Abstract
BackgroundThere is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.Methodology and Principal FindingsWe performed targeted capillary resequencing of HNF1A exons 8–10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (≤45 years) and/or family history of T2D (≥1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9−24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.Conclusions and SignificanceWe conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.
Highlights
HNF1A encodes the transcription factor hepatocyte nuclear factor 1 alpha and is the gene most commonly implicated in the pathogenesis of symptomatic Maturity-onset diabetes of the young (MODY) [1]
We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to Type 2 Diabetes (T2D)-susceptibility in European samples
In contrast with mutations which affect the function of all isoforms, mutations in exons 8–10 may display a lower penetrance and later age of onset leading to more clinical overlap with common forms of Type 2 diabetes mellitus (T2D)
Summary
HNF1A encodes the transcription factor hepatocyte nuclear factor 1 alpha and is the gene most commonly implicated in the pathogenesis of symptomatic Maturity-onset diabetes of the young (MODY) [1]. Ongoing efforts to account for this ‘‘heritability gap’’ are increasingly aimed at identification of low frequency (that is, minor allele frequency [MAF] ,5%), intermediate penetrance (allelic odds ratios, 2–5) variants Variants with such characteristics are likely to have remained hidden from view so far, since their frequency is below that targeted by GWA approaches, and the penetrance is insufficient for detection by traditional linkage analyses[6]. We focussed on exons 8–10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1–7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8–10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D
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