Abstract
The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
The Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.
Sheehy MJ, Scharf SJ, Rowe JR, Neme de Gimenez MH, Meske LM, Erlich HA et al. A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest 1989; 83: 830–835.
Hanifi Moghaddam P, de Knijf P, Roep BO, Van der Auwera B, Naipal A, Gorus F et al. Genetic structure of IDDM1: two separate regions in the major histocompatibility complex contribute to susceptibility or protection. Belgian Diabetes Registry. Diabetes 1998; 47: 263–269.
Johansson S, Lie BA, Todd JA, Pociot F, Nerup J, Cambon-Thomsen A et al. Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and -DRB1. Genes Immun 2003; 4: 46–53.
Koeleman BV, De Groot KN, Van Der Slik AR, Roep BO, Giphart MJ . Association between D6S2223 and type I diabetes independent of HLA class II in Dutch families. Diabetologia 2002; 45: 598–599.
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.
Robinson WP, Barbosa J, Rich SS, Thomson G . Homozygous parent affected sib pair method for detecting disease predisposing variants: application to insulin dependent diabetes mellitus. Genet Epidemiol 1993; 10: 273–288.
Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS, Babu SR et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci USA 2006; 103: 14074–14079.
Ide A, Babu SR, Robles DT, Wang T, Erlich HA, Bugawan TL et al. ‘Extended’ A1, B8, DR3 haplotype shows remarkable linkage disequilibrium but is similar to nonextended haplotypes in terms of diabetes risk. Diabetes 2005; 54: 1879–1883.
de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 2006; 38: 1166–1172.
Miretti MM, Walsh EC, Ke X, Delgado M, Griffiths M, Hunt S et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 2005; 76: 634–646.
Undlien DE, Lie BA, Thorsby E . HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet 2001; 17: 93–100.
Ahmad T, Neville M, Marshall SE, Armuzzi A, Mulcahy-Hawes K, Crawshaw J et al. Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum Mol Genet 2003; 12: 647–656.
Yunis EJ, Larsen CE, Fernandez-Vina M, Awdeh ZL, Romero T, Hansen JA et al. Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. Tissue Antigens 2003; 62: 1–20.
Blomhoff A, Olsson M, Johansson S, Akselsen HE, Pociot F, Nerup J et al. Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1*03 and DRB1*04 haplotypes. Genes Immun 2006; 7: 130–140.
Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK et al. Gene map of the extended human MHC. Nat Rev Genet 2004; 5: 889–899.
Williams AF, Barclay AN . The immunoglobulin superfamily—domains for cell surface recognition. Annu Rev Immunol 1988; 6: 381–405.
Partridge J, Wallace DF, Robertson A, Fox MF, Simons JP, Dooley JS et al. Cloning and molecular characterization of a cross-homologous zinc finger locus ZNF204. Genomics 1998; 50: 116–118.
Bowlus CL, Ahn J, Chu T, Gruen JR . Cloning of a novel MHC-encoded serine peptidase highly expressed by cortical epithelial cells of the thymus. Cell Immunol 1999; 196: 80–86.
Lie BA, Akselsen HE, Bowlus CL, Gruen JR, Thorsby E, Undlien DE . Polymorphisms in the gene encoding thymus-specific serine protease in the extended HLA complex: a potential candidate gene for autoimmune and HLA-associated diseases. Genes Immun 2002; 3: 306–312.
Lie BA, Viken MK, Akselsen HE, Flåm S, Pociot F, Nerup J et al. Association analysis in type 1 diabetes of the PRSS16 gene encoding a thymus-specific serine protease. Hum Immunol 2007; 68: 592–598.
Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI et al. Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001; 68: 191–197.
Pastinen T, Sladek R, Gurd S, Sammak A, Ge B, Lepage P et al. A survey of genetic and epigenetic variation affecting human gene expression. Physiol Genomics 2004; 16: 184–193.
Aly TA, Baschal EE, Jahromi MM, Fernando MS, Babu SR, Fingerlin TE et al. Analysis of single nucleotide polymorphisms identifies major type 1A diabetes locus telomeric of the major histocompatibility complex. Diabetes 2008; 57: 770–776.
Eike MC, Becker T, Humphreys K, Olsson M, Lie BA . Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B. Genes and Immunity 2009; 10: 56–67.
Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857–864.
Nejentsev S, Gombos Z, Laine AP, Veijola R, Knip M, Simell O et al. Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes 2000; 49: 2217–2221.
Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007; 450: 887–892.
Valdes AM, Erlich HA, Noble JA . Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 2005; 66: 301–313.
