Genetic susceptibility factors in type 1 diabetes: Linkage, disequilibrium and functional analyses

Current Opinion in Immunology

Volumn 10, Issue 6, 1998, Pages 682-689

  She, Jin Xiong ^a   Marron, Michele P ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HLA ANTIGEN CLASS 2; HLA DR ANTIGEN; INSULIN;

CHROMOSOME 11Q; CHROMOSOME 6Q; ETHNIC GROUP; GENE LINKAGE DISEQUILIBRIUM; GENE MAPPING; GENE MUTATION; GENETIC HETEROGENEITY; GENETIC SUSCEPTIBILITY; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; MARKER GENE; NONHUMAN; REVIEW; VARIABLE NUMBER OF TANDEM REPEAT;

EID: 0032404079     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(98)80089-7     Document Type: Article

References (64)

1. Olmos P, A'Hern R, Millward BA, Risley D, Pyke DA, Leslie RDG. The significance of the concordance rate for type 1 (insulin-dependant) diabetes in identical twins. Diabetologia. 31:1988;747-750.
2. Tattersall RB, Pyke DA. Diabetes in identical twins. Lancet. 787:1972;1120-1124.
3. Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins. Diabetologia. 20:1981;87-93.
4. Kumar D, Gemayel NS, Gill SK, Bray GA, Roy-Burman P, Deapen D, Mack TM. Type-specific concordance in young diabetic monozygotic twins. Adv Exp Med Biol. 246:1988;259-267.
5. She JX. Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today. 17:1996;323-329.
6. Davies JL, Yoshihiko K, Bennett S, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SCL, Jenkins C, Palmer SM, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 371:1994;130-136.
7. Hashimoto L, Habita C, Beressi JP, Delepine M, Besse C, Cambon-Thomsen A, Deschamps I, Rotter JI, Djoulah S, James MR, et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature. 371:1994;161-164.
8. Concannon P, Ewens-Gogolin KJ, Hinds D, Wapelhorst B, Morrison VA, Stirling B, Mitra M, Farmer J, Williams SR, Cox DR, et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. of outstanding interest Nat Genet. 19:1998;292-296 This is a genome scan using 438 microsatellite markers and 679 affected sibpairs from the US and UK. The families from the UK used in this study are a subset analyzed in reference [9]. The families from the US have also been analyzed in other studies. This study identified a novel susceptibility interval on chromosome 1. In contrast to reference [9], this paper did not provide support for linkage for any previously reported linkage intervals except IDDM1. The failure to detect linkage for the confirmed intervals in this study may be due to a number of reasons: mixing of families from different populations, inclusion of families with more than two affected siblings, marker distance from the peak loci, genetic heterogeneity, random variation and others.
9. Mein CA, Esposito L, Dunn MG, Johnson GC, Timms AE, Goy JV, Smith AN, Sebag-Montefiore L, Merriman ME, Wilson AJ, et al. A search for type 1 diabetes susceptibility genes in families from the United Kingdom. of outstanding interest Nat Genet. 19:1998;297-300 This is the second genome scan for IDDM susceptibility genes in the UK population. A total of 356 sibpairs were studied with 348 microsatellite markers throughout the entire human genome. This study provided strong linkage evidence for several previously suggested susceptibility intervals (IDDM1, IDDM2, IDDM8 and IDDM10) as well as several new intervals; however, evidence for other previously suggested intervals was weak. The success of this study contrasts with the report described in annotation [8].
10. Field LL, Tobias R, Magnus T. A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus. Nat Genet. 8:1994;189-194.
11. Owerbach D, Gabbay KH. The HOXD8 locus (2q31) is linked to type I diabetes: interaction with chromosome 6 and 11 disease susceptibility genes. Diabetes. 44:1995;132-136.
12. Luo DF, Bui MM, Muir A, Maclaren NK, Thomson G, She JX. Affected sibpair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27. Amer J Hum Genet. 57:1995;911-919.
13. Morahan G, Huang D, Tait BD, Colman PG, Harrison LC. Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus. Science. 272:1996;1811-1813.
