HLA microsatellite associations with insulin-dependent diabetes mellitus in Singaporean Chinese

Singaporean Chinese with insulin-dependent diabetes mellitus (IDDM) have previously been shown to be associated with the DRB1*0301 haplotype and the joint occurrence of DRB1*0301/*0901 and DRB1*0301/*04. The present study extended previous HLA associations by investigating the HLA region using four microsatellites (TNFa, D6S273, TAP1, DQCARII). Seventy-five IDDM patients and 80 healthy controls were studied. TNFa*3 (RR = 2.26), TNFa*12 (RR = 3.30), TAP1*9 (RR = 2.55) showed increased frequencies while TNFa*11 (RR = 0.29), TAP1*4 (RR = 0.50) showed decreased frequencies in patients compared to controls. Linkage analysis suggested that the positive associations of TNFa*3 and TAP1*9 were secondary to that of DRB1*0301. However, TNFa*12 appeared to provide additional risks to IDDM besides the DRB1*0301 haplotype, whereas TNFa*11 and TAP1*4 conferred an independent protective effect against IDDM. Our findings reinforce the notion that susceptibility to and protection against IDDM may include TNF region. In the present study, TNFa*12 seemed to be the primary association in the DRB1*0405 haplotype and may play an independent role in the pathogenesis of IDDM through TNF-alpha function.