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. 2007 May 1;6(1):75–81. doi: 10.1111/j.1582-4934.2002.tb00312.x

The study of CTLA‐4 and vitamin D receptor polymorphisms in the Romanian type 1 diabetes population

C Guja 1,✉, S Marshall 2, K Welsh 2, M Merriman 3, A Smith 3, J A Todd 3, C Ionescu‐Tîrgoviste 1
PMCID: PMC6740123  PMID: 12003670

Abstract

Several studies suggested that part of the genetic susceptibility for Type 1 diabetes (TIDM) is encoded by some polymorphisms of CTLA‐4 gene (2q33) and of Vitamin D Receptor gene (VDR; 12q12‐14). Our aim was to assess their contribution to TIDM genetic susceptibility in the Romanian population. We typed CTLA‐4 49 A/G and VDR FokI (F/f), ApaI (A/a) and TaqI (T/t) polymorphisms by Sequence Specific Primer PCR (SSP‐PCR) in 204 Romanian diabetic families (756 individuals: 212 TIDM probands and 544 unaffected parents and siblings). We studied alleles transmission using the Transmission Disequilibrium Test (TDT). We found an increased transmission of CTLA‐4 49G allele to diabetics (54.8%, p=0.11). The transmission of F (56.1%, p=0.063), a (55.7%, p=0.061) and T (51.8%, p=0.37) alleles of VDR gene to diabetics was increased but did not reach statistical significance. In conclusion we found the same increased transmission of CTLA‐4 49 G allele to diabetics as previously reported. VDR FoqI F allele seems to be predisposing while TaqI T allele seems to be protective.

