NORTH-AMERICAN TWINS WITH IDDM - GENETIC, ETIOLOGIC, AND CLINICAL-SIGNIFICANCE OF DISEASE CONCORDANCE ACCORDING TO AGE, ZYGOSITY, AND THE INTERVAL AFTER DIAGNOSIS IN 1ST TWIN

In 224 twin pairs (132 monozygotic, 86 dizygotic, and 6 of uncertain z ygosity) in whom the index twin had developed IDDM before 30 yr of age , 51 of the co-twins (38 monozygotic, 10 dizygotic, and 3 of uncertain zygosity) subsequently became diabetic. On the basis of concordance r atios, which were significantly discrepant (P < 0.01) between monozygo tic and dizygotic twins, the substantial genetic role in IDDM etiology is confirmed. For the monozygotic co-twin of an IDDM case, the relati ve risk is significantly related to an early age at proband diagnosis (P < 0.01 for 0-4 vs. 5-9 yr of age). However, among monozygotic co-tw ins at any age, IDDM risk decreases as time passes after the proband d iagnosis (P < 0.01 for 0-23 vs. greater-than-or-equal 24 mo after a pr oband diagnosis at 5-9 yr of age). Moreover, a structural-equation ana lysis suggests a profound contribution to liability (as much as 79%) f rom the twins' shared environment. Risk to like-sex male dizygotic co- twins is as high as that to monozygotic co-twins, significantly higher than that to like-sex female dyzogotic co-twins (P < 0.005), and even higher than that to male co-twins in unlike-sex dizygotic pairs (P < 0.05). Overall, the risk to the dizygotic co-twin of a case is signifi cantly higher (P < 0.001) than that to a non-twin sibling, as reported in the literature. The observed male excess is consistent with report ed patterns of IDDM in experimental animals, and in certain circumstan ces in humans. Taken together, these observations suggest an important early acquired determinant of IDDM, independent of genetic determinan ts. On the basis of Kaplan-Meier IDDM-free survival curves, if the pro band is diagnosed before 15 yr of age, the long-term risk to the co-tw in is estimated at 44% (monozygotic) and 19% (dizygotic); it reaches 6 5% for the co-twin of a monozygotic proband diagnosed before 5 yr of a ge. An IDDM discordant period of no more than 3 yr was observed in 60% of the pairs destined to become concordant, offering a very brief win dow for intervention following the recognition of high risk.