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

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.Fetuin-A (also known as α-Heremans-Schmid glycoprotein) is secreted from the liver and reversibly binds the insulin receptor tyrosine kinase in peripheral tissues, thereby inhibiting the insulin-induced intracellular signal cascade and producing peripheral insulin resistance (1–3). Elevated fetuin-A levels have been associated with the risk of incident type 2 diabetes in several human populations (4,5). Recently, we also observed an association between plasma fetuin-A concentrations and risk of type 2 diabetes in a large sample of community-living older adults who participated in the Cardiovascular Health Study (CHS) and were followed for a median of 11 years (6).Thus far, little is known about the potential causal relation between fetuin-A and type 2 diabetes. In the absence of experimental evidence that selective lowering of fetuin-A improves insulin sensitivity and reduces risk of type 2 diabetes, investigations that use genetic variants with strong influence on circulating fetuin-A levels as unconfounded proxies (i.e., Mendelian randomization) may shed light on the potential causal role of fetuin-A in type 2 diabetes.The locus (3q27) where the gene encoding fetuin-A (AHSG) is situated has been identified in human linkage studies of phenotypes such as the metabolic syndrome and type 2 diabetes (7,8). These findings were followed by direct sequencing of gene-encoding regions and the identification of nine highly correlated single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) >5% (9). Case-control studies have suggested that a few of these SNPs (rs1071592, rs4917/rs4918, and rs2248690) are associated with type 2 diabetes and insulin resistance (9,10), but none of these studies had plasma measurements of fetuin-A available to evaluate the potential causal nature of the direct association between fetuin-A and type 2 diabetes. In general, carriers of the minor alleles of promoter variant rs2248690 (T; frequency in Caucasians, ∼26%) and the tightly linked nonsynonymous amino acid substitution variants rs4917 (T; frequency in Caucasians, ∼33%) and rs4918 (G; frequency in Caucasians, ∼34%), have lower levels of circulating fetuin-A compared with carriers of the normal wild-type alleles (11–14).By incorporating information for polymorphisms at the AHSG locus with our previous analysis of plasma fetuin-A in relation to risk of incident type 2 diabetes in the CHS (6), we aimed to address this potential causative association.