Preferential transmission of maternal allele with DQA1*0301-DQB1*0302 haplotype to affected offspring in families with type 1 diabetes

Abstract

To approach the possible involvement of an epigenetic mechanism in the pathogenesis of type 1 diabetes, we investigate here a parent-of-origin effect in transmission of the susceptible alleles at HLA-DQ loci by the transmission disequilibrium test. When we examined alleles of affected offspring of Japanese origin in 28 nuclear families, the maternal alleles were significantly different from the paternal alleles. Furthermore, the maternal alleles with the susceptible DQA1*0301-DQB1*0302 haplotype showed strong transmission disequilibrium with antiglutamic acid decarboxylase antibody-positive type 1 diabetes, while the paternal alleles with the same haplotype did not. This differential transmission disequilibrium of the susceptible allele was confirmed by the contingency table analysis for transmitted or nontransmitted alleles of both parental origin. The unique transmission of the susceptible allele observed supports the hypothesis that an epigenetic mechanism including genomic imprinting at the HLA-DQ region is involved in the pathogenesis and the genetic complexity of type 1 diabetes.

Characteristics of youth with type 1 diabetes (T1D) with and without a parent with T1D in the T1D exchange clinic registry

“…In our population, the number of participants with a father with T1D was twice that of participants with a mother with T1D. This finding has been reported previously, but remains poorly understood. One study suggested differential transmission of human leukocyte antigen genes predisposing to T1D .…”

Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

“…A few studies have evaluated parental inheritance of HLA in other autoimmune diseases. In type 1 diabetes, parent-of-origin skewing in HLA inheritance has been described in some, but not all, studies [8, 9]. In patients with multiple sclerosis, HLA transmission was distorted by the parent of origin and by gender of the affected offspring [7].…”

HLA-DQ Haplotypes in Spanish and German Families with Graves' Disease: Contribution to DQA1*0501-DQB1*0301 Mediated Genetic Susceptibility from Fathers

“…In type 1 diabetes the parent of origin effects of HLA have been described but with controversial interpretations (26,(28)(29)(30)(31)(32). In thyroid autoimmunity the pattern of parental HLA transmission revealed a preferential transmission of HLA susceptibility alleles from the fathers to affected offspring, whereas maternal susceptibility alleles were not transmitted more often than expected (33).…”

“…It has been proposed to explain at least in part the complex 1 inheritance of some common diseases such as asthma, polycystic ovarian syndrome, and type 1 diabetes (24)(25)(26)(27)(28). So far no parent of origin effect has been demonstrated in Graves' disease (29).…”