14. Delepine M, Pociot F, Habita C, Hashimoto L, Froguel P, Rotter J, Cambon-Thomsen A, Deschamps I, Djoulah S, Weissenbach J, et al. Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6. of special interest Amer J Hum Genet. 60:1997;174-187 This study identified the IDDM15 susceptibility interval on chromosome 6q; however, the region is loosely linked to the HLA (IDDM1) interval. The authors presented a new method to calculate linkage for loci that are linked to a known susceptibility gene.
15. Field LL, Tobias R, Thomson G, Plon S. Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31. Genomics. 33:1996;1-8.
16. Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Amer J Hum Genet. 40:1987;1-14.
17. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 11:1995;241-247.
18. Thomson G. Identifying complex disease genes: progress and paradigms. Nat Genet. 8:1994;108-110.
19. Luo DF, Buzzetti R, Rotter JI, Maclaren NK, Raffel LJ, Nistico L, Giovannini C, Pozzilli P, Thomson G, She JX. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8. Hum Mol Genet. 5:1996;693-698.
20. Davies LD, Cucca F, Goy JV, Atta ZAA, Merriman ME, Wilson A, Barnett AH, Bain SC, Todd JA. Saturation multipoint linkage mapping of chromosome 6q in type 1 diabetes. Hum Mol Genet. 5:1996;1071-1074.
21. Julier C, Hyer RN, Davies J, Merlin F, Soularue P, Briant L, Cathelineau G, Deschamps I, Rotter JI, Froguel P, et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 354:1991;155-158.
22. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, Bell JI. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet. 4:1993;305-310.
23. Bui MM, Luo DF, She JY, Maclaren NK, Muir A, Thomson G, She JX. Paternally transmitted IDDM2 influences diabetes susceptibility despite bialellic expression of the insulin gene in human pancreas. J Autoimmun. 9:1996;97-103.
24. Pugliese A, Awdeh ZL, Alper CA, Jackson RA, Eisenbarth GS. The paternally inherited insulin gene B allele (1,428 Fok I site) confers protection from insulin-dependent diabetes in families. J Autoimmun. 7:1994;687-694.
25. Bain SC, Prins JB, Hearne CM, Rodrigues NR, Rowe BR, Pritchard LE, Ritchie RJ, Hall JRS, Undlien DE, Ronningen KS, et al. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nat Genet. 2:1992;212-215.
26. Bennett ST, Lucassen AM, Gough SCL, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 9:1995;284-292.
27. Lernmark A, Ott J. Sometimes it's hot, sometimes it's not. Nat Genet. 19:1998;213-214.
28. + subsets of sibpairs.
29. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 273:1996;1516-1517.
30. Spielman RS, Mcginnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Amer J Hum Genet. 52:1993;506-512.
31. Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E, Martinez-Larrad MT, Rios MS, Chow CC, Cockram CS, et al. The CTLA4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum Mol Genet. 5:1996;1075-1080.
32. Marron MP, Raffel LJ, Garchon H-J, Jacob CO, Serrano-Rios M, Larrad MTM, Teng W-P, Park Y, Zhang Z-X, Goldstein DR, et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. of outstanding interest Hum Mol Genet. 8:1997;1275-1282 In this study, the authors analyzed a multiethnic collection of multiplex (two or more affected members) and simplex (one affected member) diabetic families and showed significant linkage disequilibrium with the 49-A/G and the (AT)n microsatellite markers within the CTLA4 gene. This paper demonstrates the importance of multiethnic collection of families in mapping studies of complex disease genes and the importance of combining families in ways that may have a biological meaning.
33. Copeman JB, Cucca F, Hearne CM, Cornall RJ, Reed PW, Ronningen KS, Undlien DE, Nistico L, Buzzetti R, Tosi R, et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nat Genet. 9:1995;80-85.
34. Luo DF, Maclaren NK, Huang HS, Muir A, She JX. Intrafamilial and case-control association analyses of D2S152 in insulin-dependent diabetes mellitus. Autoimmunity. 21:1995;143-145.
