Despoina Manousaki1,2, Jack W Kent3, Karin Haack3, Sirui Zhou4,5, Pingxing Xie4,6, Celia M Greenwood1,2,7, Paul Brassard1,4, Deborah E Newman3, Shelley Cole3, Jason G Umans8,9, Guy Rouleau2,6,10, Anthony G Comuzzie3, J Brent Richards11,2,4,12. 1. Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. 2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 3. Texas Biomedical Research Institute, San Antonio, TX. 4. Department of Medicine, McGill University, Montreal, Quebec, Canada. 5. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. 6. Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada. 7. Department of Oncology, McGill University, Montreal, Quebec, Canada. 8. MedStar Health Research Institute, Hyattsville, MD. 9. Georgetown-Howard Universities Center for Clinical and Translational Science, Washington. 10. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. 11. Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada brent.richards@mcgill.ca. 12. Department of Twin Research and Genetic Epidemiology, King's College London, London, U.K.
Abstract
OBJECTIVE: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit. RESEARCH DESIGN AND METHODS: Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study. Association testing evaluated the effect of the TBC1D4 variant on diabetes-related metabolic traits and diagnosis. RESULTS: The TBC1D4 mutation was present in 27% of Canadian and Alaskan Inuit. It was strongly associated with higher glucose (effect size +3.3 mmol/L; P = 2.5 x 10-6) and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in homozygote carriers. TBC1D4 carriers with prediabetes and type 2 diabetes had an increased risk of remaining undiagnosed unless postprandial glucose values were tested (odds ratio 5.4 [95% CI 2.5-12]) compared with noncarriers. Of carriers with prediabetes or type 2 diabetes, 32% would remain undiagnosed without an oral glucose tolerance test (OGTT). CONCLUSIONS: Disruption of TBC1D4 is common among North American Inuit, resulting in exclusively elevated postprandial glucose. This leads to underdiagnosis of type 2 diabetes, unless an OGTT is performed. Accounting for genetic factors in the care of Inuit with diabetes provides an opportunity to implement precision medicine in this population.
OBJECTIVE: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit. RESEARCH DESIGN AND METHODS: Exome sequencing of the TBC1D4 variant was performed in 114 Inuit from Nunavik, Canada, and Sanger sequencing was undertaken in 1,027 Alaskan Inuit from the Genetics of Coronary Artery Disease in Alaskan Natives (GOCADAN) Study. Association testing evaluated the effect of the TBC1D4 variant on diabetes-related metabolic traits and diagnosis. RESULTS: The TBC1D4 mutation was present in 27% of Canadian and Alaskan Inuit. It was strongly associated with higher glucose (effect size +3.3 mmol/L; P = 2.5 x 10-6) and insulin (effect size +175 pmol/L; P = 0.04) 2 h after an oral glucose load in homozygote carriers. TBC1D4 carriers with prediabetes and type 2 diabetes had an increased risk of remaining undiagnosed unless postprandial glucose values were tested (odds ratio 5.4 [95% CI 2.5-12]) compared with noncarriers. Of carriers with prediabetes or type 2 diabetes, 32% would remain undiagnosed without an oral glucose tolerance test (OGTT). CONCLUSIONS: Disruption of TBC1D4 is common among North American Inuit, resulting in exclusively elevated postprandial glucose. This leads to underdiagnosis of type 2 diabetes, unless an OGTT is performed. Accounting for genetic factors in the care of Inuit with diabetes provides an opportunity to implement precision medicine in this population.
Authors: Mark J O'Connor; Philip Schroeder; Alicia Huerta-Chagoya; Paula Cortés-Sánchez; Silvía Bonàs-Guarch; Marta Guindo-Martínez; Joanne B Cole; Varinderpal Kaur; David Torrents; Kumar Veerapen; Niels Grarup; Mitja Kurki; Carsten F Rundsten; Oluf Pedersen; Ivan Brandslund; Allan Linneberg; Torben Hansen; Aaron Leong; Jose C Florez; Josep M Mercader Journal: Diabetes Date: 2022-03-01 Impact factor: 9.337