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

Lars E Laugsand; Joachim H Ix; Traci M Bartz; Luc Djousse; Jorge R Kizer; Russell P Tracy; Abbas Dehghan; Kathryn Rexrode; Oscar L Lopez; Eric B Rimm; David S Siscovick; Christopher J O'Donnell; Anne Newman; Kenneth J Mukamal; Majken K Jensen

doi:10.1016/j.atherosclerosis.2015.08.031

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

Atherosclerosis. 2015 Nov;243(1):44-52. doi: 10.1016/j.atherosclerosis.2015.08.031. Epub 2015 Sep 5.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁴ Boston Veterans Affairs Healthcare System, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
⁵ 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.
⁶ Department of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, USA.
⁷ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁸ Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ UPMC/University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA, USA.
¹⁴ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

PMID: 26343871
PMCID: PMC4609621
DOI: 10.1016/j.atherosclerosis.2015.08.031

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: Coronary heart disease; Fetuin-A; Mendelian randomization; Meta-analysis; Single nucleotide polymorphisms.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Carotid Intima-Media Thickness
Coronary Vessels / pathology
Female
Genetic Variation
Genotype
Heart Diseases / blood
Heart Diseases / genetics*
Humans
Insulin Resistance
Longitudinal Studies
Male
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Prospective Studies
Risk Factors
Vascular Calcification / pathology
alpha-2-HS-Glycoprotein / genetics*
alpha-2-HS-Glycoprotein / metabolism*

Substances

AHSG protein, human
alpha-2-HS-Glycoprotein

Abstract

Publication types

MeSH terms

Substances

Grants and funding