Prevention of IDDM: the genetic epidemiologic perspective

Rational prevention of insulin-dependent diabetes mellitus (IDDM) requires knowledge about the aetiology and pathogenesis of the disease. The causation of IDDM is complex, involving genetic susceptibility as well as non-genetic determinants. The evidence of a genetic component to IDDM is based on the high concordance rate in monozygotic twins as compared with dizygotic twins, the higher recurrence risk among relatives of patients with IDDM as compared with the general population risk, and the well-established associations with genetic markers, including specific alleles from the HLA-locus. The evidence of a non-genetic component to IDDM is primarily based on the fact that the concordance rate in monozygotic twins is far from unity; the huge geographical variation in the incidence of IDDM, even between genetically similar populations, and the increasing incidence in many populations provide further support; associations between the risk of developing IDDM and exposure to several non-genetic determinants, including nutrients and viral infections, have been established and serve as additional evidence. In general, the relative risks conferred by the non-genetic determinants are rather small, and it is unknown how these factors initiate the autoimmune-mediated process that destroys the beta-cells of the pancreas. Recent findings suggest that non-genetic factors interact with genetic susceptibility genes in the causation of IDDM. Firstly, it appears that the increase in the incidence of IDDM has predominantly been observed in populations with high frequency of susceptibility genes. Secondly, it seems that the risk of IDDM among relatives of patients with IDDM is positively correlated with the general population risk level. All these lines of evidence considered together suggest that IDDM may develop from several different combinations of susceptibility genes acting together with non-genetic exposures. If so, prevention of IDDM will require assessment of disease risk at individual rather than at population level. Since genetic screening is neither feasible nor ethically acceptable in the population at large, possible prevention of IDDM will be restricted to individuals who, by means of a positive family history, may be classified as being at high disease risk.