The Genetic Landscape of Renal Complications in Type 1 Diabetes
Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of...
| Hoofdauteurs: | , , , , , , |
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| Formaat: | Journal article |
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American Society of Nephrology
2016
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| _version_ | 1826302837357805568 |
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| author | Sandholm, N van Zuydam, N Ahlqvist, E Rayner, N Juliusdottir, T McCarthy, M SUMMIT Consortium |
| author_facet | Sandholm, N van Zuydam, N Ahlqvist, E Rayner, N Juliusdottir, T McCarthy, M SUMMIT Consortium |
| author_sort | Sandholm, N |
| collection | OXFORD |
| description | Diabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (p=6x10-3 7 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 11 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (p=1.1×10-4 13 ). Pathway analysis implicated ascorbate and aldarate metabolism (p=9×10-6), and pentose and glucuronate interconversions (p=3×10-6 14 ) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease. |
| first_indexed | 2024-03-07T05:53:29Z |
| format | Journal article |
| id | oxford-uuid:e9b5a714-84ee-4c98-82ee-6d30a57919b0 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T05:53:29Z |
| publishDate | 2016 |
| publisher | American Society of Nephrology |
| record_format | dspace |
| spelling | oxford-uuid:e9b5a714-84ee-4c98-82ee-6d30a57919b02022-03-27T10:56:12ZThe Genetic Landscape of Renal Complications in Type 1 DiabetesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e9b5a714-84ee-4c98-82ee-6d30a57919b0Symplectic Elements at OxfordAmerican Society of Nephrology2016Sandholm, Nvan Zuydam, NAhlqvist, ERayner, NJuliusdottir, TMcCarthy, MSUMMIT ConsortiumDiabetes is the leading cause of end stage renal disease. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2,843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (p=6x10-3 7 ). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (p=2.2×10-5) and the risk of type 2 diabetes (p=6.1x10-4 11 ) were associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (p=1.1×10-4 13 ). Pathway analysis implicated ascorbate and aldarate metabolism (p=9×10-6), and pentose and glucuronate interconversions (p=3×10-6 14 ) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease. |
| spellingShingle | Sandholm, N van Zuydam, N Ahlqvist, E Rayner, N Juliusdottir, T McCarthy, M SUMMIT Consortium The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title | The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title_full | The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title_fullStr | The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title_full_unstemmed | The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title_short | The Genetic Landscape of Renal Complications in Type 1 Diabetes |
| title_sort | genetic landscape of renal complications in type 1 diabetes |
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