02899nas a2200361 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520184400283653002802127653001802155653003002173653001202203653001102215653001302226653001102239653000902250653003602259100002202295700002002317700001802337700002002355700002102375700001802396700002402414700002002438700001902458700002402477856003602501 2013 eng d a1935-554800aGenetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.0 aGenetically elevated fetuinA levels fasting glucose levels and r c2013 Oct a3121-70 v363 a

OBJECTIVE: 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.

10aalpha-2-HS-Glycoprotein10aBlood Glucose10aDiabetes Mellitus, Type 210aFasting10aFemale10aGenotype10aHumans10aMale10aPolymorphism, Single Nucleotide1 aJensen, Majken, K1 aBartz, Traci, M1 aDjoussé, Luc1 aKizer, Jorge, R1 aZieman, Susan, J1 aRimm, Eric, B1 aSiscovick, David, S1 aPsaty, Bruce, M1 aIx, Joachim, H1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/5995