Rhodes DA, Stammers M, Malcherek G, Beck S, Trowsdale J . The cluster of BTN genes in the extended major histocompatibility complex. Genomics 2001; 71: 351–362.
Ruddy DA, Kronmal GS, Lee VK, Mintier GA, Quintana L, Domingo Jr R et al. A 1.1-Mb transcript map of the hereditary hemochromatosis locus. Genome Res 1997; 7: 441–456.
Linsley PS, Peach R, Gladstone P, Bajorath J . Extending the B7 (CD80) gene family. Protein Sci 1994; 3: 1341–1343.
Colhoun HM, McKeigue PM, Smith GD . Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865–872.
Clarke GM, Carter KW, Palmer LJ, Morris AP, Cardon LR . Fine-mapping vs replication in whole genome association studies. Am J Hum Genet 2007; 81: 995–1005.
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD et al. Global variation in copy number in the human genome. Nature 2006; 444: 444–454.
Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315: 848–853.
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.
Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007; 80: 1037–1054.
Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007; 39: 721–723.
Aitman TJ, Dong R, Vyse TJ, Norsworthy PJ, Johnson MD, Smith J et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006; 439: 851–855.
van Ommen G-JB . Frequency of new copy number variation in humans. Nat Genet 2005; 37: 333–334.
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P et al. Large-scale copy number polymorphism in the human genome. Science 2004; 305: 525–528.
Goidts V, Cooper D, Armengol L, Schempp W, Conroy J, Estivill X et al. Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome. Hum Genet 2006; 120: 270–284.
Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L et al. The DNA sequence and analysis of human chromosome 6. Nature 2003; 425: 805–811.
The International HapMap Consortium. The International HapMap Project. Nature 2003; 426: 789–796.
Barker DL, Hansen MST, Faruqi AF, Giannola D, Irsula OR, Lasken RS et al. Two methods of whole-genome amplification enable accurate genotyping across a 2320-SNP linkage panel. Genome Res 2004; 14: 901–907.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Becker T, Knapp M . Maximum-likelihood estimation of haplotype frequencies in nuclear families. Genet Epidemiol 2004; 27: 21–32.
Valdes AM, Thomson G . Detecting disease-predisposing variants: the haplotype method. Am J Hum Genet 1997; 60: 703–716.
Acknowledgements
This study was supported by the Juvenile Diabetes Research Foundation International (1-2004-793, 1-2000-514, 1-2000-515), the University of Oslo, the Functional Genomics program (FUGE), the Norwegian Research Council, the Norwegian Diabetes Association, the NovoNordisk Foundation and the Eastern Norway Regional Health Authority. We thank the Norwegian Study Group for Childhood Diabetes, the Danish Study Group of Diabetes in Childhood, the Danish IDDM Epidemiology and Genetics Group, the Swedish Childhood Diabetes Study, the Diabetes Incidence Study in Sweden, the French Network Inserm for IDDM and MS in Atlantic Pyrenees (Dr A Cambon-Thomsen) and the Regional Observatory of health in Aquitaine region (Dr J Doutreix) for the collection of samples used in this study and the bilateral French Norwegian collaborative program AURORA for allowing exchanges and the discussion of analyses. The MassARRAY genotyping service was provided by the national technology platform CIGENE (Centre For Integrative Genetics) supported by the Functional Genomics Program (FUGE) in the Research Council of Norway. This research uses resources provided by the Type 1 Diabetes Genetics Consortium, 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 the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Resources from the freely available Bioportal (http://www.bioportal.uio.no) were used for some of the statistical analyses. We are grateful to Kristina Gervin and Siri T Flåm for their excellent technical assistance, especially with the SNPlex genotyping, Hege Dahlen Sollid for help with the haplotype analyses and Morten C Eike for assistance with the compilation of the HLA data for the T1DGC families.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Viken, M., Blomhoff, A., Olsson, M. et al. Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun 10, 323–333 (2009). https://doi.org/10.1038/gene.2009.13
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2009.13
Keywords
This article is cited by
-
Analysis of macaque BTN3A genes and transcripts in the extended MHC: conserved orthologs of human γδ T cell modulators
Immunogenetics (2019)
-
Thymus-specific serine protease, a protease that shapes the CD4 T cell repertoire
Immunogenetics (2019)
-
Evolutionary and polymorphism analyses reveal the central role of BTN3A2 in the concerted evolution of the BTN3 gene family
Immunogenetics (2017)
-
Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection
Genes & Immunity (2015)
-
Immune modulation by butyrophilins
Nature Reviews Immunology (2014)