Insulin gene VNTR polymorphisms −2221MspI and −23HphI are associated with type 1 diabetes and latent autoimmune diabetes in adults: a meta-analysis

Acta Diabetologica - Tập 52 - Trang 1143-1155 - 2015
Na Zhang1, Weihuang Huang1, Fang Dong1, Yang Liu1, Baohuan Zhang1, Lipeng Jing1, Man Wang1, Guang Yang2, Chunxia Jing1
1Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
2Department of Parasitology, School of Medicine, Jinan University, Guangzhou, China

Tóm tắt

A variable number of tandem repeat (VNTRs) region in the insulin gene (INS) possibly influences the progression of type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). However, effects of INS VNTR polymorphisms in these contexts remain inconclusive. We performed a systematic review of work on the INS VNTR −2221MspI and −23HphI polymorphisms to estimate the overall effects thereof on disease susceptibility; we included 17,498 T1D patients and 24,437 controls, and 1960 LADA patients and 5583 controls. For T1D, the C allele at −2221MspI and the A allele at −23HphI were associated with estimated relative risks of 2.13 (95 % CI 1.94, 2.35) and 0.46 (95 % CI 0.44, 0.48), which contributed to absolute increases of 46.76 and 46.98 % in the risk of all T1D, respectively. The estimated lambda values were 0.44 and 0.42, respectively, suggesting that a co-dominant model most likely explained the effects of −2221MspI and −23HphI on T1D. For −23HphI, the A allele carried an estimated relative risk of 0.55 (95 % CI 0.50, 0.61) for LADA and increased the risk of all LADA by 36.94 %. The λ value was 0.43, suggesting that a co-dominant model most likely explained the effect of −23HphI on LADA. Our results support the existence of associations of INS with T1D and LADA.

