doi: 10.1161/01.STR.0000019909.71547.AA
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(Stroke. 2002;33:1876.)
© 2002 American Heart Association, Inc.
Original Contributions |
Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes
From the Department of Public Health Sciences (L.A.L, C.D.L., L.E.W., S.S.R.), the Department of Biochemistry (D.W.B.), the Division of Radiologic Sciences (J.J.C.), the Department of Neurology (W.A.R.), and the Department of Internal Medicine/Nephrology (B.I.F.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Barry I. Freedman, MD, Department of Internal Medicine/Nephrology, Wake Forest University, School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail bfreedma{at}wfubmc.edu
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Abstract |
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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.
Key Words: atherosclerosis • carotid arteries • diabetes mellitus • epidemiology • genetics • hereditary disease • ultrasonics
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Introduction |
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Carotid artery intima-medial thickness (IMT), measured by high-resolution B-mode ultrasonography, has proven to be an excellent marker of subclinical atherosclerotic cardiovascular disease (CVD). Increasing carotid IMT has been associated with an enhanced risk of myocardial infarction and stroke in older adults lacking a prior history of CVD.1,2
Several studies (Cardiovascular Health Study [CHS],3 Atherosclerosis Risk in Communities [ARIC],4 and Insulin Resistance Atherosclerosis Study [IRAS]5) have shown that hypertension, hyperlipidemia, male sex, age, smoking, and postmenopausal status are consistent and independent factors that contribute to increasing carotid IMT. Additionally, certain forms of antihypertensive6 and lipid-lowering7 therapies have been associated with regression or reduced progression of IMT. However, the role of genetic factors in determining carotid IMT is still largely unknown. Two family studies have attempted to determine the contribution of inherited and environmental factors to variability in carotid IMT. These reports, in nondiabetic families, estimated heritability to be 
0.908 and 0.30,9 supporting the presence of strong independent genetic contributions to carotid IMT.
Atherosclerotic CVD is known to develop at an accelerated rate in individuals with impaired glucose tolerance and type 2 diabetes mellitus.10,11 This is particularly true in individuals with diabetic nephropathy12 or microalbuminuria.13 It is likely that a combination of environmental and inherited factors (pleiotropic genes mediating susceptibility to both diabetes and atherosclerosis) are involved in this relationship, although their relative contributions are unknown. Therefore, we measured common carotid artery IMT in affected siblings from multiplex diabetic families to examine its heritability in this population.
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Subjects and Methods |
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The present study was organized and conducted in Forsyth County, NC, to study CVD in families affected with type 2 diabetes mellitus. Siblings concordant for diabetes were recruited from internal medicine clinics, endocrinology clinics, and community advertising. Type 2 diabetes was defined as a clinical diagnosis of diabetes after the age of 34 years in the absence of historical evidence of diabetic ketoacidosis. Unaffected siblings, similar in age to the siblings with diabetes, were also invited to participate. For the purposes of this analysis, only diabetic family members were included. The sample includes white and African American participants. Individuals with serious health conditions, eg, renal replacement therapy, were not eligible to participate. Individuals reporting previous carotid endarterectomy (n=2) were excluded from all analyses. The present study was approved by the Institutional Review Board at Wake Forest University School of Medicine. All participants gave informed consent.
The participant examinations were conducted in the General Clinical Research Center of the Wake Forest University Baptist Medical Center and included interviews for medical history and health behaviors, anthropometric measures, resting blood pressure, a 12-lead ECG, a fasting blood draw, and a spot urine collection. Laboratory assays included urine albumin and creatinine, total cholesterol, LDL, HDL, triglycerides, hemoglobin A1c, fasting glucose, and blood chemistries. DNA was isolated from a blood sample and stored for later studies.
For measurement of IMT, the participant was examined in the supine position. A plastic arc marked with an angle scale and positioned near the shoulders of the participant was used as a reference to measure the ultrasound transducer interrogation angle during the study. The sonographer scanned from the head of the examination table.
