and 3,549 controls and showed no evidence of association with T1D (Table 3).
As a potential atopy/asthma susceptibility locus, ADAM33 was considered as a candidate gene for T1D because atopic illness and T1D have been inversely associated . No functional candidate SNPs in ADAM33 have been identified, but it is plausible that the SNPs in introns or the 3' region are located in regulatory sequences and thus may affect transcriptional efficiency or transcript stability . We genotyped six SNPs that showed a P ≤ 0.03 in asthma case-control data  in set 1 families (Tables 1 and 4). One SNP, ADAM33 V4 (rs2787094), showed P = 0.0004 (RR = 0.78, 95% CI = 0.67–0.89) initially in 754 families, and P = 4.4 × 10-6 (RR = 0.77, 95% CI = 0.69–0.86) when genotyped in the additional set 2 families. However, we did not obtain additional support for association in 4,326 cases and 4,610 controls (P = 0.57) (Table 4).
Finally, we genotyped the NFKB1 dinucleotide repeat (CA) microsatellite polymorphism, which has been associated with T1D , albeit inconsistently  (Table 1). In our set 1 families, we failed to find any evidence for an association with T1D (P = 0.68).
Co-localization and overlapping of genetic loci in autoimmune diseases suggests that in some cases, common biological pathways may be involved in the aetiology of T1D and other clinically distinct immune-mediated diseases. In this study we examined 16 genes implicated in autoimmune and other immune-mediated diseases and report that none of the variants tested, consistently showed P values of less than 0.05 in association tests with T1D. Our data indicate that, although common immune-mediated disease loci are present in the genome, there are disease genes that are distinct to certain diseases. Indeed, the known T1D susceptibility loci follow this observation: while both CTLA4 and PTPN22 loci are associated with several autoimmune diseases [3, 38], the insulin VNTR locus is likely to be T1D-specific rather than a general autoimmune locus .
The possibility remains that some of the investigated genes and variants are associated with T1D, albeit with weak genetic effects, such as with ORs of less than 1.3, for which the sample size employed in our study does not provide sufficient statistical power. Even a case-control sample of 8,000 cases and 8,000 controls would only have 48% statistical power at a type 1 error rate α of 0.001 for a disease variant with a MAF of 0.10 and OR of 1.15. As genotyping costs decrease, it will be necessary to test the variants in larger sample sets than reported here, because the identification of genetic effects with ORs in the 1.15–1.25 range can be instrumental in the understanding of the disease process of T1D . For example, we note that an observed genetic effect of OR 1.15, such as that exerted by the T1D susceptibility locus CTLA4, does not reflect the importance of the biological effect contributed by the locus through the protein(s) it encodes and the pathways it regulates .
Lack of association with variants tested here may also be partly due to false positive results obtained in the reported primary disease association studies. As shown in Table 1, these generally employed small sample sets, which is a common explanation in the reporting of P values that cannot be replicated in independent studies using larger sample sizes [39–42]. Nevertheless, for ORs >1.5 our present study had good statistical power even for alleles at 0.01 frequency.
type: 1 diabetes
single nucleotide polymorphisms
minor allele frequency
systemic lupus erythemastosus
Cucca F, Lampis R, Congia M, Angius E, Nutland S, Bain SC, Barnett AH, Todd JA: A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum Mol Genet. 2001, 10: 2025-2037. 10.1093/hmg/10.19.2025.
Barratt BJ, Payne F, Lowe CE, Hermann R, Healy BC, Harold D, Concannon P, Gharani N, McCarthy MI, Olavesen MG, McCormack R, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Gillespie KM, Tuomilehto-Wolf E, Tuomilehto J, Bennett ST, Clayton DG, Cordell HJ, Todd JA: Remapping the insulin gene IDDM2 locus in type 1 diabetes. Diabetes. 2004, 53: 1884-1889.
Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003, 423: 506-511. 10.1038/nature01621.
Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004, 36: 337-338. 10.1038/ng1323.
Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L, Barratt BJ, Guja C, Ionescu-Tirgoviste C, Savage DA, Dunger DB, Widmer B, Strachan DP, Ring SM, Walker N, Clayton DG, Twells RC, Gough SC, Todd JA: Replication of an Association Between the Lymphoid Tyrosine Phosphatase Locus (LYP/PTPN22) With Type 1 Diabetes, and Evidence for Its Role as a General Autoimmunity Locus. Diabetes. 2004, 53: 3020-3023.
Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring SM, McArdle W, Pembrey ME, Strachan DP, Dunger DB, Twells RC, Clayton DG, Todd JA: Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet. 2005, 76: 773-779. 10.1086/429843.
Tait KF, Collins JE, Heward JM, Eaves I, Snook H, Franklyn JA, Barnett AH, Todd JA, Maranian M, Compston A, Sawcer S, Gough SC: Evidence for a Type 1 diabetes-specific mechanism for the insulin gene-associated IDDM2 locus rather than a general influence on autoimmunity. Diabet Med. 2004, 21: 267-270. 10.1111/j.1464-5491.2004.01129.x.
Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK: A Missense Single-Nucleotide Polymorphism in a Gene Encoding a Protein Tyrosine Phosphatase (PTPN22) Is Associated with Rheumatoid Arthritis. Am J Hum Genet. 2004, 75:
Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW: Genetic Association of the R620W Polymorphismof Protein Tyrosine Phosphatase PTPN22 with Human SLE. Am J Hum Genet. 2004, 75: 504-507. 10.1086/423790.
Kristiansen OP, Larsen ZM, Pociot F: CTLA-4 in autoimmune diseases – a general susceptibility gene to autoimmunity?. Genes Immun. 2000, 1: 170-184. 10.1038/sj.gene.6363655.
Watanabe T, Kitani A, Murray PJ, Strober W: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol. 2004, 5: 800-808. 10.1038/ni1092.
Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005, 307: 731-734. 10.1126/science.1104911.
Harrison LC, Honeyman MC: Cow's milk and type 1 diabetes: the real debate is about mucosal immune function. Diabetes. 1999, 48: 1501-1507.
Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, Meeks J, Powell RJ, Isenberg DA, Walport MJ, Vyse TJ: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet. 2004, 13: 137-147. 10.1093/hmg/ddh021.
Szalai AJ, McCrory MA, Cooper GS, Wu J, Kimberly RP: Association between baseline levels of C-reactive protein (CRP) and a dinucleotide repeat polymorphism in the intron of the CRP gene. Genes Immun. 2002, 3: 14-19. 10.1038/sj.gene.6363820.
Shirakawa T, Mao XQ, Sasaki S, Enomoto T, Kawai M, Morimoto K, Hopkin J: Association between atopic asthma and a coding variant of Fc epsilon RI beta in a Japanese population. Hum Mol Genet. 1996, 5: 2068-10.1093/hmg/5.8.1129.
Shirakawa T, Li A, Dubowitz M, Dekker JW, Shaw AE, Faux JA, Ra C, Cookson WO, Hopkin JM: Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor. Nat Genet. 1994, 7: 125-129. 10.1038/ng0694-125.
Knapp M: A note on power approximations for the transmission/disequilibrium test. Am J Hum Genet. 1999, 64: 1177-1185.
Bain SC, Todd JA, Barnett AH: The British Diabetic Association – Warren repository. Autoimmunity. 1990, 7: 83-85.
Lernmark A, Ducat L, Eisenbarth G, Ott J, Permutt MA, Rubenstein P, Spielman R: Family cell lines available for research. Am J Hum Genet. 1990, 47: 1028-1030.
Patterson CC, Carson DJ, Hadden DR: Epidemiology of childhood IDDM in Northern Ireland 1989–1994: low incidence in areas with highest population density and most household crowding. Northern Ireland Diabetes Study Group. Diabetologia. 1996, 39: 1063-1069.
Vella A, Howson JM, Barratt BJ, Twells RC, Rance HE, Nutland S, Tuomilehto-Wolf E, Tuomilehto J, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Todd JA: Lack of association of the Ala(45)Thr polymorphism and other common variants of the NeuroD gene with type 1 diabetes. Diabetes. 2004, 53: 1158-1161.
T1D Cases. [http://www-gene.cimr.cam.ac.uk/ucdr/grid.shtml]
1958 Controls. [http://www.cls.ioe.ac.uk/studies.asp?section=000100020003]
Burren OS, Healy BC, Lam AC, Schuilenburg H, Dolman GE, Everett VH, Laneri D, Nutland S, Rance HE, Payne F, Smyth D, Lowe C, Barratt BJ, Twells RC, Rainbow DB, Wicker LS, Todd JA, Walker NM, Smink LJ: Development of an integrated genome informatics, data management and workflow infrastructure: a toolbox for the study of complex disease genetics. Hum Genomics. 2004, 1: 98-109.