Tài liệu tham khảo

Palmer JP, Hampe CS, Chiu H, Goel A, Brooks-Worrell BM (2005) Is latent autoimmune diabetes in adults distinct from type 1 diabetes or just type 1 diabetes at an older age? Diabetes 54(Suppl. 2):S62–S67 Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553. doi:10.1002/(sici)1096-9136(199807)15:7<539:aid-dia668>3.0.co;2-s Palmer JP, Hirsch IB (2003) What’s in a name: latent autoimmune diabetes of adults, type 1.5, adult-onset, and type 1 diabetes. Diabetes Care 26(2):536–538 Daneman D (2006) Type 1 diabetes. Lancet 367(9513):847–858 Huang G, Wang X, Li Z, Li H, Li X, Zhou Z (2012) Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese. Acta Diabetol 49(5):327–331. doi:10.1007/s00592-010-0196-2 Markle JG, Frank DN, Mortin-Toth S et al (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339(6123):1084–1088. doi:10.1126/science.1233521 Knip M, Akerblom HK (1999) Environmental factors in the pathogenesis of type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 107(Suppl. 3):S93–S100. doi:10.1055/s-0029-1212160 Dahlquist GG (1997) Viruses and other perinatal exposures as initiating events for beta-cell destruction. Ann Med 29(5):413–417 Dong F, Yang G, Pan HW et al (2014) The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis. Acta Diabetol 51(5):691–703. doi:10.1007/s00592-014-0613-z Barrett JC, Clayton DG, Concannon P et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41(6):703–707. doi:10.1038/ng.381 Bennett ST, Lucassen AM, Gough SC et al (1995) Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9(3):284–292. doi:10.1038/ng0395-284 Zanda M, Onengut-Gumuscu S, Walker N et al (2014) A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes. PLoS Genet 10(5):e1004367. doi:10.1371/journal.pgen.1004367 Ramos-Lopez E, Lange B, Kahles H et al (2008) Insulin gene polymorphisms in type 1 diabetes, Addison’s disease and the polyglandular autoimmune syndrome type II. BMC Med Genet 9:65. doi:10.1186/1471-2350-9-65 Bennett ST, Todd JA (1996) Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–370. doi:10.1146/annurev.genet.30.1.343 Desai M, Zeggini E, Horton VA et al (2006) The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults. Diabetes 55(6):1890–1894. doi:10.2337/db06-0089 Laine AP, Holmberg H, Nilsson A et al (2007) Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations. Dis Markers 23(3):139–145 Chentoufi AA, Polychronakos C (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 51(5):1383–1390 Vafiadis P, Ounissi-Benkalha H, Palumbo M et al (2001) Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 86(8):3705–3710. doi:10.1210/jcem.86.8.7733 Kisand K, Uibo R (2012) LADA and T1D in Estonian population—two different genetic risk profiles. Gene 497(2):285–291. doi:10.1016/j.gene.2012.01.089 Laine AP, Hermann R, Knip M, Simell O, Akerblom HK, Ilonen J (2004) The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population. Tissue Antigens 63(1):72–74 Haller K, Kisand K, Nemvalts V, Laine AP, Ilonen J, Uibo R (2004) Type 1 diabetes is insulin -2221 MspI and CTLA-4 +49 A/G polymorphism dependent. Eur J Clin Invest 34(8):543–548. doi:10.1111/j.1365-2362.2004.01385.x Julier C, Lucassen A, Villedieu P et al (1994) Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes. Am J Hum Genet 55(6):1247–1254 Hauache OM, Reis AF, Oliveira CS, Vieira JG, Sjoroos M, Ilonen J (2005) Estimation of diabetes risk in Brazilian population by typing for polymorphisms in HLA-DR-DQ, INS and CTLA-4 genes. Dis Markers 21(3):139–145 Awata T, Kawasaki E, Ikegami H et al (2007) Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes. J Clin Endocrinol Metab 92(5):1791–1795. doi:10.1210/jc.2006-2242 Bennett ST, Wilson AJ, Cucca F et al (1996) IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 9(3):415–421. doi:10.1006/jaut.1996.0057 Turunen JA, Wessman M, Forsblom C et al (2006) Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. Immunogenetics 58(5–6):331–338. doi:10.1007/s00251-006-0088-3 Chung HR, Yang SW, Shin CH et al (2010) The association of variable number of tandem repeats of the insulin gene with susceptibility to type 1 diabetes among Korean subjects. Diabetes Metab Res Rev 26(6):474–480. doi:10.1002/dmrr.1103 Stene LC, Thorsby PM, Berg JP, Ronningen KS, Undlien DE, Joner G (2006) The relation between size at birth and risk of type 1 diabetes is not influenced by adjustment for the insulin gene (−23HphI) polymorphism or HLA-DQ genotype. Diabetologia 49(9):2068–2073. doi:10.1007/s00125-006-0292-6 Fajardy I, Vambergue A, Stuckens C, Weill J, Danze PM, Fontaine P (2002) CTLA-4 49 A/G dimorphism and type 1 diabetes susceptibility: a French case–control study and segregation analysis. Evidence of a maternal effect. Eur J Immunogenet 29(3):251–257 Graham J, Hagopian WA, Kockum I et al (2002) Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51(5):1346–1355 Ferreira AC, Gomes KB, Sampaio IB, Oliveira VC, Pardini VC, Godard AL (2009) Type 1 diabetes susceptibility determined by HLA alleles and CTLA-4 and insulin genes polymorphisms in Brazilians. Arq Bras Endocrinol Metab 53(3):368–373 Undlien DE, Bennett ST, Todd JA et al (1995) Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene. Diabetes 44(6):620–625 Cejkova P, Novota P, Cerna M et al (2008) HLA DRB1, DQB1 and insulin promoter VNTR polymorphisms: interactions and