Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.
OBJECTIVE
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).


CONCLUSIONS
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.
Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Lars E
LE
Laugsand
Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Divisions of Nephrology and Preventive Medicine, University of California San Diego, San Diego, CA, USA.
Joachim H
JH
Ix
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Traci M
TM
Bartz
Boston Veterans Affairs Healthcare System, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
Luc
L
Djousse
Department of Medicine, and Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, NY, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jorge R
JR
Kizer
Department of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, USA.
Russell P
RP
Tracy
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Abbas
A
Dehghan
Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
Kathryn
K
Rexrode
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Oscar L
OL
Lopez
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Eric B
EB
Rimm
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
David S
DS
Siscovick
National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Christopher J
CJ
O'Donnell
UPMC/University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA, USA.
Anne
A
Newman
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Kenneth J
KJ
Mukamal
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Majken K
MK
Jensen
D000368:Aged; D000369:Aged, 80 and over; D059168:Carotid Intima-Media Thickness; D003331:Coronary Vessels / Q000473:pathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006331:Heart Diseases / Q000097:blood / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D061205:Vascular Calcification / Q000473:pathology; D060749:alpha-2-HS-Glycoprotein / Q000235:genetics* / Q000378:metabolism*
C556354:AHSG protein, human; D060749:alpha-2-HS-Glycoprotein
Coronary heart disease; Fetuin-A; Mendelian randomization; Meta-analysis; Single nucleotide polymorphisms