التفاصيل البيبلوغرافية
| العنوان: |
Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas |
| المؤلفون: |
Adem Y Dawed (8596079), Sook Wah Yee (259951), Kaixin Zhou (60302), Nienke van Leeuwen (11412716), Yanfei Zhang (488656), Moneeza K Siddiqui (11412717), Amy Etheridge (2830739), Federico Innocenti (25628), Fei Xu (368913), Josephine H. Li (9556600), Joline W Beulens (9628418), Amber A van der Heijden (11236701), Roderick C Slieker (11236693), Yu-Chuan Chang (1847710), Josep M. Mercader (7439093), Varinderpal Kaur (713069), John S. Witte (9046614), Ming Ta Michael Lee (7327049), Yoichiro Kamatani (140517), Yukihide Momozawa (356235), Michiaki Kubo (128298), Colin N A Palmer (7949651), Jose C. Florez (8811083), Monique M. Hedderson (3148482), Leen M. ‘t Hart (4729788), Kathleen M. Giacomini (259990), Ewan R Pearson (8616627), the MetGen Plus Consortium (11412734), the DIRECT Consortium (11412750) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Clinical Sciences not elsewhere classified, Sulfonylurea(s), Hemoglobin A1c (HbA1c), Statins, Drug Interaction, Pharmacogenomics |
| الوصف: |
Objective: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However there exists significant variability in glycaemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. Research design and methods: As an initiative of the Metformin Genetics Plus (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia, 5,485 white Europeans with type 2 diabetes treated with sulfonylurea were recruited from 6 referral centres in Europe and North America. We first estimated heritability using generalized restricted maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis-eQTLs and functional validation in cellular models. Finally, we examined for a possible drug-drug-gene interactions. Results: After establishing that sulfonylurea response is heritable (37±11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (p < 5×10 -8 ). The C-allele at rs1234032 , near GXYLT1 , was associated with 0.14% (1.5 mmol/mol), p=2.39×10 −8 ) lower reduction in HbA1c. Similarly, the C-allele was associated with higher glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3, 029 human whole blood samples, the C-allele is a cis-eQTL for increased expression of GXYLT1 (β=0.21, p=2.04 ×10 -58 ). The C-allele of rs10770791, in an intronic region of SLCO1B1 , was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (p=4.80×10 −8 ). In 1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced SLCO1B1 expression (p=1.61×10 −7 ) which, together with functional ... |
| نوع الوثيقة: |
still image |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/figure/Genome-Wide_Meta-analysis_Identifies_Genetic_Variants_Associated_With_Glycemic_Response_to_Sulfonylureas/16593023Test |
| DOI: |
10.2337/figshare.16593023.v1 |
| الإتاحة: |
https://doi.org/10.2337/figshare.16593023.v1Test |
| حقوق: |
CC BY-NC-SA 4.0 |
| رقم الانضمام: |
edsbas.2B97D868 |
| قاعدة البيانات: |
BASE |
