Genetic Heterogeneity, ModesofInheritance, andRiskEstimates foraJoint StudyofCaucasians withInsulin-dependent Diabetes Mellitus

Summary From11studies, atotal of1,792 Caucasian probands withinsulin-dependent diabetes mellitus (IDDM)are analyzed. Antigen genotype frequencies inpatients, transmission fromaffected parents toaffected children, andtherelative frequencies ofHLA-DR3and-DR4homozygous patients all indicate that DR3predisposes ina"recessive"-like andDR4ina"dominant"-like or"intermediate" fashion, after allowing forthe DR3/DR4synergistic effect. Removal ofDR3andDR4reveals anoverall protective effect ofDR2, predisposing effects ofDRiandDRw8,andaslight protective effect ofDR5andapredisposing effect of DRw6.Analysis ofaffected-parent-to-affected-chil d dataindicates that asubset ofDR2maypredispose. Thenon-DR3, non-DR4antigens arenotindependently associated withDR3andDR4;thelargest effect isadeficiency ofDR2,followed byexcesses ofDRI,DRw8,andDRw6,inDR4individuals, ascompared withDR3individuals. HLA-Blocus distributions onpatient haplotypes indicate that onlysubsets ofboth DR3andDR4arepredisposing. Thepresence orabsence ofAspatposition 57oftheDQI3 gene, recently implicated inIDDM predisposition, isnotbyitself sufficient toexplain theinheritance ofIDDM.Ata minimum, thedistinguishing features oftheDR3-associated andDR4-associated predisposition remain to beidentified atthemolecular level. Riskestimates forsibs ofprobands arecalculated based onanoverall sibling risk of6%;estimates forthose sharing two,one,orzero haplotypes are12.9%, 4.5%,and1.8%, respectively. Riskestimates subdivided bytheDR typeoftheproband arealso calculated, thehighest being19.2%forsibs sharing twohaplotypes withaDR3/DR4proband.