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: | , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2009
|
| _version_ | 1826305190790168576 |
|---|---|
| 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 (< or =45 years) and/or family history of T2D (> or =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 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 | 2024-03-07T06:29:08Z |
| format | Journal article |
| id | oxford-uuid:f55b3ede-aeff-4b5e-8b91-29e10b314745 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:29:08Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:f55b3ede-aeff-4b5e-8b91-29e10b3147452022-03-27T12:26:47ZLow frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to type 2 diabetes.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f55b3ede-aeff-4b5e-8b91-29e10b314745EnglishSymplectic Elements at Oxford2009Jafar-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 (< or =45 years) and/or family history of T2D (> or =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 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 | 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 |
| work_keys_str_mv | AT jafarmohammadib lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT grovesc lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT owenk lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT fraylingt lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT hattersleya lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT mccarthym lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes AT gloyna lowfrequencyvariantsintheexonsonlyencodingisoformaofhnf1adonotcontributetosusceptibilitytotype2diabetes |