Preferential Transmission of Diabetic Alleles within the HLA Gene Complex

Cm, Vadheim; Ji, Rotter; Nk, Maclaren; Wj, Riley; Ce, Anderson

doi:10.1056/nejm198611203152103

Cited by 96 publications

(51 citation statements)

References 34 publications

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“…Overtransmission of DR4 from non-diabetic fathers to both diabetic and non-diabetic offspring has also been claimed [28] but reports from several investigators [16,[29][30][31] as well as our own data, have failed to show any significant differences of transmission between parents. On the other hand, the overtransmission reported for paternal [32] or maternal [33] AIB8 (DR3) haplotypes related to the sex of the offspring in diabetic and healthy families still remains to be confirmed.…”

Section: Discussionmentioning

confidence: 51%

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

et al. 1990

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Summary. The susceptibility determinants of Type 1 (insulindependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p < 0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.Key words: Type 1 (insulin-dependent) diabetes mellitus, HLA DR3, 4, shared haplotypes, segregation, multiple affected siblings, risk for siblings, maternal effect.Susceptibility to Type 1 (insulin-dependent) diabetes mellitus is associated with the HLA antigens, DR3 and DR4 [1][2][3][4] in Caucasian populations. The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1-8] with a heterozygous DR3, DR4 phenotype. These observations have led to the hypothesis that two susceptibility genes associated with the DR3 and DR4 haplotype are involved in the inheritance of the disease [2, 9-13]. Though, the exact nature of the molecule(s) responsible, and their role in the pathogenesis of the disease has not been elucidated, strong evidence suggests an autoimmune mechanism, probably triggered by environmental factors [14].It has long been supposed that DR3 and DR4 associated susceptibility genes play different roles in the pathology of Type 1 diabetes, determining the clinical and genetic heterogeneity of the disease [15]. Recent data do indeed suggest that they probably do not have equivalent effects on susceptibility [16][17][18].In this study we present evidence for the different effects of the paternal or maternal origin of DR3 and DR4 antigens on the risk for siblings of diabetic children. Subjects and methodsAmong 325 unrelated, Causasian French families of Type I diabetic patients who had been consecutively ascertained for HLA typing since 1978 (Herold series), 287 families were selected according to the following criteria: (1) unaffected pa...

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Section: Discussionmentioning

confidence: 51%

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

et al. 1990

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“…The mechanism by which Type I diabetes is more frequent in fathers of Type I diabetes children is poorly understood. An increase in the paternal transmission of HLA susceptibility genes was suggested earlier [25,26], but a recent study of 172 multiplex diabetic pedigrees from the United Kingdom found no evidence for this [27]. It is possible, that an interaction between the diabetic mother and fetus takes place which provides protection for the offspring in later life.…”

Section: Discussionmentioning

confidence: 97%

Familial Risk of Type I diabetes in European Children

Dahlquist¹,

Patterson²

1998

Diabetologia

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“…Third, fetuses exposed to maternal diabetes could be protected from subsequent manifestation of T1D and thus could also lead to the observed preferential transmission [Warram et al, 1984]. Fourth, the diabetogenic genes may be preferentially transmitted from fathers to offspring, regardless of whether the fathers are themselves diabetic or not [Vadheim et al, 1986]. Data from 107 nuclear families appeared to support this hypothesis, which was confirmed by Field [1989Field [ , 1994.…”

Section: Introductionmentioning

confidence: 83%

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

Guo

Tuomilehto

2002

Genetic Epidemiology

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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

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Preferential Transmission of Diabetic Alleles within the HLA Gene Complex

Cited by 96 publications

References 34 publications

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

Familial Risk of Type I diabetes in European Children

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

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