High-resolution B-mode carotid ultrasonography was performed by using a 7.5-MHz transducer and a Biosound Esaote (AU5) ultrasound machine, and B-mode images were recorded on an S-VHS videocassette. Scans were performed on both the right and left extracranial carotid arteries by trained and certified ultrasound technicians. A preliminary exploratory transverse scan was performed to assess the participant’s anatomy and to detect the presence of significant atherosclerotic disease. A second exploratory longitudinal scan was then performed on the common carotid, the bulb, and the internal carotid to assist in interpreting the presence of significant disease. Standardized longitudinal images were then acquired of the near and far walls of the distal 10-mm portion of the common carotid artery at 5 predefined interrogation angles spaced 30° apart on each side. The mean value of IMT was then measured offline in a total of 20 arterial segments, including both sides of the neck. The entire procedure takes 30 minutes. The mean value of up to 20 mean common carotid IMT values is the outcome variable reported in the present study.
Statistical Methods
To determine the contribution of genetic factors to carotid IMT, we analyzed the carotid IMT data obtained on diabetes-affected family members by using the SOLAR software package (Version 1.4.1).14 SOLAR performs a variance components analysis of family data that decomposes the total variance of the phenotype (carotid IMT) into components that are due to genetic (polygenic) effects (additive genetic variance), measured covariates, and random environmental effects. The relative contribution of genetic factors to carotid IMT variation is then estimated by the heritability (h2), defined by the ratio of the genetic variance component to the residual (after removal of covariates) phenotypic variance. A series of models was developed that incorporates an increasing number of covariates known to be associated with IMT to determine the extent of genetic factors contributing to the variation in carotid IMT independent of the measured risk factors. Model 1 was adjusted for age, sex, and ethnicity. Model 2 was additionally adjusted for fasting glucose and total cholesterol. Model 3 was additionally adjusted for hypertension status and current smoking status. Significance of the h2 values was determined by likelihood ratio tests, in which the likelihood of the models with the additive genetic variance component and covariates was compared with the model with the likelihood in which the additive genetic variance component was constrained to be 0.
To investigate the potential relationships between carotid IMT and the above-mentioned demographic characteristics and anthropometric, clinical, and laboratory measures, we used a mixed model ANOVA approach, implemented by the SAS software package, assuming exchangeable correlation among pedigree members and the sandwich estimator of the variance-covariance matrix.15 This approach allows for the correlation due to the family structures present in our data.
Transformations were performed on body mass index (square root), HDL, triglycerides, albumin/creatinine ratio, and pack years (logarithm) to reduce the influence of extreme values. All continuous covariates were standardized to a mean of 0 and a variance of 1 to facilitate the interpretation of the results. All tests for covariate effects were based on models that included age and sex. A multivariable model containing age, sex, ethnicity, smoking status (current and former), education level (high-school graduate versus not and college graduate versus not), diabetes treatment (insulin, oral hypoglycemic, neither), hypertension status, total cholesterol, and fasting glucose was then examined to test each covariate effect after adjusting for all other covariates. The covariates for this model were selected a priori and not as a result of exploratory analysis.
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Results |
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The analysis sample consisted of 252 diabetic individuals from 122 families. Pedigree size ranged from 2 to 7, with 99 pedigrees consisting of sibling pairs, 9 consisting of 3 members, and 1 each of 4, 5, and 7 members. Participants were all informed by their physician that they were diabetic, and 241 (95.6%) of 252 are currently receiving, or at some point received, oral hypoglycemic medication/insulin therapy. Of the remaining 11 patients, 6 had a fasting blood sugar >126 mg/dL, and 1 patient had hemoglobin A1c >7.5% at the screening visit. Four diet-controlled patients (4 [1.5%] of 252) had normal fasting glucose and hemoglobin A1c levels. Historical fasting glucose levels were not available for these 4 participants. Eleven singletons were also included in the sample descriptives and the association analysis but were excluded in the h2 analysis. The average age of participants was 60.6 years, and the average duration of diagnosed diabetes was 11.2 years. Fifty-nine percent (n=149) of the sample were female, and 11% (n=28) were African American. Thirty-three percent (n=82) were being treated with insulin, 76% (n=192) were taking oral hypoglycemics, and 36% (n=91) were taking lipid-lowering medications. The mean carotid IMT for this sample was 0.674 mm (SD 0.134), with a median value of 0.644 mm and a range from 0.460 to 1.316 mm. Additional sample descriptives are shown in Table 1.
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Results of the heritability analysis are listed in Table 2. The h2 value of carotid IMT, adjusted for age, sex, and race was 0.32 (P=0.02). After additional adjustment was made for total cholesterol, h2 was determined to be 0.38 (P=0.008). Further adjustment for hypertension status and current smoking status resulted in an even larger estimate (h2 0.41, P=0.004). These increases occur because adjustment for measured covariates reduces the overall remaining unexplained variance, allowing the genetic contribution to become more apparent.
