Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes: The Cardiovascular Health Study*
Bartz, Traci M.
Kizer, Jorge R.
Zieman, Susan J.
Siscovick, David S.
Psaty, Bruce M.
Ix, Joachim H.
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CitationJensen, Majken K., Traci M. Bartz, Luc Djoussé, Jorge R. Kizer, Susan J. Zieman, Eric B. Rimm, David S. Siscovick, Bruce M. Psaty, Joachim H. Ix, and Kenneth J. Mukamal. 2013. “Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes: The Cardiovascular Health Study*.” Diabetes Care 36 (10): 3121-3127. doi:10.2337/dc12-2323. http://dx.doi.org/10.2337/dc12-2323.
AbstractOBJECTIVE Fetuin-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 AND METHODS Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993. RESULTS Common 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 association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.
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