35. Merriman T, Twells R, Merriman M, Eaves I, Cox R, Cucca F, McKinney P, Shield J, Baum D, Bosi E, et al. Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21. of special interest Hum Mol Genet. 6:1997;1003-1010 This paper presents highly significant evidence for linkage disequilibrium with a marker in the IDDM6 region in 1056 families but complete absence of linkage disequilibrium in a second data set of 390 families. The authors explained the observations by different susceptibility haplotypes in the second data set; however, random variation should not be ignored in the interpretation of such discrepancies between data sets.
36. Reed P, Cucca F, Jenkins S, Merriman M, Wilson A, McKinney P, Bosi E, Joner G, Ronningen K, Thorsby E, et al. Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11. of special interest Hum Mol Genet. 6:1997;1011-1016 This paper presents evidence of linkage and disequilibrium in the IDDM10 region.
37. Fu J, Ikegami H, Kawaguchi Y, Fujisawa T, Kawabata Y, Hamada Y, Ueda H, Shintani M, Nojima K, Babaya N, et al. Association of distal chromosome 2q with IDDM in Japanese subjects. Diabetologia. 41:1998;228-232.
38. Donner H, Rau H, Walfish PG, Braun J, Siegmund T, Finke R, Herwig J, Usadel KH, Badenhoop K. CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab. 82:1997;143-146.
39. Lowe RM, Sund GC, Graham KI, Landin-Olsson M, Lernmark A. The 3′-end CTLA4-4 gene (AT) microsatellite is associated with type 1 diabetes in 0-34 year old Swedish patients and controls. Diabetes. 47:1998;A204. (suppl 2).
40. Awata T, Kurihara S, Iitaka M, Takei SI, Inoue I, Ishii C, Negishi K, Izumida T, Yoshida Y, Hagura R, et al. Association of CTLA4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves' disease and Hashimoto's thyroiditis) in the Japanese population. Diabetes. 47:1998;128-129.
41. Yanagawa T, Hidaka Y, Guimaracs V, Soliman M, DeGroot LJ. CTLA4 gene polymorphism associated with Graves' disease in a Caucasian population. J Clin Endocrinol Metab. 80:1995;41-45.
42. Marron MP, Zeidler A, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Larrad MTM, Park YS, Rotter JI, Maclaren NK, She JX. IDDM12 is located within 100kb of DNA near CTLA4 on 2q33. Diabetes. 47:1998;A217. (suppl 2).
43. Vartdal F, Johansen BH, Friede T, Thorpe CJ, Stevanovic S, Eriksen JE, Sletten K, Thorsby E, Rammensee HG, Sollid LM. The peptide binding motif of the disease associated HLA-DQ (alpha 1* 0501, beta 1* 0201) molecule. Eur J Immunol. 26:1996;2764-2772.
44. Godkin A, Friede T, Davenport M, Stevanovic S, Willis A, Jewell D, Hill A, Rammensee HG. Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 (DQ 3 2). Int Immunol. 9:1997;905-911.
45. Ettinger RA, Kwok WW. A peptide binding motif for HLA DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. of special interest J Immunol. 160:1998;2365-2373 The researchers have established a binding motif for HLA-DQB1*0602 using binding studies with overlapping peptides from insulin. This motif was used to predict peptides from the autoantigens glutamic acid decarboxylase 65, IA-2 and proinsulin. Analysis of binding of these peptides revealed that 79% of the peptides that were predicted to be able to bind to HLA-DQB1*0602 did so in vitro.
46. Kwok WW, Domeier ML, Raymond FC, Byers P, Nepom GT. Allele-specific motifs characterize HLA-DQ interactions with a diabetes-associated peptide derived from glutamic acid decarboxylase. J Immunol. 156:1996;2171-2177.
47. Kwok WW, Domeier ME, Johnson ML, Nepom GT, Koelle DM. HLA-DQB1 codon 57 is critical for peptide binding and recognition. J Exp Med. 183:1996;1253-1258.
48. Nepom BS, Nepom GT, Coleman M, Kwok WK. Critical contribution of beta chain residue 57 in peptide binding ability of both HLA-DR and -DQ molecules. Proc Natl Acad Sci USA. 93:1996;7202-7206.
49. Reizis B, Altmann DM, Cohen IR. Biochemical characterization of the human diabetes-associated HLA-DQ8 allelic product: similarity to the major histocompatibility complex class II I-A(g)7 protein of non-obese diabetic mice. Eur J Immunol. 27:1997;2478-2483.
