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867 SELECTIVE TRANSMISSION OF INSULIN DEPENDENT DIABETES GENES?

A major unresolved puzzle in IDDM genetics is the high frequency of this previously fatal disorder. One possible selective advantage would be differential transmission of diabetes predisposing genes. If so, we would predict that HLA alleles DR3 and DR4 will be preferentially transmitted to offspring compared to other allelee. In addition, if this mechanism operates via in utero selection, then certain HLA mating types may be more common among parents with a history of spontaneous abortion (SAB). We tested these hypotheses in 107 families ascertained through a child with IDDM. Affected and unaffected offspring inherited a parents' DR3 allele significantly more often than expected (67% vs 50%; p <.001). In addition, both affected and unaffected offspring inherited a father's DR4 allele significantly more often than a mother's DR4 allele (72.1% vs 55.6%; p <.005), providing an explanation for the recent observation that risk for IDDM is higher in offspring of male IDDMs. In support of the hypothesis that distorted transmission is mediated by in utero selection, we observed that IDDM couples with SABs had a DR4 father and DR3 haplotype mother significantly more often than did non-SAB IDDM couples (71.4% vs 21.8%; p < .001). Thus our data provide evidence for preferential in utero survival and transmission of HLA alleles that predipose to IDDM, and in addition provide a potential mechanism for the maintenance of the high population frequency for this previously genetically lethal disease.