Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes The Cardiovascular Health Study

OBJECTIVEdFetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (.5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN ANDMETHODSdGenetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individ-uals 65 years of age or older in 1992–1993. RESULTSdCommon AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P, 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95 % CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an asso-ciation between genetically predicted fetuin-A levels and fasting glucose (20.3 mg/dL [95 % CI, 21.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fastin