50. Buckner J, Kwok WW, Nepom B, Nepom GT. Modulation of HLA-DQ binding properties by differences in class II dimer stability and pH-dependent peptide interactions. J Immunol. 157:1996;4940-4945.
51. Congia M, Patel S, Cope AP, De Virgiliis S, Sonderstrup G. T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. of special interest Proc Natl Acad Sci USA. 95:1998;3833-3838 The researchers immunized HLA-DR4-transgenic mice with human pre-proinsulin, proinsulin and insulin. The authors have identified a naturally processed immunodominant epitope recognized by 25 out of 28 T-cell hybridomas that were tested. This epitope spans the c-peptide/A-chain junction of proinsulin which is cleaved during processing to mature insulin.
52. Wicker LS, Chen SL, Nepom GT, Elliott JF, Freed DC, Bansal A, Zheng S, Herman A, Lernmark A, Zaller DM, et al. Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401. J Clin Invest. 98:1996;2597-2603.
53. Patel SD, Cope AP, Congia M, Chen TT, Kim E, Fugger L, Wherrett D, Sonderstrup-McDevitt G. Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(alpha1*010, beta1*0401) transgenic mice. of special interest Proc Natl Acad Sci USA. 94:1997;8082-8087 The researchers have identified T cell epitopes of human GAD65 in HLA-DRB1*0401-transgenic mice. Six of the ten regions identified are recognized by multiple T cell hybridomas, with two of the most commonly recognized regions overlapping those reported in [52]. These studies identified epitopes that can be naturally processed and presented by HLA-DR4 molecules and which confer susceptibility to type 1 diabetes.
54. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependant diabetes mellitus. Diabetes. 33:1984;176-183.
55. Bennett ST, Wilson AJ, Esposito L, Bouzekri N, Undlien DE, Cucca F, Nistico L, Buzzetti F, Bosi E, Pociot F, et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group. Nat Genet. 17:1997;350-352.
56. Awata T, Kurihara S, Kikuchi C, Takei S, Inoue I, Ishii C, Takahashi K, Negishi K, Yoshida Y, Hagura R, et al. Evidence for association between the class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population. Diabetes. 46:1997;1637-1642.
57. Kennedy GC, German MS, Rutter WJ. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet. 9:1995;293-297.
58. Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C. Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun. 9:1996;397-403.
59. Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, Barnett AH, Bain SC, Todd JA. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun. 9:1996;415-421.
60. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasingle S, Colle E, Polychronakos C. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. of outstanding interest Nat Genet. 15:1997;289-292 Using reverse-transcriptase polymerase chain reactions, the researchers amplified insulin mRNA from VNTR class I/III heterozygous fetal thymi. They show a 2-3-fold increase of insulin expression from class III alleles in the thymus. This corresponds with another report [61] and is in contrast to previous findings by these researchers and others, of decreased expression from class III alleles in pancreas [58,59].
61. Pugliese A, Zeller M, Fernandez AJ, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. of outstanding interest Nat Genet. 15:1997;293-297 Similar to [60], the researchers detected insulin expression in 36 out of 37 fetal and postnatal (up to 13 years of age) thymi. Relative quantitation of alleles from VNTR class I/III heterozygotes revealed a 2.5-fold increase in insulin expression from class III alleles.
62. Vafiadis P, Grabs R, Goodyer CG, Colle E, Polychronakos C. A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes. Diabetes. 47:1998;831-836.
63. Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C. The lns 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem. 273:1998;14158-14164.
64. Hodge SE, Anderson CE, Neiswanger K, Field LL, Spence MA, Sparkes RS, Sparkes MC, Crist M, Terasaki PI, Rimoin DL, Rotter JI. Close genetic linkage between diabetes mellitus and kidd blood group. Lancet. 8252:1981;893-895.