Abstract
Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case–control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic, dominant and recessive genetic model. A total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn’t included in the following meta-analysis because the distribution of genotypes in the control group didn’t comply with Hardy–Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls) and for rs3087243 (820 cases and 4824 controls) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.
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References
Alshareef SA, Omar SM, Hamdan HZ, Adam I (2019) Cytotoxic T-lymphocyte antigen-4 +49A/G polymorphisms in Sudanese adults with type 1 diabetes and latent autoimmune diabetes. BMC Res Notes 12:769. https://doi.org/10.1186/s13104-019-4814-y
Andersen MK, Hansen T (2019) Genetic aspects of latent autoimmune diabetes in adults: a mini-review. Curr Diabetes Rev 15:194–198. https://doi.org/10.2174/1573399814666180730123226
Atabani SF, Thio CL, Divanovic S, Trompette A, Belkaid Y, Thomas DL, Karp CL (2005) Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol 35:2157–2162. https://doi.org/10.1002/eji.200526168
Barreto M, Santos E, Ferreira R, Fesel C, Fontes MF, Pereira C, Martins B, Andreia R, Viana JF, Crespo F, Vasconcelos C, Ferreira C, Vicente AM (2004) Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet 12:620–626. https://doi.org/10.1038/sj.ejhg.5201214
Buzzetti R, Zampetti S, Maddaloni E (2017) Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 13:674–686. https://doi.org/10.1038/nrendo.2017.99
Buzzetti R, Di Pietro S, Giaccari A, Petrone A, Locatelli M, Suraci C, Capizzi M, Arpi ML, Bazzigaluppi E, Dotta F, Bosi E and Non Insulin Requiring Autoimmune Diabetes Study G (2007) High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care 30:932–938. https://doi.org/10.2337/dc06-1696
Caputo M, Cerrone GE, López AP, Villalba A, Krochik GA, Cédola FN, Targovnik HM, Frechtel GD (2005) Cytotoxic T lymphocyte antigen 4 heterozygous codon 49 A/G dimorphism is associated to latent autoimmune diabetes in adults (LADA). Autoimmunity 38:277–281. https://doi.org/10.1080/08916930500158203
Cosentino A, Gambelunghe G, Tortoioli C, Falorni A (2002) CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. Ann New York Academy Sci 958:337–340
Delitala AP, Fanciulli G, Zoledziewska M, Pitzalis M, Pusceddu P, Frongia P, Puddu L, Errigo A, Maioli M, Delitala G, Pes GM (2015) Allelic variant in CTLA4 is associated with thyroid failure and faster β-cell exhaustion in latent autoimmune diabetes in adults. J Diabetes 7:68–73. https://doi.org/10.1111/1753-0407.12137
Douroudis K, Prans E, Kisand K, Nemvalts V, Uibo R (2009) Cytotoxic T-lymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults. Clin Chim Acta 403:226–228. https://doi.org/10.1016/j.cca.2009.03.036
Grant SF, Hakonarson H, Schwartz S (2010) Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocr Rev 31:183–193. https://doi.org/10.1210/er.2009-0029
Haller K, Kisand K, Pisarev H, Salur L, Laisk T, Nemvalts V, Uibo R (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 69:121–127. https://doi.org/10.1111/j.1399-0039.2006.00745.x
Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, Mauricio D, De Leiva A, Yderstraede K, Beck-Neilsen H, Tuomilehto J, Sarti C, Thivolet C, Hadden D, Hunter S, Schernthaner G, Scherbaum WA, Williams R, Brophy S, Pozzilli P, Leslie RD, Lc A (2013) Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care 36:908–913. https://doi.org/10.2337/dc12-0931
Jin P, Huang G, Lin J, Yang L, Xiang B, Zhou W, Zhou Z (2011) High titre of antiglutamic acid decarboxylase autoantibody is a strong predictor of the development of thyroid autoimmunity in patients with type 1 diabetes and latent autoimmune diabetes in adults. Clin Endocrinol (oxf) 74:587–592. https://doi.org/10.1111/j.1365-2265.2011.03976.x
Jin P, Xiang B, Huang G, Zhou Z (2015) The association of cytotoxic T-lymphocyte antigen-4 + 49A/G and CT60 polymorphisms with type 1 diabetes and latent autoimmune diabetes in Chinese adults. J Endocrinol Invest 38:149–154. https://doi.org/10.1007/s40618-014-0162-x
Kisand K, Uibo R (2012) LADA and T1D in Estonian population - two different genetic risk profiles. Gene 497:285–291. https://doi.org/10.1016/j.gene.2012.01.089
Korolija M, Renar IP, Hadzija M, Medvidovic EP, Pavkovic P, Jokic M, Hadzija MP (2009) Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with Type 1 Diabetes in Croatians. Diabetes Res Clin Pract 86:e54–e57. https://doi.org/10.1016/j.diabres.2009.09.012
Lee CS, Lee YJ, Liu HF, Su CH, Chang SC, Wang BR, Chen TL, Liu TL (2003) Association of CTLA4 gene A-G polymorphism with rheumatoid arthritis in Chinese. Clin Rheumatol 22:221–224. https://doi.org/10.1007/s10067-003-0720-7
Leslie RD, Pozzilli P (1994) Type I diabetes masquerading as type II diabetes. Possible implications for prevention and treatment. Diabetes Care 17:1214–1219. https://doi.org/10.2337/diacare.17.10.1214