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Age and male sex were positively and significantly associated with IMT (P=0.0001 and P=0.0002, respectively). Ethnicity (P=0.04) was also a significant predictor of carotid IMT, with African American ethnicity being associated with higher IMT. Because of this observation, all subsequent models were also adjusted for ethnicity. The results from the sex-, age-, and ethnicity-adjusted bivariate analysis are presented in Table 3. The strongest predictors of carotid IMT were total cholesterol (P=0.009), smoking status (never, former, and current); (former, P=0.002; current, P=0.0007), and LDL cholesterol (P=0.049). Log-triglycerides were marginally positively associated with carotid IMT (P=0.095). No other covariates met statistical significance at the 5% level.
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A multivariable model containing age, sex, ethnicity, smoking status (current smoker, former smoker), education level (high-school graduate versus not), hypertension status, fasting glucose, and total cholesterol was created, and smoking status, total cholesterol, and hypertension status were determined to be statistically significant, with adjustment made for the other covariates. The direction and magnitude of the coefficients for each measure remained similar to the bivariate analyses. The results of this analysis are shown in Table 4.
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Discussion |
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To our knowledge, this is the first analysis of the heritability of carotid IMT in families with multiple members having type 2 diabetes mellitus. The observed h2 value (0.41) for carotid IMT is similar to that observed for coronary artery calcium (CAC) content (0.50) in the same study.16 The adjusted estimate of CAC heritability was measured in a subsample of 56 of these families whose members had a measure of CAC estimated via fast-gated helical CT. Taken together, these 2 reports provide empirical evidence that subclinical CVD has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.
The heritability of carotid IMT has been determined in 2 other family studies. Duggirala et al8 detected an extremely high heritability of carotid IMT among siblings from Mexico City (from 0.86 to 0.92), suggesting a strong genetic component to atherosclerosis. This estimate, adjusted for a number of established CVD risk factors, in 46 mixed-ethnicity sibships of various sizes was based on a sample from an epidemiological survey in Mexico City. A potential explanation for this extremely high heritability estimate value may be that the participants in that study had a higher degree of similarity among environmental exposures than is usually seen in other, more general, populations, or it may be that the estimate was dominated by a single large family. In another family study, genetic factors were reported to contribute to 30% of the variability for carotid IMT.9 Although these 2 reports detected a genetic component to carotid IMT, they were in nondiabetic families with different ethnicity than the families in the present study. Additionally, the methodology used by Zannad et al9 to estimate heritability was different from that used by us. In Zannad et al,9 nuclear families were ascertained with relatively young children, in whom the carotid IMT measures are not expected to be variable in the absence of disease. Thus, the power for estimating the contribution of genetic factors in that setting would not be substantial.
Several studies have examined candidate genes for association with IMT, although the findings have been inconsistent. Candidate genes that have been examined include apoE,17–20 paraoxonase,21–24 ACE,22,25–27 cholesterol ester transfer protein,28 ß3-adrenergic receptor,29 and methylenetetrahydrofolate.22,30,31 The inconsistency among the results from these studies provides additional support for the necessity of a genome-wide linkage scan for this trait.
The associations we observed between carotid IMT and total serum cholesterol, LDL cholesterol, and smoking are consistent with other studies of individuals with type 2 diabetes5,32 and with studies of nondiabetic individuals.33–36 These findings are congruent with the results of a study by Stamler et al,37 in which the risk factors for CVD mortality were similar in diabetic and nondiabetic men. We did not observe a significant association between carotid IMT and hypertension status until we adjusted for a number of other CVD risk factors. Hypertension was extremely prevalent (76%) in this sample. This result may indicate that the effects of hypertension on CVD development may not be as strong in such a high-risk population, as has been detected in a number of studies in nondiabetic subjects.3,33,38 In another study of 271 patients with type 2 diabetes, hypertension status was not a significant predictor of IMT after adjustment was made for other CVD risk factors.39 The nonsignificant positive trend for IMT with myocardial infarction and stroke are of smaller magnitude, as reported previously by others in nondiabetic subjects.2
There was no statistical evidence of an association between the disease duration of diabetes and IMT. However, there was suggestive evidence of a trend for fasting glucose levels and carotid IMT, especially after multivariable adjustment. These results are consistent with those reported by Wagenknecht et al,5 who examined these factors in 489 unrelated individuals with type 2 diabetes. They observed that common carotid IMT was increased by 26 µm per 1 SD of fasting glucose, but they did not observe an association between the duration of diabetes in participants with established diabetes and IMT. Our estimate of a 12-µm (0.012-mm) increase in carotid IMT per 1 SD of fasting glucose is of somewhat smaller magnitude. We also examined diabetes treatment (insulin, oral hypoglycemic, none) as a surrogate measure of disease severity. Treatment was not associated with carotid IMT in this sample. However, the observed null findings may be unique to this sample and should not be interpreted as proof that these associations do not exist.
