Recent genome-wide association studies have identified 1q31 (RGS1), 2q11–12 (IL18RAP), 3p21 (CCR1/CCR3/CCR2), 3q25–26 (IL12A/SCHIP1), 3q28 (LPP), 4q27 (IL2/IL21), 6q25 (TAGAP) and 12q24 (SH2B3) as susceptibility regions for coeliac disease (CD). We have earlier replicated association with the IL2/IL21 region. This study aimed at replicating the remaining regions in a family cohort using the transmission disequilibrium test, which is not prone to population stratification as a source of false-positive results. Nine single nucleotide polymorphisms (SNPs) within these regions were genotyped in 325 Swedish–Norwegian CD families. We found significant associations with the same alleles in the regions 1q31 (rs2816316; Pnc=0.0060), 3p21 (rs6441961; Pnc=0.0006), 3q25–26 (rs17810564; Pnc=0.0316 and rs9811792; Pnc=0.0434) and 3q28 (rs1464510; Pnc=0.0037). Borderline, but non-significant, associations were found for rs917997 (IL18RAP), whereas no evidence for association could be obtained for rs13015714 (IL18RAP) or rs1738074 (TAGAP). The lack of replication of the latter SNPs could be because of limited power. rs3184504 (SH2B3) was not analysed because of assay failure. The most significantly associated region, 3p21 (CCR1/CCR3/CCR2), was further analysed by typing of 30 SNPs, with the aim of identifying the causal variant responsible for the initial association. Several SNPs showed association with CD, but none displayed associations stronger than rs6441961, nor did any of them add to the effect initially marked by rs6441961 in a conditional analysis. However, differential effects of rs6441961*C carrying haplotypes were indicated, and we thus cannot exclude the possibility that our inability to obtain evidence for multiple independent effects in the CCR1/CCR3/CCR2 gene region was related to a power issue.
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Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG et al. Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 2006; 55: 803–808.
Sollid LM . Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002; 2: 647–655.
Greco L, Romino R, Coto I, Di CN, Percopo S, Maglio M et al. The first large population based twin study of coeliac disease. Gut 2002; 50: 624–628.
Lettre G, Rioux JD . Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet 2008; 17: R116–R121.
van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 2007; 39: 827–829.
Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 2007; 81: 1284–1288.
Adamovic S, Amundsen SS, Lie BA, Gudjonsdottir AH, Ascher H, Ek J et al. Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families. Genes Immun 2008; 9: 364–367.
Romanos J, Barisani D, Trynka G, Zhernakova A, Bardella MT, Wijmenga C . Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J Med Genet 2009; 46: 60–63.
Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008; 40: 395–402.
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
Gudjonsdottir AH, Nilsson S, Ek J, Kristiansson B, Ascher H . The risk of celiac disease in 107 families with at least two affected siblings. J Pediatr Gastroenterol Nutr 2004; 38: 338–342.
Louka AS, Nilsson S, Olsson M, Talseth B, Lie BA, Ek J et al. HLA in coeliac disease families: a novel test of risk modification by the ‘other’ haplotype when at least one DQA1*05-DQB1*02 haplotype is carried. Tissue Antigens 2002; 60: 147–154.
Walker-Smith J, Guandalini S, Schmitz J, Schmerling D, Visakorpi J . Report of working group of European Society of Paediatric Gastroenterology and Nutrition: revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65: 909–911.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.
Clark VJ, Dean M . Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes. Hum Genomics 2004; 1: 255–273.
Clark VJ, Dean M . Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation. Hum Genomics 2004; 1: 195–207.
Melum E, Karlsen TH, Broome U, Broome U, Thorsby E, Schrumpf E et al. The 32-base pair deletion of the chemokine receptor 5 gene (CCR5-Delta32) is not associated with primary sclerosing cholangitis in 363 Scandinavian patients. Tissue Antigens 2006; 68: 78–81.
O’Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Lie BA, Todd JA, Pociot F, Nerup J, Akselsen HE, Joner G et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am J Hum Genet 1999; 64: 793–800.
Koskinen LL, Einarsdottir E, Dukes E, Heap GA, Dubois P, Korponay-Szabo IR et al. Association study of the IL18RAP locus in three European populations with coeliac disease. Hum Mol Genet 2009; 18: 1148–1155.
Benkirane M, Jin DY, Chun RF, Koup RA, Jeang KT . Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32. J Biol Chem 1997; 272: 30603–30606.
Prahalad S . Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun 2006; 7: 264–268.
Lindner E, Nordang GB, Melum E, Flato B, Selvaag AM, Thorsby E et al. Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis. BMC Med Genet 2007; 8: 33–38.
Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307: 1434–1440.
Mamtani M, Rovin B, Brey R, Camargo JF, Kulkarni H, Herrera M et al. CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus. Ann Rheum Dis 2008; 67: 1076–1083.
Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008; 359: 2767–2777.
This work was supported by grants from the Research Council of Norway, the Swedish Medical Research Council and the Swedish Research Council. The Sequenom genotyping service was provided by the National Technology Platform Centre for Integrative Genetics (CIGENE) supported by the functional genomics program (FUGE) of the Research Council of Norway. The TaqMan genotyping was performed at Swegene Genomics and Bioinformatics Core Facilities in Göteborg. We would like to thank all the families who participated in the study, Britt-Marie Käck, and the Celiac Society in Sweden for help with collecting families and blood samples, as well as David A van Heel for communicating unpublished results.
Supplementary information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)
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Amundsen, S., Rundberg, J., Adamovic, S. et al. Four novel coeliac disease regions replicated in an association study of a Swedish–Norwegian family cohort. Genes Immun 11, 79–86 (2010). https://doi.org/10.1038/gene.2009.67
- coeliac disease
- genetic association
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