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

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been show n to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of <1-2 cM of CTLA4. To define more precisely the IDDM12 interval, we genotyped a multiethnic (U .S. Caucasian, Mexican-American, French, Spanish, Korean, and Chinese) coll ection of 178 simplex and 350 multiplex families for 10 polymorphic markers within a genomic interval of similar to 300 kb, which contains the candida te genes CTLA4 and CD28. The order of these markers (D2S346, CD28, GGAA19E0 7, D2S307, D2S72, CTLA4, D2S105, and GATA52A04) was determined by sequence tagged site content mapping of bacterial artificial chromosome (BAC) and ye ast artificial chromosome (YAC) clones. The transmission disequilibrium tes t (TDT) analyses of our data revealed significant association/linkage with three markers within CTLA4 and two immediate flanking markers (D2S72 and D2 S105) on each side of CTLA4 but not with more distant markers including the candidate gene CD28. Tsp analyses revealed significant association only wi th the three polymorphic markers within the CTLA4 gene. The markers linked and associated with type 1 diabetes are contained within a phagemid artific ial chromosome clone of 100 kb, suggesting that the IDDM12 locus is either CTLA4 or an unknown gene in very close proximity.