Leslie RD, Williams R, Pozzilli P (2006) Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab 91:1654–1659. https://doi.org/10.1210/jc.2005-1623
Liu B, Xiang Y, Liu Z, Zhou Z (2020) Past, present and future of latent autoimmune diabetes in adults. Diabetes Metab Res Rev 36:e3205. https://doi.org/10.1002/dmrr.3205
Moher D, Liberati A, Tetzlaff J, Altman DG and Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097
Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E, Larrad MT, Rios MS, Chow CC, Cockram CS, Jacobs K, Mijovic C, Bain SC, Barnett AH, Vandewalle CL, Schuit F, Gorus FK, Tosi R, Pozzilli P, Todd JA (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry Hum Mol Genet 5:1075–1080. https://doi.org/10.1093/hmg/5.7.1075
Ounissi-Benkalha H, Polychronakos C (2008) The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med 14:268–275. https://doi.org/10.1016/j.molmed.2008.04.002
Pang H, Xia Y, Luo S, Huang G, Li X, Xie Z, Zhou Z (2021) Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus. J Med Genet 58:289–296. https://doi.org/10.1136/jmedgenet-2020-107350
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 59:302–310. https://doi.org/10.2337/db09-0923
Qi X, Wang J, Xu Z, Sun J, Keller L, Xu W (2014) Relationship of CTLA-4 gene to latent autoimmune diabetes in adults and Type 2 diabetes: a population-based case-control study. Diabetes Management 4:131–139. https://doi.org/10.2217/dmt.13.70
Radtke MA, Midthjell K, Nilsen TI, Grill V (2009) Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trondelag Health (HUNT) study. Diabetes Care 32:245–250. https://doi.org/10.2337/dc08-1468
Redondo MJ, Evans-Molina C, Steck AK, Atkinson MA, Sosenko J (2019) The influence of type 2 diabetes-associated factors on Type 1 diabetes. Diabetes Care 42:1357–1364. https://doi.org/10.2337/dc19-0102
Rolandsson O, Palmer JP (2010) Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia 53:1250–1253. https://doi.org/10.1007/s00125-010-1713-0
Sachan A, Zaidi G, Sahu RP, Agrawal S, Colman PG, Bhatia E (2015) Low prevalence of latent autoimmune diabetes in adults in northern India. Diabet Med 32:810–813. https://doi.org/10.1111/dme.12644
Sharma C, Osman W, Afandi B, Aburawi EH, Beshyah SA, Al-Mahayri Z, Al-Rifai RH, Al Yafei Z, ElGhazali G, Alkaabi J (2021) Association of variants in PTPN22, CTLA-4, IL2-RA, and INS genes with type 1 diabetes in Emiratis. Ann Hum Genet 85:48–57. https://doi.org/10.1111/ahg.12406
Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissen M, Ehrnstrom BO, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150–157. https://doi.org/10.2337/diabetes.48.1.150
Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L (2014) The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383:1084–1094. https://doi.org/10.1016/S0140-6736(13)62219-9
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 (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511. https://doi.org/10.1038/nature01621
Westra HJ, Martinez-Bonet M, Onengut-Gumuscu S, Lee A, Luo Y, Teslovich N, Worthington J, Martin J, Huizinga T, Klareskog L, Rantapaa-Dahlqvist S, Chen WM, Quinlan A, Todd JA, Eyre S, Nigrovic PA, Gregersen PK, Rich SS, Raychaudhuri S (2018) Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes. Nat Genet 50:1366–1374. https://doi.org/10.1038/s41588-018-0216-7
Xiang Y, Zhou Z, Deng C, Leslie RD (2013) Latent autoimmune diabetes in adults in Asians: similarities and differences between East and West. J Diabetes 5:118–126. https://doi.org/10.1111/1753-0407.12029
Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47:174–192. https://doi.org/10.1007/s12016-014-8422-2
Zhou Z, Xiang Y, Ji L, Jia W, Ning G, Huang G, Yang L, Lin J, Liu Z, Hagopian WA, Leslie RD and Group LCS (2013) Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes 62:543–550. https://doi.org/10.2337/db12-0207
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This work was supported by the National Natural Science Foundation of China (grant numbers 82070813, 81873634, 81400783), the National Key R&D Program of China (grant numbers 2016YFC1305000, 2016YFC1305001, 2018YFC1315603), and the Hunan Province Natural Science Foundation of China (Grant No. 2018JJ2573, 2020JJ2053).
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ZX and ZZ participated in research design. HP, SL, GH, and XL selected the articles. HP performed the data analysis. The manuscript was drafted by HP and critically reviewer and discussed with other co-authors. All the authors read and approved the final manuscript.
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Pang, H., Luo, S., Huang, G. et al. The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms with Latent Autoimmune Diabetes in Adults: A Meta-Analysis. Biochem Genet 60, 1222–1235 (2022). https://doi.org/10.1007/s10528-021-10152-w
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DOI: https://doi.org/10.1007/s10528-021-10152-w