Our observation of significantly greater carotid IMT in African Americans versus whites is consistent with findings reported by D’Agostino et al40 in a study of 1020 nondiabetic subjects from IRAS. In that study, the authors reported that even after adjustment was made for major CVD risk factors and insulin sensitivity, African Americans had a significantly greater IMT than did non-Hispanic whites (0.864 versus 0.823 mm, respectively). Our finding is similar, with African Americans having an average carotid IMT 0.060 mm greater than that of whites, an effect equivalent in the present study to 10 years of increased age. A number of other large studies of carotid IMT did not report an association between carotid IMT and race and did not adjust for its effects in other analyses. Our finding is in accordance with the increased rate of stroke in African Americans versus whites.41 It is interesting to note that the opposite trend (ie, whites with a higher rate than African Americans) was apparent in CAC measured in this same study group.16 In contrast, IMT and CAC are both positively associated with age, male sex, smoking, and (to a lesser degree) triglycerides.
A limitation of the present study is that in using a traditional sibling-pair design, we can only estimate heritability by using sibling correlations. Thus, the estimated heritability includes both dominance and epistatic effects (potentially inflating the "true" estimate). Furthermore, the power of the variance components approach is due, in part, to the inclusion of additional relative pairs. In restricting the sample to sibling pairs, some loss of power and accuracy occurs. On the other hand, inclusion of covariates in the model reduces the phenotypic variance, thereby increasing the ability to estimate the genetic contribution to variation in IMT. Thus, our estimates of heritability of IMT were found to be statistically significant and of moderate magnitude, providing further support for the genetic basis of IMT in families affected with type 2 diabetes.
In conclusion, the established CVD risk factors (older age, male sex, African American race, total cholesterol, and LDL cholesterol) are important correlates of IMT in persons with type 2 diabetes. In addition, our findings of IMT heritability in the range of 40% warrants further investigation for specific genes contributing to variation in this trait. Although candidate gene studies can be informative, they may have limited utility in identifying the quantitative trait loci involved in complex diseases and in determining whether genome-wide linkage analysis scans are necessary. The moderate degree of heritability that we observed for IMT and the heritabilities observed for other traits associated with CVD in the present study indicate that this sample may be useful in efforts to map genes contributing to atherosclerotic CVD.
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Acknowledgments |
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This study was supported in part by the General Clinical Research Center of the Wake Forest University School of Medicine (grant M01 RR07122), by an American Diabetes Association grant, and by National Heart, Lung, and Blood Institute grant R01 HL-67342 awarded to Dr Bowden. The investigators acknowledge the cooperation of our participants and the work of the study recruiters Judy Brown and Bonnie Dryman, IMT sonographers Lois Hoots and Teresa Crotts, and database manager Stephanie Beck.
Received December 11, 2001; revision received March 1, 2002; accepted April 3, 2002.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999; 340: 14–22.
2. Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G, Barnes RW, Rosamond W, Crow RS, Rautaharju PM, Heiss G. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke. 1995; 26: 385–391.
3.
O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK Jr, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study: the CHS Collaborative Research Group. Stroke. 1992; 23: 1752–1760.
4.
Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M, Zlzola C. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC Study. Am J Epidemiol. 1991; 134: 250–256.
5.
Wagenknecht LE, D’Agostino R Jr, Savage PJ, O’Leary DH, Saad MF, Haffner SM. Duration of diabetes and carotid wall thickness: the Insulin Resistance Atherosclerosis Study (IRAS). Stroke. 1997; 28: 999–1005.
6.
Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events: PREVENT investigators. Circulation. 2000; 102: 1503–1510.
