@article {1380, title = {Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 May 15}, pages = {2316-22}, abstract = {

BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD).

METHODS AND RESULTS: Among 3710 community-living individuals >= 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 {\textpm} 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01).

CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those >= 75 years of age.

}, keywords = {African Continental Ancestry Group, Age Distribution, Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Humans, Incidence, Life Style, Lipids, Male, Pilot Projects, Prevalence, Proportional Hazards Models, Residence Characteristics, Risk Factors, Sex Distribution}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.111.072751}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth J and Kizer, Jorge R and Zieman, Susan J and Siscovick, David S and Mozzaffarian, Dariush and Jensen, Majken K and Nelson, Lauren and Ruderman, Neil and Djouss{\'e}, Luc} } @article {5995, title = {Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.}, journal = {Diabetes Care}, volume = {36}, year = {2013}, month = {2013 Oct}, pages = {3121-7}, abstract = {

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.

}, keywords = {alpha-2-HS-Glycoprotein, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Female, Genotype, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1935-5548}, doi = {10.2337/dc12-2323}, author = {Jensen, Majken K and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Zieman, Susan J and Rimm, Eric B and Siscovick, David S and Psaty, Bruce M and Ix, Joachim H and Mukamal, Kenneth J} } @article {6666, title = {Association of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {30}, year = {2015}, month = {2015 Aug}, pages = {1394-402}, abstract = {

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women >=65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95\% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95\% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95\% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95\% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95\% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.

}, keywords = {Adult, Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Bone Density, Cross-Sectional Studies, Female, Follow-Up Studies, Fractures, Bone, Humans, Incidence, Male, Models, Biological}, issn = {1523-4681}, doi = {10.1002/jbmr.2475}, author = {Fink, Howard A and B{\r u}zkov{\'a}, Petra and Garimella, Pranav S and Mukamal, Kenneth J and Cauley, Jane A and Kizer, Jorge R and Barzilay, Joshua I and Jalal, Diana I and Ix, Joachim H} } @article {6853, title = {Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.}, journal = {Atherosclerosis}, volume = {243}, year = {2015}, month = {2015 Nov}, pages = {44-52}, abstract = {

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).

METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.

RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12\% lower fetuin-A concentrations per minor allele (P~<~0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95\% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95\% CI: 0.70-1.00) for rs2248690 and 0.97 (95\% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).

CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

}, keywords = {Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Carotid Intima-Media Thickness, Coronary Vessels, Female, Genetic Variation, Genotype, Heart Diseases, Humans, Insulin Resistance, Longitudinal Studies, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Vascular Calcification}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.08.031}, author = {Laugsand, Lars E and Ix, Joachim H and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Tracy, Russell P and Dehghan, Abbas and Rexrode, Kathryn and Lopez, Oscar L and Rimm, Eric B and Siscovick, David S and O{\textquoteright}Donnell, Christopher J and Newman, Anne and Mukamal, Kenneth J and Jensen, Majken K} }