Keywords: type I diabetes, genetic, CTLA‐4, vitamin D receptor, Romania

References

  • 1. Cudworth A., Woodrow J., HL‐A system and diabetes mellitus, Diabetes, 24: 345–349, 1974. [DOI] [PubMed] [Google Scholar]
  • 2. Todd JA., A protective role of the environment in the development of type 1 diabetes?, Diabetic Med., 8: 906–910, 1991. [DOI] [PubMed] [Google Scholar]
  • 3. Kyvik K.O., Green A., Beck‐Nielsen H., Concordance rates of insulin dependent diabetes mellitus: a population based study of young Dansih twins, B.M.J., 311: 913–917, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Singal D.P., Blajchman M.A., Histocompatibility antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus, Diabetes, 22: 429–432, 1973. [DOI] [PubMed] [Google Scholar]
  • 5. Nerup J., Platz P., Anderson O.O., Christy M., Lyngsoe J., Poulsen J.E., Ryder L.P., Nielsen L.S., Thomsen M., Svejgaard A., HLA antigens and diabetes mellitus, Lancet, 2: 864–866, 1974. [DOI] [PubMed] [Google Scholar]
  • 6. Todd J.A., Bell J.I., McDevitt H.O., HLA‐DQ beta gene contributes to susceptibility and resistance to insulin‐dependent diabetes mellitus, Nature, 329: 599–604, 1987. [DOI] [PubMed] [Google Scholar]
  • 7. Sheehy M.J., Scharf S.J., Rowe J.R., Neme D.G.M., Meske L.M., Erlich H.A., Nepom B.S., A diabetes‐susceptible HLA haplotype is best defined by a combination of HLA‐DR and ‐DQ alleles, J. Clin. Invest., 83: 830–835, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Bennett S.T., Lucassen A.M., Gough S.C.L., Powell E.E., Undlien D.E., Pritchard L.E., Merriman M.E. et al., Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus, Nature Genet, 9: 284–292, 1995. [DOI] [PubMed] [Google Scholar]
  • 9. Nistico L., Buzzetti R., Pritchard L.E., van den Auwera B., Giovannini C., Bosi E., Larrad M.T.M. et al., The CTLA‐4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes, Hum. Mol. Genet., 5: 1075–1080, 1996. [DOI] [PubMed] [Google Scholar]
  • 10. Todd J.A., Farrall M., Panning for gold: genomewide scanning for linkage in type 1 diabetes, Hum. Mol. Genet., 5: 1443–1448, 1996. [DOI] [PubMed] [Google Scholar]
  • 11. Davies J.L., Kawaguchi Y., Bennett S.T., Copeman J.B., Cordell H.J., Pritchard L.E., Reed P.W., Gough S.C.L., Jenkins S.C., Palmer S.M., Balfour K.M., Rowe B.R., Farrall M., Barnett A.H., Bain S.C, Todd J.A., A genome‐wide search for human type 1 diabetes susceptibility genes, Nature, 371: 130–136, 1994. [DOI] [PubMed] [Google Scholar]
  • 12. Todd J.A., Genetic analysis of type 1 diabetes using whole genome approaches, Proc. Natl. Acad. Sci. USA, 92: 8560–8565, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Mein C.A., Esposito L., Dunn M.G., Johnson G.C., Timms A.E., Goy J.V., Smith A.N., Sebag‐ Montefiore L., Merriman M.E., Wilson A.J., Pritchard L.E., Cucca F., Barnett A.H., Bain S.C., Todd J.A., A search for type 1 diabetes susceptibility genes in families from the United Kingdom, Nat. Genet., 19: 297–300, 1998. [DOI] [PubMed] [Google Scholar]
  • 14. Ionescu‐Tîrgovite C., Guja C., Herr M., Cucca F., Welsh K., Bunce M., Marshall S., Todd J.A., Low frequency of HLA DRB1*03 ‐ DQB1*02 and DQB1*0302 haplotypes in Romania is consistent with the country's low incidence of type 1 diabetes, Diabetologia, 44: B60–B66, 2001. [DOI] [PubMed] [Google Scholar]
  • 15. Bunce M., O'Neill C.M., Barnardo M.C.N.M., Krausa P., Browning M.J., Morris P.J., Welsh K.I., Phototyping: comprehensive DNA typing for HLA‐A, B, C, DRB1, DRB3, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequencespecific primers (PCR‐SSP), Tissue Antigens, 46: 355–367, 1995. [DOI] [PubMed] [Google Scholar]
  • 16. McLaren A.J., Marshall S.E., Haldar N.A., Mullighan C.G., Fuggle S.V., Morris P.J., Welsh K.I., Adhesion molecule polymorphisms in chronic renal allograft failure, Kidney International, 55: 1977–1982, 1999. [DOI] [PubMed] [Google Scholar]
  • 17. Mullighan C.G., Marshall S.E., Bunce M., Welsh K.I., Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency, Genes and Immunity, 1: 137–148, 1999. [DOI] [PubMed] [Google Scholar]
