Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes
Background: There 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 implic...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2009
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| _version_ | 1826269133750140928 |
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| author | Jafar-Mohammadi, B Groves, C Owen, K Frayling, T Hattersley, A McCarthy, M Gloyn, A |
| author_facet | Jafar-Mohammadi, B Groves, C Owen, K Frayling, T Hattersley, A McCarthy, M Gloyn, A |
| author_sort | Jafar-Mohammadi, B |
| collection | OXFORD |
| description | Background: There 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 findings: We 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 rd61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and significance: We 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. |
| first_indexed | 2024-03-06T21:20:18Z |
| format | Journal article |
| id | oxford-uuid:413a6f03-75c1-4eea-83be-8c5ef09f54ff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:20:18Z |
| publishDate | 2009 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:413a6f03-75c1-4eea-83be-8c5ef09f54ff2022-03-26T14:42:21ZLow frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:413a6f03-75c1-4eea-83be-8c5ef09f54ffMedical sciencesGenetics (medical sciences)DiabetesEnglishOxford University Research Archive - ValetPublic Library of Science2009Jafar-Mohammadi, BGroves, COwen, KFrayling, THattersley, AMcCarthy, MGloyn, ABackground: There 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 findings: We 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 rd61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. Conclusions and significance: We 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. |
| spellingShingle | Medical sciences Genetics (medical sciences) Diabetes Jafar-Mohammadi, B Groves, C Owen, K Frayling, T Hattersley, A McCarthy, M Gloyn, A Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title | Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title_full | Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title_fullStr | Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title_full_unstemmed | Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title_short | Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to Type 2 diabetes |
| title_sort | low frequency variants in the exons only encoding isoform a of hnf1a do not contribute to susceptibility to type 2 diabetes |
| topic | Medical sciences Genetics (medical sciences) Diabetes |
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