Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33.

Abstract

T ype 1 diabetes is an autoimmune disease characterized by the T-cell-mediated destruction of the insulin-secreting -cells of the pancreatic islets (1,2). It is a complex disease involving numerous susceptibility genes and environmental factors, which may act as triggers of the autoimmune response. Much research has been focused on identifying type 1 diabetes susceptibility genes in an effort to enhance the prediction of which individuals are at high risk of developing the disease, as well as to understand the pathogenesis in order to prevent the disease. Thus far, only two susceptibility regions have been well characterized. I D D M 1 maps to the HLA region and actually contains multiple susceptibility genes (3-11). I D D M 2 h a s been identified as the variable number of tandem repeats immediately 5 to the insulin gene (12-19), which appears to play a role in the level of gene expression (13,14,(20)(21)(22). Many additional susceptibility intervals have been suggested by complete or partial genome scans conducted by multiple labs (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Several of these intervals (I D D M 4, I D D M 5, I D D M 8, and I D D M 1 2) have been confirmed in additional data sets (33-35), but the exact genes responsible for increased susceptibility to type 1 diabetes have not been i d e n t i fied. Other proposed susceptibility intervals remain to be confir m e d .One of the confirmed type 1 diabetes susceptibility loci is I D D M 1 2 , located on chromosome 2q33. Initial studies provided evidence of linkage and association of a polymorphic marker in the C T L A 4 gene with type 1 diabetes in Italian and Spanish families (35). These results were confirmed in an additional data set that included French, Spanish, MexicanAmerican, and U.S. Caucasian families (34). Case-control studies of a Belgian and German data set provided additional c o n firmation of association between C T L A 4 p o l y m o r p h i s m s and type 1 diabetes (35,36). There is also association of C T L A 4 polymorphisms with Graves' disease and Hashimoto's thyroiditis, both autoimmune thyroid diseases (36)(37)(38)(39)(40).Although these studies of I D D M 1 2 provided convincing evidence for I D D M 1 2, the precise location of the gene responsible for the disease is not well defined. Although C T L A 4 is an ideal candidate gene for autoimmune diseases, the association between type 1 diabetes and CTLA4 p o l ymorphisms could be due to linkage disequilibrium of the RESEARCH DESIGN AND METHODSS u b j e c t s . Genomic DNA was obtained from members of 178 simplex and 350 multiplex (with two or more affected children) type 1 diabetes families (Ta b l e 1). The collection includes U.S. Caucasian, Mexican-American, French, Spanish, Italian, Korean, and Chinese families. All diabetic patients participating in this study were diagnosed using the criteria of the National Diabetes Data Group. The clinical information on the patients has been described in previous publications (34,44). G e n o t y p i n g . Microsatellite repeats were ge...

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

“…3 These results were confirmed in other populations such as Asians, populations of European ancestry, and Mexican-Americans. [11][12][13][14][15][16] Nevertheless, in other studies with populations of European ancestry, no evidence of association was found. [17][18][19][20] Recently, an association with a novel polymorphism at position 159 has been found in West African populations, but not in Chinese.…”

Genetic control of autoimmunity in Type I diabetes and associated disorders

“…However, transmission disequilibrium test (TDT) analyses in a multiethnic population did not show an association with CD28 [123].…”

Genetics of type 1 diabetes mellitus

“…In addition, knowledge of the functional properties of CTLA-4 supports this possibility 169 and a single study did not find support for CD28 as the candidate gene of this region. 170 There is a microsatellite marker in the 3ЈUTR of the CTLA4 sequence, and several polymorphisms have been detected at CTLA4. 39 These polymorphisms, in particular the exon 1 (49 GϾA) SNP, have been investigated by TDT analysis in several populations, 41,140,[171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186] and combined data sets from these large studies support linkage of the CTLA4 locus to T1D.…”