Abstract
We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease. We identified rare missense mutations (p.Pro191Leu/rs143150225 and p.Ala252Val/rs147624636) in two heterozygous cases. The two CD36 mutation carriers had no family history of T2D and no clustering of cardio-metabolic complications. While the p.Pro191Leu mutation was found in 84 heterozygous carriers from five ethnic groups from the genome aggregation database (global frequency: 0.0297%, N = 141,321), only one European carrier of the p.Ala252Val mutation was identified (global frequency: 0.00040%, N = 125,523). The Pro191 and Ala252 amino acids were not conserved (74.8% and 68.9% across 131 animal species, respectively). In vitro experiments showed that the two CD36 mutant proteins are expressed and trafficked to the plasma membrane where they bind modified low-density-lipoprotein (LDL) cholesterol as normal. However, molecular modelling of the recent CD36 crystal structure showed that Pro191 was located at the exit/entrance gate of the lipid binding chamber and Ala252 was in line with the chamber. Overall, our data do not support a major contribution of CD36 rare coding mutations to T2D and its cardio-metabolic complications in the French population.
Highlights
We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease
Mutations detected in French individuals presenting with both T2D and cardio-metabolic complications
A significant enrichment in p.Pro191Leu and p.Ala252Val mutations was observed in the French probands within our study, as compared to the European global population and European controls from Genome Aggregation Database (gnomAD)
Summary
We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease. Genetic manipulations of Cd36 in rodent/rat models have indicated an important role of this molecule in insulin resistance, glucose intolerance, dyslipidemia, hypertension, and coronary heart disease[11,15,16]. Rare loss-of-function coding mutations in CD36 confer impaired fatty acid metabolism, glucose intolerance, type 2 diabetes, atherosclerosis, arterial hypertension, and cardiomyopathy in humans[22]. To gain more insight into the contribution of CD36 rare coding mutations to T2D and its cardio-metabolic complications, we screened 184 unrelated French individuals of European ancestry presenting simultaneously with T2D, arterial hypertension, dyslipidemia and history of coronary heart disease
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