  • 18. Ionescu‐Tirgoviste C., Serban V., Guja C., Mota M., Creteanu G., Calin A., Morosanu M., Ferariu I., Halmagy I., Cristescu J., Strugariu M., Minescu A., Barbul R., Very low incidence of type 1 diabetes in children in Romania, Diabetologia, 42: A85, 1999. [Google Scholar]
  • 19. EURODIAB ACE Study Group. , Variation and trends in incidence of childhood diabetes in Europe, Lancet, 355: 873–876, 2000. [PubMed] [Google Scholar]
  • 20. Bunce M., The development and applications of a single PCR‐based method of HLA genotyping, PhD thesis, Oxford Brookes University, Oxford , 1996. [Google Scholar]
  • 21. Spielman R.S., McGinnis R.E., Ewens W.J., Transmission test for linkage disequilibrium: the insulin gene region and insulin‐dependent diabetes mellitus (IDDM), Am. J. Hum. Genet., 52: 506–516, 1993. [PMC free article] [PubMed] [Google Scholar]
  • 22. Guja C., Todd J.A., Smith A., Welsh K., Marshall S., Ionescu‐Tîrgovite C. Analysis of the CTLA‐4 and vitamin D receptor gene polymorphisms in Romanian type 1 diabetic families, Diabetologia, 43: A7 (Abstract), 2000. [Google Scholar]
  • 23. Copeman J.B., Cucca F., Hearne C.M., Cornall R.J., Reed P.W., Ronningen K.S. et al., Linkage disequilibrium mapping ofa type 1 diabetes susceptibility gene (IDDM7) to human chromosome 2q31–q33, Nat. Genet., 9: 80–85, 1995. [DOI] [PubMed] [Google Scholar]
  • 24. Owerbach D., Gabbay K.H., The search for IDDM susceptibility genes: the next generation, Diabetes, 45: 544–551, 1996. [DOI] [PubMed] [Google Scholar]
  • 25. Marron M.P., Raffel L.J., Garchon H.J., Jacob C.O., Serrano‐Rios M., Larrad M.T.M et al., Insulin‐dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups, Hum. Mol. Genet. 6: 1275–1282, 1997. [DOI] [PubMed] [Google Scholar]
  • 26. Esposito L., Hill N., Pritchard L.E., Cucca F., Muxworthy C., Merriman M.E. et al., Analysis of putative loci IDDM7, IDDM12, IDDM13 and candidate genes NRAMP1 and IA‐2 and the interleukin‐1 gene cluster, Diabetes, 47: 17971–800, 1998. [DOI] [PubMed] [Google Scholar]
  • 27. Awata T., Kurihara S., Iitaka M., Takei S.I., Inou I., Ishii C. et al., Association of CTLA4 gene A‐G polymosphism (IDDM12 locus) with acute‐onset and insulin depleted IDDM as well as autoimmune thyroid disease (Grave's disease and Hashimoto's thyroiditis) in the Japanese popualtion, Diabetes, 47: 128–129, 1998. [DOI] [PubMed] [Google Scholar]
  • 28. Buzzetti R., Petrone A., Mesturino G., Giorgi R., Fiori R., Nistico L. et al., Major role for CTLA‐4 gene in DR4‐positive type 1 diabetic patients and in DR3 negative Grave's disease patients, Diabetologia, 42: A74 (Abstract), 1999. [Google Scholar]
  • 29. Thomasset M., Vitamin D and the immune system, Pathol. Biol., 42: 163–172, 1994. [PubMed] [Google Scholar]
  • 30. Mathieu C., Waer M., Laureys J., Rutgeerts O., Bouillon R., Prevention of autoimmune diabetes in NOD mice by 1,25 dihydoxyvitamin D3, Diabetologia, 37: 552–558, 1994. [DOI] [PubMed] [Google Scholar]
  • 31. EURODIAB Substudy 2 Study Group. , Vitamin D supplement in early childhood and risk for Type 1 (insulin‐dependent) diabetes mellitus, Diabetologia, 42: 51–54, 1999. [DOI] [PubMed] [Google Scholar]
  • 32. Gross C., Krishnan A.V., Malloy P.J., Eccleshall T.R., Zhao X.Y., Feldman D., The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants, J. Bone Miner Res., 13: 1691–1699, 1998. [DOI] [PubMed] [Google Scholar]
  • 33. McDermott M.F., Ramachandran A., Ogunkolade B.W., Aganna E., Curtis D., Boucher B.J., Snehalatha C., Hitman G.A., Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians, Diabetologia, 40: 971–975, 1997. [DOI] [PubMed] [Google Scholar]
  • 34. Pani M.A., Knapp M., Donner H., Braun J., Baur M.P., Usadel K.H., Badenhoop K., Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in germans, Diabetes, 49: 504–507, 2000. [DOI] [PubMed] [Google Scholar]
  • 35. Malecki M.T., Klupa T., Moczulski D., Warram J.H., Krolewski A.S. No evidence of association between vitamin D receptor (VDR) gene polymorphisms and type 1 diabetes in caucasians, Diabetologia, 43: A7 (Abstract), 2000. [Google Scholar]

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