A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk.
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglyc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Diabetes Association
2017
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| _version_ | 1797055984659595264 |
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| author | Manning, A Highland, H Gasser, J Mahajan, A Chen, Y Pearson, R McVean, G Robertson, N Rayner, N van de Bunt, G Groves, C Neville, M Blancher, C Buck, G Buck, D Trakalo, J Owen, K Levy, J Karpe, F Farmer, A Donnelly, P McCarthy, M Gloyn, A Lindgren, C |
| author_facet | Manning, A Highland, H Gasser, J Mahajan, A Chen, Y Pearson, R McVean, G Robertson, N Rayner, N van de Bunt, G Groves, C Neville, M Blancher, C Buck, G Buck, D Trakalo, J Owen, K Levy, J Karpe, F Farmer, A Donnelly, P McCarthy, M Gloyn, A Lindgren, C |
| author_sort | Manning, A |
| collection | OXFORD |
| description | To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2. |
| first_indexed | 2024-03-06T19:17:06Z |
| format | Journal article |
| id | oxford-uuid:18c8992b-2055-4a17-91a7-12463fcd91ea |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:17:06Z |
| publishDate | 2017 |
| publisher | American Diabetes Association |
| record_format | dspace |
| spelling | oxford-uuid:18c8992b-2055-4a17-91a7-12463fcd91ea2022-03-26T10:45:12ZA low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:18c8992b-2055-4a17-91a7-12463fcd91eaEnglishSymplectic Elements at OxfordAmerican Diabetes Association2017Manning, AHighland, HGasser, JMahajan, AChen, YPearson, RMcVean, GRobertson, NRayner, Nvan de Bunt, GGroves, CNeville, MBlancher, CBuck, GBuck, DTrakalo, JOwen, KLevy, JKarpe, FFarmer, ADonnelly, PMcCarthy, MGloyn, ALindgren, CTo identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2. |
| spellingShingle | Manning, A Highland, H Gasser, J Mahajan, A Chen, Y Pearson, R McVean, G Robertson, N Rayner, N van de Bunt, G Groves, C Neville, M Blancher, C Buck, G Buck, D Trakalo, J Owen, K Levy, J Karpe, F Farmer, A Donnelly, P McCarthy, M Gloyn, A Lindgren, C A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title | A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title_full | A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title_fullStr | A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title_full_unstemmed | A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title_short | A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and Type 2 Diabetes risk. |
| title_sort | low frequency inactivating akt2 variant enriched in the finnish population is associated with fasting insulin levels and type 2 diabetes risk |
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