| Title: |
Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes. |
| Authors: |
Gardner, EJ; Kentistou, KA; Stankovic, S; Lockhart, S; Wheeler, E; Day, FR; Kerrison, ND; Wareham, NJ; Langenberg, C; O'Rahilly, S; Ong, KK; Perry, JRB |
| Publisher Information: |
Elsevier |
| Publication Year: |
2022 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Subject Terms: |
IGF1; Mendelian randomization; UK Biobank; exome-wide association study; type 2 diabetes |
| Description: |
Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency < 0.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n = 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (GCK, GIGYF1, HNF1A) in addition to missense variants in ZEB2 (n = 31 carriers; odds ratio [OR] = 5.5 [95% confidence interval = 2.5-12.0]; p = 6.4 × 10-7), MLXIPL (n = 245; OR = 2.3 [1.6-3.2]; p = 3.2 × 10-7), and IGF1R (n = 394; OR = 2.4 [1.8-3.2]; p = 1.3 × 10-10). Carriers of damaging missense variants within IGF1R were also shorter (-2.2 cm [-1.8 to -2.7]; p = 1.2 × 10-19) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3 nmol/L [1.7-2.9]; p = 2.8 × 10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target. |
| Document Type: |
article in journal/newspaper |
| File Description: |
None - ? |
| Language: |
English |
| Relation: |
Cell Genom; https://qmro.qmul.ac.uk/xmlui/handle/123456789/103561 |
| DOI: |
10.1016/j.xgen.2022.100208 |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/103561; https://doi.org/10.1016/j.xgen.2022.100208 |
| Rights: |
Creative Commons Attribution (CC BY 4.0) ; © 2022 The Authors. |
| Accession Number: |
edsbas.4C789361 |
| Database: |
BASE |