Published Online
on June 1, 2004

A more recent version of this article appeared on June 15, 2004

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Submitted on June 3, 2003
Revised on February 26, 2004
Accepted on March 2, 2004

G(-30)A Polymorphism in the Pancreatic Promoter of the Glucokinase Gene Associated With Angiographic Coronary Artery Disease and Type 2 Diabetes Mellitus

Winfried März MD^*, Markus Nauck MD, Michael M. Hoffmann PhD, Dietmar Nagel PhD, Bernhard O. Boehm MD, Wolfgang Koenig MD, Dietrich Rothenbacher MD, MPH, and Bernhard R. Winkelmann MD

From the Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria (W.M.); Division of Clinical Chemistry, Department of Medicine, University Hospital, Freiburg, Germany (M.N., M.M.H.); Institute of Clinical Chemistry, General Hospital, Ludwigshafen, Germany (D.N.); Division of Endocrinology and Diabetes, Department of Medicine (B.O.B.), and Department of Internal Medicine II, Cardiology (W.K.), University of Ulm, Ulm, Germany; and Department of Epidemiology, German Center for Research on Ageing (D.R.), and Cooperation Unit Pharmacogenomics/Applied Genomics (B.R.W.), University of Heidelberg, Heidelberg, Germany.

^* To whom correspondence should be addressed. E-mail: winfried.maerz{at}klinikum-graz.at.

Background--Type 2 diabetes mellitus (T2DM) increases the risk of coronary artery disease (CAD). A G(-30)A polymorphism in the -cell-specific promoter of glucokinase (GK-30PM) has been implicated in reduced pancreatic -cell function. Its impact on CAD has not been examined.

Methods and Results--The glucokinase G(-30)A variant was determined in 2567 patients with angiographic CAD and in 731 individuals in whom CAD had been ruled out by angiography. In carriers of the A allele, the adjusted OR of CAD was 1.39 (95% CI, 1.15 to 1.70). Corresponding ORs were 1.27 (95% CI, 1.02 to 1.59) and 1.92 (95% CI, 1.26 to 2.93) in individuals without and with T2DM, respectively. The prevalence of the A allele increased in parallel with the Friesinger coronary score. Patients with T2DM were more frequent among carriers of 1 A allele (OR, 1.17; 95% CI, 1.00 to 1.28). This association was stronger if CAD patients only were considered. The A allele was associated with higher glucose (fasting, P=0.002; 2 hours after oral glucose, P=0.017) and glycohemoglobin (HbA1c; P=0.002). Furthermore, presence of 1 A allele was negatively related to -cell function, estimated by percent (P=0.012) and by the ratios of proinsulin to insulin (P=0.025) and proinsulin to C peptide (P=0.019).

Conclusions--The A allele of the pancreatic promoter of glucokinase increases the risk of CAD in individuals with and without T2DM. Furthermore, at least in CAD, it is associated with an augmented prevalence of T2DM.

Key words: coronary disease • diabetes mellitus • genetics • glucose • myocardial infarction

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