the association with adult-onset diabetes mellitus in Czech patients. Int J Immunogenet 35(2):133–140. doi:10.1111/j.1744-313X.2008.00749.x Laine AP, Knip M, Ilonen J, Finnish Pediatric Diabetes Register (2013) Transmission disequilibrium analysis of 31 type 1 diabetes susceptibility loci in Finnish families. Tissue Antigens 82(1):35–42. doi:10.1111/tan.12143 Bjornvold M, Undlien DE, Joner G et al (2008) Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes. Diabetologia 51(4):589–596. doi:10.1007/s00125-008-0932-0 Haller K, Kisand K, Pisarev H et al (2007) Insulin gene VNTR, CTLA-4 +49A/G and HLA-DQB1 alleles distinguish latent autoimmune diabetes in adults from type 1 diabetes and from type 2 diabetes group. Tissue Antigens 69(2):121–127. doi:10.1111/j.1399-0039.2006.00745.x Cervin C, Lyssenko V, Bakhtadze E et al (2008) Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes 57(5):1433–1437. doi:10.2337/db07-0299 Cooper JD, Smyth DJ, Smiles AM et al (2008) Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40(12):1399–1401. doi:10.1038/ng.249 Overland HS, Pettersen EF, Ronneseth A, Wergeland HI (2010) Phagocytosis by B-cells and neutrophils in Atlantic salmon (Salmo salar L.) and Atlantic cod (Gadus morhua L.). Fish Shellfish Immunol 28(1):193–204. doi:10.1016/j.fsi.2009.10.021 Chen X, Li X, Wang P et al (2010) Novel association strategy with copy number variation for identifying new risk Loci of human diseases. PLoS One 5(8):e12185. doi:10.1371/journal.pone.0012185 Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N et al (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464(7289):713–720. doi:10.1038/nature08979 Thakkinstian A, McKay GJ, McEvoy M et al (2011) Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HuGE review and meta-analysis. Am J Epidemiol 173(12):1365–1379. doi:10.1093/aje/kwr025 Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. doi:10.1002/sim.1186 DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188 Rossman MD, Thompson B, Frederick M (2003) HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 73(4):720–735. doi:10.1086/378097 Hayden KM, Zandi PP, Lyketsos CG et al (2005) Apolipoprotein E genotype and mortality: findings from the Cache County Study. J Am Geriatr Soc 53(6):935–942. doi:10.1111/j.1532-5415.2005.53301.x Pettersen E, Skorpen F, Kvaloy K, Midthjell K, Grill V (2010) Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord–Trondelag Health Study. Diabetes 59(1):302–310. doi:10.2337/db09-0923 Stead JD, Buard J, Todd JA, Jeffreys AJ (2000) Influence of allele lineage on the role of the insulin minisatellite in susceptibility to type 1 diabetes. Hum Mol Genet 9(20):2929–2935 Smyth DJ, Plagnol V, Walker NM et al (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359(26):2767–2777. doi:10.1056/NEJMoa0807917 Howson JM, Rosinger S, Smyth DJ, Boehm BO, ADBW-END Study Group, Todd JA (2011) Genetic analysis of adult-onset autoimmune diabetes. Diabetes 60(10):2645–2653. doi:10.2337/db11-0364 Ioannidis JP, Boffetta P, Little J et al (2008) Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 37(1):120–132. doi:10.1093/ije/dym159 Moreno SG, Sutton AJ, Turner EH et al (2009) Novel methods to deal with publication biases: secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications. BMJ 339:b2981. doi:10.1136/bmj.b2981 Brophy S, Yderstraede K, Mauricio D et al (2008) Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults. Diabetes Care 31(3):439–441. doi:10.2337/dc07-1308 Desai M, Zeggini E, Horton VA et al (2007) An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 50(1):68–73. doi:10.1007/s00125-006-0513-z Kantarova D, Buc M (2007) Genetic susceptibility to type 1 diabetes mellitus in humans. Physiol Res 56(3):255–266 Rajasalu T, Haller K, Salur L et al (2007) Insulin VNTR I/III genotype is associated with autoantibodies against glutamic acid decarboxylase in newly diagnosed type 1 diabetes. Diabetes Metab Res Rev 23(7):567–571. doi:10.1002/dmrr.745 Achenbach P, Hummel M, Thumer L, Boerschmann H, Hofelmann D, Ziegler AG (2013) Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children. Diabetologia 56(7):1615–1622. doi:10.1007/s00125-013-2896-y Pugliese A (2005) The insulin gene in type 1 diabetes. IUBMB Life 57(7):463–468. doi:10.1080/15216540500163301 Vafiadis P, Bennett ST, Todd JA et al (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15(3):289–292. doi:10.1038/ng0397-289 Pugliese A, Zeller M, Fernandez A Jr et al (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15(3):293–297. doi:10.1038/ng0397-293 Wong FS, Janeway CA Jr (1999) Insulin-dependent diabetes mellitus and its animal models. Curr Opin Immunol 11(6):643–647 Heino M, Peterson P, Kudoh J et al (1999) Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun 257(3):821–825. doi:10.1006/bbrc.1999.0308 Cai CQ, Zhang T, Breslin MB, Giraud M, Lan MS (2011) Both polymorphic variable number of tandem repeats and autoimmune regulator modulate differential expression of insulin in human thymic epithelial cells. Diabetes 60(1):336–344. doi:10.2337/db10-0255 Anderson MS, Venanzi ES, Klein L et al (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597):1395–1401. doi:10.1126/science.1075958 Fung EY, Smyth DJ, Howson JM et al (2009) Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 10(2):188–191. doi:10.1038/gene.2008.99