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Diabetes Care 29:2445-2451, 2006
DOI: 10.2337/dc06-0871
© 2006 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

Combination of Multiple Genetic Risk Factors Is Synergistically Associated With Carotid Atherosclerosis in Japanese Subjects With Type 2 Diabetes

Yoshimitsu Yamasaki, MD, PHD1, Naoto Katakami, MD, PHD1, Ken’ya Sakamoto, MD, PHD1, Hideaki Kaneto, MD, PHD1, Munehide Matsuhisa, MD, PHD1, Hiroshi Sato, MD, PHD1, Masatsugu Hori, MD, PHD1, Masakazu Haneda, MD, PHD2, Atsunori Kashiwagi, MD, PHD3, Yasushi Tanaka, MD, PHD4, Ryuzo Kawamori, MD, PHD5 and Shin-ichi Kuno, PHD6,7

1 Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan
2 Second Department of Medicine, Asahikawa Medical College, Asahikawa, Japan
3 Department of Medicine, Shiga University of Medical Science, Shiga, Japan
4 Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
5 Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
6 Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
7 Clinical Genome Informatics Center, Kobe University Graduate School of Medicine, Kobe, Japan

Address correspondence and reprint requests to Yoshimitsu Yamasaki, Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan. E-mail: yamasaki{at}medone.med.osaka-u.ac.jp

OBJECTIVE— Several genetic risk factors, such as single nucleotide polymorphisms (SNPs), in candidate genes have been reported to be responsible for intima-media thickness (IMT), which is one of the surrogate end points of cardiovascular events. However, the synergistic effects of SNPs have not been evaluated in detail.

RESEARCH DESIGN AND METHODS— We measured the average IMT of the common and internal carotid artery in Japanese type 2 diabetic patients (n = 690) (>50 years old) using ultrasonography. We also determined their genotypes regarding 106 SNPs in candidate genes responsible for cardiovascular diseases. Among the 106 SNPs, we selected 40 common (frequency of minor allele ≥10%) SNPs. We compared the average IMT of subjects with and without any pairs of four genotypes selected from the 40 common SNPs.

RESULTS— The combination of methylen-tetrahydrofolate reductase 677 TT genotype and lymphotoxin-{alpha} (LTA) 252 GG genotype and that of ACE DD genotype and LTA 252 GG genotype were evaluated as responsible for a statistically significant (P = 2.7 x 10–9 and 3.5 x 10–6, respectively) increase in average IMT (mean [±SD] 1.54 ± 0.60 and 1.43 ± 0.58 mm, respectively) compared with those of the subjects without these combinations (1.04 ± 0.34 and 1.04 ± 0.34 mm, respectively). No single genotype was shown to be responsible for the statistically significant difference in average IMT after Bonferroni’s multiple comparison procedure.

CONCLUSIONS— The present analysis demonstrates an approach to evaluate combinations of multiple genetic risk factors that are synergistically associated with carotid atherosclerosis.

Abbreviations: IMT, intima-media thickness • LTA, lymphotoxin-{alpha} • MTHFR, methylene-tetrahydrofolate reductase • SNP, single nucleotide polymorphism • TNF, tumor necrosis factor


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Copyright © 2006 by the American Diabetes Association.