ANALYSIS OF HLA HAPLOTYPES IN FAMILIES WITH TYPE-1 DIABETES-MELLITUS IN LA-REUNION ISLAND

To analyse HLA and insulin-dependent diabetes mellitus (IDDM) associat ion in the ethnically mixed population of La Reunion island, we carrie d out a family study on 70 diabetic subjects. HLA-DQA1, -DQB1 and -DRB 1 typing was performed by polymerase chain reaction-restriction fragme nt length polymorphism (PCR-RFLP), completed by PCR-sequence-specific oligonucleotide (SSO) and PCR-sequence-specific priming (SSP). Haploty pe-relative risks (HRR) were determined with the non-transmitted paren tal haplotypes as controls, and relative risks (RR) were calculated wi th a classical case-control study. The most significant risks were fou nd for the cis and trans combinations between DQA103 or *0501 (Arg52( +)) and DQB102 or *0302 (Asp57(-)) alleles, suggesting a direct role for the HLA-DQ heterodimer in IDDM susceptibility. Interestingly, due to the mixed origin of the population, the trans-encoded DQ molecules in the (DR3)-DQA10501-DQB1*02/(DR4)-DQA1*03-DQB1*0302 subjects were a lso found cis-encoded in patients with the (DR7 or 9)-DQA103-DQB1*02 haplotype and in a patient with the rare (DR11)-DQA10501-DQB1*0302 ha plotype. A relative predispositional effect (RPE) analysis gave signif icant haplotype-IDDM(+) associations in the following order: (DR3)-DQA 10501-DQB1*02 > (DR4)-DQA1*03-DQB1*0302 > (DR9)-DQA1*03-DQB*02 > (DR7 )-DQA103-DQB1*02 > (DR2)-DQA1*01-DQB1*0502. No protective effect rema ined significant once the susceptible haplotypes were removed. A strat ification study showed a stronger influence of the DQ genes than DRB1 alleles within the DR7 haplotypes. On the other hand, IDDM subjects wi th only one susceptible haplotype had inherited this haplotype more of ten from their father than from their mother. This paternal effect cou ld be related to the greater risk of IDDM in offspring of diabetic fat hers than the risk in offspring of diabetic mothers.