Mitchell AA, Cutler DJ, Chakravarti A: Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet. 2003, 72: 598-610. 10.1086/368203.
Cordell HJ, Clayton DG: A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet. 2002, 70: 124-141. 10.1086/338007.
Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, Nutland S, Howson JM, Faham M, Moorhead M, Jones HB, Falkowski M, Hardenbol P, Willis TD, Todd JA: Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet. 2005, 37: 1243-1246. 10.1038/ng1653.
Chapman JM, Cooper JD, Todd JA, Clayton DG: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered. 2003, 56: 18-31. 10.1159/000073729.
Nakagawa Y, Kawaguchi Y, Twells RC, Muxworthy C, Hunter KM, Wilson A, Merriman ME, Cox RD, Merriman T, Cucca F, McKinney PA, Shield JP, Tuomilehto J, Tuomilehto-Wolf E, Ionesco-Tirgoviste C, Nistico L, Buzzetti R, Pozzilli P, Joner G, Thorsby E, Undlien DE, Pociot F, Nerup J, Ronningen KS, Todd JA, et al: Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13. Am J Hum Genet. 1998, 63: 547-556. 10.1086/301974.
Cardwell CR, Shields MD, Carson DJ, Patterson CC: A meta-analysis of the association between childhood type 1 diabetes and atopic disease. Diabetes Care. 2003, 26: 2568-2574.
Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002, 418: 426-430. 10.1038/nature00878.
Hegazy DM, O'Reilly DA, Yang BM, Hodgkinson AD, Millward BA, Demaine AG: NFkappaB polymorphisms and susceptibility to type 1 diabetes. Genes Immun. 2001, 2: 304-308. 10.1038/sj.gene.6363776.
Gylvin T, Bergholdt R, Nerup J, Pociot F: Characterization of a nuclear-factor-kappa B (NFkappaB) genetic marker in type 1 diabetes (T1DM) families. Genes Immun. 2002, 3: 430-432. 10.1038/sj.gene.6363916.
Maier LM, Wicker LS: Genetic susceptibility to type 1 diabetes. Curr Opin Immunol. 2005, 17: 601-608. 10.1016/j.coi.2005.09.013.
Wang WY, Barratt BJ, Clayton DG, Todd JA: Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet. 2005, 6: 109-118. 10.1038/nrg1522.
Dahlman I, Eaves IA, Kosoy R, Morrison VA, Heward J, Gough SC, Allahabadia A, Franklyn JA, Tuomilehto J, Tuomilehto-Wolf E, Cucca F, Guja C, Ionescu-Tirgoviste C, Stevens H, Carr P, Nutland S, McKinney P, Shield JP, Wang W, Cordell HJ, Walker N, Todd JA, Concannon P: Parameters for reliable results in genetic association studies in common disease. Nat Genet. 2002, 30: 149-150. 10.1038/ng825.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003, 33: 177-182. 10.1038/ng1071.
Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG: Genetic associations in large versus small studies: an empirical assessment. Lancet. 2003, 361: 567-571. 10.1016/S0140-6736(03)12516-0.
Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, Bae SC, Tokuhiro S, Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo S, Yumura W, Mimori A, Koike T, Nakamura Y, Sasazuki T, Yamamoto K: A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet. 2005, 37: 478-485. 10.1038/ng1540.
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, Sangiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science. 2005, 308: 385-389. 10.1126/science.1109557.
Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003, 34: 395-402. 10.1038/ng1206.
Kaijzel EL, van Dongen H, Bakker AM, Breedveld FC, Huizinga TW, Verweij CL: Relationship of polymorphisms of the Interleukin-1 gene cluster to occurrence and severity of rheumatoid arthritis. Tissue Antigens. 2002, 59: 122-126. 10.1034/j.1399-0039.2002.590208.x.
Timms AE, Crane AM, Sims AM, Cordell HJ, Bradbury LA, Abbott A, Coyne MR, Beynon O, Herzberg I, Duff GW, Calin A, Cardon LR, Wordsworth BP, Brown MA: The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet. 2004, 75: 587-595. 10.1086/424695.
Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, Nagasaki M, Ohtsuki M, Ono M, Furukawa H, Nagashima M, Yoshino S, Mabuchi A, Sekine A, Saito S, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet. 2003, 35: 341-348. 10.1038/ng1267.
Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, Siminovitch KA: Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet. 2004, 36: 471-475. 10.1038/ng1339.
Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z, Delmonte T, Kocher K, Miller K, Guschwan S, Kulbokas EJ, O'Leary S, Winchester E, Dewar K, Green T, Stone V, Chow C, Cohen A, Langelier D, Lapointe G, Gaudet D, Faith J, Branco N, Bull SB, McLeod RS, Griffiths AM, Bitton A, Greenberg GR, Lander ES, Siminovitch KA, Hudson TJ: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet. 2001, 29: 223-228. 10.1038/ng1001-223.
Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, Wong K, Abecasis GR, Jones EY, Harper JI, Hovnanian A, Cookson WO: Gene polymorphism in Netherton and common atopic disease. Nat Genet. 2001, 29: 175-178. 10.1038/ng728.
Kabesch M, Carr D, Weiland SK, von Mutius E: Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clin Exp Allergy. 2004, 34: 340-345. 10.1111/j.1365-2222.2004.01860.x.
Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J, Anvret M: Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 2005, 6: 145-152. 10.1038/sj.gene.6364171.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001, 411: 599-603. 10.1038/35079107.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001, 411: 603-606. 10.1038/35079114.
Rahman P, Bartlett S, Siannis F, Pellett FJ, Farewell VT, Peddle L, Schentag CT, Alderdice CA, Hamilton S, Khraishi M, Tobin Y, Hefferton D, Gladman DD: CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet. 2003, 73: 677-681. 10.1086/378076.
Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP: CARD15 mutations in Blau syndrome. Nat Genet. 2001, 29: 19-20. 10.1038/ng720.
Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, Gordon D, Heffernan M, Daw JA, Robarge J, Ott J, Kwok PY, Menter A, Bowcock AM: A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet. 2003, 35: 349-356. 10.1038/ng1268.
Howard TD, Postma DS, Jongepier H, Moore WC, Koppelman GH, Zheng SL, Xu J, Bleecker ER, Meyers DA: Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol. 2003, 112: 717-722. 10.1016/S0091-6749(03)01939-0.
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/7/20/prepub
We thank the Juvenile Diabetes Research Foundation, the Wellcome Trust, Diabetes UK and the Medical Research Council, for financial support. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. We gratefully acknowledge the participation of all patients, controls and family members.
Thanks to Helen Stevens, Gillian Coleman, Sarah Field, Trupti Mistry, Sally Clayton, Matthew Hardy, Pamela Lauder, Meeta Maisuria, William Meadows and Sarah Wood for preparing DNA samples. We acknowledge use of DNA collections from Cristian Guja (Romania), Kjersti Ronningen and Dag Undlien (Norway), David Savage, Chris Patterson and Peter Maxwell (Northern Ireland), David Dunger and Barry Widmer (JDRF/WT Diabetes and Inflammation Laboratory UK GRID Cases) and David Strachan (1958 British Birth Cohort controls). Adrian Vella is a Mayo Foundation scholar, and Kieran Holland received financial support from the Royal College of Pathologists of Australasia.
The author(s) declare that they have no competing interests.
DJS performed sequencing, SNP genotyping, data analysis and drafted the manuscript. JMMH performed statistical analysis and drafted the manuscript. FP performed sequencing, SNP genotyping and data analysis. LMM performed sequencing, SNP genotyping, data analysis and drafted the manuscript. JDC performed statistical analysis. KH & CL performed sequencing and SNP genotyping. JH, RB, AV & ID performed SNP genotyping and data analysis.
ACL coordinated annotation of genes. SN prepared DNA samples. NMW managed the data. RCJT coordinated the study. JAT participated in the conception, design and coordination of the study and drafted the manuscript. All authors read and approved the final manuscript.
Deborah J Smyth, Joanna MM Howson contributed equally to this work.
About this article
Cite this article
Smyth, D.J., Howson, J.M., Payne, F. et al. Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases. BMC Med Genet 7, 20 (2006). https://doi.org/10.1186/1471-2350-7-20
- Systemic Lupus Erythematosus
- PTPN22 Gene
- Good Statistical Power
- Atopic Illness
- Functional Candidate SNPs