Preferential transmission of type 1 diabetes from parents to offspring: fact or artifact?

It has been widely reported that men with type 1 diabetes (T1D) tend to be more likely to transmit the disease to their offspring than their female counterparts in Caucasoid populations. Several theories to explain this preferential transmission have been proposed, but so far none of them has been unequivocally proven. Whatever the mechanism, confirmation or refutation of this observation is nonetheless important and practical to the design of future genetic studies of T1D. We carried out some statistical modeling of the preferential transmission. The well-established fact that males have higher a prevalence of T1D than females, an apparent sex difference in fecundity, and a possible misclassification of gestational diabetes mellitus (GDM) as T1D in women have been considered. We demonstrated, first, that the ascertainment of study families through the affected offspring with T1D would generate a higher proportion of fathers than mothers having T1D, even though there was no preferential transmission at all. This can be explained by the male preponderance in T1D prevalence as compared with females, coupled with a greater likelihood of being selected and/or recruited for study in families with T1D fathers due to the fecundity difference. Second, when the study population is ascertained through affected parents, misclassification of mothers with GDM as T1D, and the existence of male/female difference in fecundity in conjunction with a birth order effect, can contribute to the observed preferential transmission, even though there was none. In light of the plausibility of assumptions employed in the analysis and, in particular, an apparent failure to critically examine the effects of these causes of bias in earlier studies, it is perhaps prudent to say that the jury for the existence of preferential transmission in T1D is still out.