INSULIN-DEPENDENT DIABETES-MELLITUS (IDDM) IS ASSOCIATED WITH CTLA4 POLYMORPHISMS IN MULTIPLE ETHNIC-GROUPS

Linkage disequilibrium (association) analysis was used to evaluate a c andidate region near the CTLA4/CD28 genes using a multi-ethnic collect ion of families with one or more children affected by IDDM. In the dat a set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a hi ghly significant deviation for transmission of alleles at the (AT)(n) microsatellite marker in the 3' untranslated region (P = 0.002) and th e A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G allel es is also highly significant (P = 0.00005) in the combined data set ( 669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significa nt heterogeneity was observed in these data sets. The British, Sardini an and Chinese data sets did not show any deviation for the A/G polymo rphism, while the Caucasian-American data set showed a weak transmissi on deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean po pulation (P = 0.03). These results suggest that a true IDDM susceptibi lity locus (designated IDDM12) is located near CTLA4.