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Association of 2-Heremans-Schmid Glycoprotein Polymorphisms with Subclinical Atherosclerosis

Departments of Biochemistry (A.B.L., K.P.B., D.W.B.), Center for Human Genomics (A.B.L., K.P.B., J.P.L., D.W.B.), Molecular Genetics (J.P.L., D.W.B.), Public Health Sciences (C.D.L., J.T.Z., S.S.R.), Comparative Medicine (T.C.R.), Radiology (J.J.C.), and Internal Medicine (B.I.F., D.W.B.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Donald W. Bowden, Ph.D., Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157. E-mail: dbowden{at}wfubmc.edu.

Context: Cardiovascular disease is significantly increased in individuals with type 2 diabetes mellitus (T2DM), especially in the presence of calcified atherosclerotic plaque. Fetuin A is an important mineralization inhibitor, and polymorphisms in the corresponding 2-Heremans-Schmid glycoprotein (AHSG) gene have been shown to be associated with serum fetuin A levels and free phosphate levels, as well as cardiovascular disease death.

Objective: This study investigated whether polymorphisms in AHSG contribute to the development of calcified atherosclerotic plaque in the coronary and carotid arteries and to carotid artery intima-media thickness.

Design: Eleven single nucleotide polymorphisms (SNPs) in AHSG were genotyped and evaluated for association with quantitative measures of subclinical atherosclerosis.

Participants: Subjects were 829 T2DM-affected European Americans from 368 families in the Diabetes Heart Study.

Main Outcome Measures: Participants were phenotyped for cardiovascular risk factors and atherosclerosis traits. The extent of coronary artery calcified plaque (CorCP) and carotid artery calcified plaque (CarCP) was measured using quantitative computed tomography, and carotid artery intima-media thickness was measured using high-resolution B mode ultrasonography.

Results: Four SNPs in AHSG were nominally associated with CorCP in European Americans with T2DM (P < 0.05). Two 3-SNP haplotypes in the exon 6–7 region were associated with CorCP in European Americans with T2DM (P < 0.06).

Conclusions: Sequence variants in the AHSG gene affect the extent of CorCP in T2DM-affected European Americans, consistent with the known biological role of AHSG in vascular calcification. These data implicate AHSG in the development of vascular calcified plaque in diabetic subjects.

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