Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes

Background and Purpose— Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors. Methods— To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A1c, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure. Results— The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17, P =0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16, P =0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status. Conclusions— These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.

[1]  A. Folsom,et al.  Beta3-adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study. Atherosclerosis Risk in Communities. , 1999, Human genetics.

[2]  E. Boerwinkle,et al.  Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. , 1995, American journal of human genetics.

[3]  A. Rantala,et al.  Association between angiotensin converting enzyme gene polymorphism and carotid atherosclerosis , 1996, Journal of hypertension.

[4]  A. Hofman,et al.  Apolipoprotein E and Carotid Artery Atherosclerosis: The Rotterdam Study , 2001, Stroke.

[5]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[6]  Michael E. Miller,et al.  Effect of Amlodipine on the Progression of Atherosclerosis and the Occurrence of Clinical Events , 2000, Circulation.

[7]  J F Toole,et al.  Risk factors for extracranial carotid artery atherosclerosis. , 1987, Stroke.

[8]  C. Furberg,et al.  Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II) , 1995, The American journal of cardiology.

[9]  M. Laakso,et al.  Diabetes and atherosclerosis: an epidemiologic view. , 1987, Diabetes/metabolism reviews.

[10]  L. Chambless,et al.  Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. , 1991, American journal of epidemiology.

[11]  J D Dawson,et al.  Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine study. , 1999, Circulation.

[12]  T. Shoji,et al.  Correlation between the intima-media thickness of the carotid artery and aortic pulse-wave velocity in patients with type 2 diabetes. Vessel wall properties in type 2 diabetes. , 1999, Diabetes care.

[13]  P. Moulin,et al.  Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus. , 1998, Atherosclerosis.

[14]  A. Rantala,et al.  Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima‐media thickness , 2001, European journal of clinical investigation.

[15]  J. Ferrières,et al.  Carotid intima-media thickness and coronary heart disease risk factors in a low-risk population. , 1999, Journal of hypertension.

[16]  F. Baralle,et al.  Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[17]  R. Schmidt,et al.  Paraoxonase PON1 polymorphism leu-Met54 is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. , 1998, Stroke.

[18]  Eary,et al.  CAROTID-ARTERY INTIMA AND MEDIA THICKNESS AS A RISK FACTOR FOR MYOCARDIAL INFARCTION AND STROKE IN OLDER ADULTS , 2000 .

[19]  T. Lehtimäki,et al.  Relationship between high-density lipoprotein paraoxonase gene M/L55 polymorphism and carotid atherosclerosis differs in smoking and nonsmoking men. , 2001, Metabolism: clinical and experimental.

[20]  S. Fukumoto,et al.  Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients. , 1996, Circulation.

[21]  A. Folsom,et al.  β3-Adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study , 1999, Human Genetics.

[22]  Richard A. Kronmal,et al.  Distribution and Correlates of Sonographically Detected Carotid Artery Disease in the Cardiovascular Health Study , 1992, Stroke.

[23]  T. Lehtimäki,et al.  Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men. , 2000, Atherosclerosis.

[24]  W. Kannel,et al.  Diabetes and cardiovascular disease. The Framingham study. , 1979, JAMA.

[25]  W. Beischer,et al.  Determinants of carotid artery wall thickening in young patients with Type 1 diabetes mellitus , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[26]  M. Offidani,et al.  Angiotensin converting enzyme gene polymorphism and carotid atherosclerosis in a low‐risk population , 1995, Journal of hypertension.

[27]  H. Mabuchi,et al.  An unsolved mystery of promoter variation in CETP gene and atherosclerosis , 2001, European Journal of Clinical Investigation.

[28]  S. Kiechl,et al.  Impaired glucose tolerance, Type II diabetes mellitus and carotid atherosclerosis: prospective results from the Bruneck Study , 2000, Diabetologia.

[29]  R. Bergman,et al.  Ethnic differences in carotid wall thickness. The Insulin Resistance Atherosclerosis Study. , 1996, Stroke.

[30]  P. Savage,et al.  Duration of diabetes and carotid wall thickness. The Insulin Resistance Atherosclerosis Study (IRAS). , 1997, Stroke.

[31]  R. Duggirala,et al.  Genetic basis of variation in carotid artery wall thickness. , 1996, Stroke.

[32]  Elena Tremoli,et al.  Carotid Artery Intima-Media Thickness Measured by Ultrasonography in Normal Clinical Practice Correlates Well With Atherosclerosis Risk Factors , 2000, Stroke.

[33]  A. Karter,et al.  Ischemic heart disease and stroke mortality in African-American, Hispanic, and non-Hispanic white men and women, 1985 to 1991. , 1998, The Western journal of medicine.

[34]  T. Elatrozy,et al.  Insulin resistance, cardiovascular risk factors and ultrasonically measured early arterial disease in normotensive Type 2 diabetic subjects , 2000, Diabetes/metabolism research and reviews.

[35]  N. Bornstein,et al.  The A677V methylenetetrahydrofolate reductase gene polymorphism and carotid atherosclerosis. , 1999, Stroke.

[36]  S. Haffner,et al.  Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). , 1997, Stroke.

[37]  Mark Von Tress,et al.  Generalized, Linear, and Mixed Models , 2003, Technometrics.

[38]  G. Siest,et al.  Genetics strongly determines the wall thickness of the left and right carotid arteries , 1998, Human Genetics.

[39]  C. Langefeld,et al.  Familial aggregation of coronary artery calcium in families with type 2 diabetes. , 2001, Diabetes.

[40]  J. Neaton,et al.  Diabetes, Other Risk Factors, and 12-Yr Cardiovascular Mortality for Men Screened in the Multiple Risk Factor Intervention Trial , 1993, Diabetes Care.

[41]  C. Wolfe,et al.  Increased Common Carotid Intima-Media Thickness in UK African Caribbeans and Its Relation to Chronic Inflammation and Vascular Candidate Gene Polymorphisms , 2001, Stroke.

[42]  P M Rautaharju,et al.  Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. , 1995, Stroke.

[43]  A. Gnasso,et al.  Lack of association between carotid intima-media thickness and methylenetetrahydrofolate reductase gene polymorphism or serum homocysteine in non-insulin-dependent diabetes mellitus. , 2000, Metabolism: clinical and experimental.