Coffee intake and risk of obesity, metabolic syndrome and type 2 diabetes: a Mendelian randomization study

Coffee is one of the most widely consumed beverages. We tested the hypothesis that genetically high coffee intake is associated with low risk of obesity, metabolic syndrome and type 2 diabetes, and with related components thereof.We included 93,179 individuals from two large general population cohorts in a Mendelian randomization study. We tested first whether high coffee intake is associated with low risk of obesity, metabolic syndrome and type 2 diabetes, and with related components thereof, in observational analyses; second, whether five genetic variants near the CYP1A1, CYP1A2 and AHR genes are associated with coffee intake; and third, whether the genetic variants are associated with obesity, metabolic syndrome and type 2 diabetes, and with related components thereof. Finally, we tested the genetic association with type 2 diabetes in a meta-analysis including up to 78,021 additional individuals from the DIAGRAM consortium.Observationally, high coffee intake was associated with low risk of obesity, metabolic syndrome and type 2 diabetes. Further, high coffee intake was associated with high body mass index, waist circumference, weight, height, systolic/diastolic blood pressure, triglycerides and total cholesterol and with low high-density lipoprotein cholesterol, but not with glucose levels. In genetic analyses, 9-10 vs 0-3 coffee-intake alleles were associated with 29% higher coffee intake. However, genetically derived high coffee intake was not associated convincingly with obesity, metabolic syndrome, type 2 diabetes, body mass index, waist circumference, weight, height, systolic/diastolic blood pressure, triglycerides, total cholesterol, high-density lipoprotein cholesterol or glucose levels. Per-allele meta-analysed odds ratios for type 2 diabetes were 1.01 (0.98-1.04) for AHR rs4410790, 0.98 (0.95-1.01) for AHR rs6968865, 1.01 (0.99-1.03) for CYP1A1/2 rs2470893, 1.01 (0.98-1.03) for CYP1A1/2 rs2472297 and 0.98 (0.95-1.01) for CYP1A1 rs2472299.High coffee intake was associated observationally with low risk of obesity, metabolic syndrome and type 2 diabetes, and was associated observationally with related components thereof, but with no genetic evidence to support corresponding causal relationships.