7. Byington RP, Furberg CD, Crouse JRIII, Espeland MA, Bond MG. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol. 1995; 76: 54C–59C.[CrossRef][Medline] [Order article via Infotrieve]
8. Duggirala R, Villalpando CG, O’Leary DH, Stern MP, Blangero J. Genetic basis of variation in carotid artery wall thickness. Stroke. 1996; 27833–837.
9. Zannad F, Visvikis S, Gueguen R, Sass C, Chapet O, Herbeth B, Siest G. Genetics strongly determines the wall thickness of the left and right carotid arteries. Hum Genet. 1998; 103: 183–188.[CrossRef][Medline] [Order article via Infotrieve]
10.
Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA. 1979; 241: 2035–2038.
11. Pyörälä K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987; 3: 463–524.[Medline] [Order article via Infotrieve]
12. Frost D, Beischer W. Determinants of carotid artery wall thickening in young patients with type 1 diabetes mellitus. Diabet Med. 1998; 15: 851–857.[CrossRef][Medline] [Order article via Infotrieve]
13.
Mykkanen L, Zaccaro DJ, O’Leary DH, Howard G, Robbins DC, Haffner SM. Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects: the Insulin Resistance Atherosclerosis Study (IRAS). Stroke. 1997; 28: 1710–1716.
14. Almasy L, Blangero J. Multipoint quantitative trait linkage analysis in general pedigrees. Am J Hum Genet. 1998; 62: 1198–1211.[CrossRef][Medline] [Order article via Infotrieve]
15. McCulloch CE, Searle SR. Generalized, Linear and Mixed Models. New York, NY: John Wiley and Sons Inc; 2001.
16.
Wagenknecht LE, Bowden DW, Carr JJ, Langefeld CD, Freedman BI, Rich SS. Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes. 2001; 50: 861–866.
17.
Slooter AJ, Bots ML, Havekes LM, del Sol AI, Cruts M, Grobbee DE, Hofman A, Van Broeckhoven C, Witteman JC, van Duijn CM. Apolipoprotein E and carotid artery atherosclerosis: the Rotterdam study. Stroke. 2001; 32: 1947–1952.
18. Ilveskoski E, Loimaala A, Mercuri MF, Lehtimaki T, Pasanen M, Nenonen A, Oja P, Bond MG, Koivula T, Karhunen PJ, et al. Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men. Atherosclerosis. 2000; 153: 147–153.[CrossRef][Medline] [Order article via Infotrieve]
19.
Cattin L, Fisicaro M, Tonizzo M, Valenti M, Danek GM, Fonda M, Da Col PG, Casagrande S, Pincetri E, Bovenzi M, et al. Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. Arterioscler Thromb Vasc Biol. 1997; 17: 91–94.
20. de Andrade M, Thandi I, Brown S, Gotto A Jr, Patsch W, Boerwinkle E. Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet. 1995; 56: 1379–1390.[Medline] [Order article via Infotrieve]
21. Malin R, Loimaala A, Nenonen A, Mercuri M, Vuori I, Pasanen M, Oja P, Bond G, Koivula T, Lehtimaki T. Relationship between high-density lipoprotein paraoxonase gene M/L55 polymorphism and carotid atherosclerosis differs in smoking and nonsmoking men. Metabolism. 2001; 50: 1095–1101.[CrossRef][Medline] [Order article via Infotrieve]
22.
Markus H, Kapozsta Z, Ditrich R, Wolfe C, Ali N, Powell J, Mendell M, Cullinane M. Increased common carotid intima-media thickness in UK African Caribbeans and its relation to chronic inflammation and vascular candidate gene polymorphisms. Stroke. 2001; 32: 2465–2471.
23.
Schmidt H, Schmidt R, Niederkorn K, Gradert A, Schumacher M, Watzinger N, Hartung HP, Kostner GM. Paraoxonase PON 1 polymorphism leu-Met54 is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. Stroke. 1998; 29: 2043–2048.
24. Cao H, Girard-Globa A, Serusclat A, Bernard S, Bondon P, Picard S, Berthezene F, Moulin P. Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus. Atherosclerosis. 1998; 138: 361–366.[CrossRef][Medline] [Order article via Infotrieve]
25.
Hosoi M, Nishizawa Y, Kogawa K, Kawagishi T, Konishi T, Maekawa K, Emoto M, Fukumoto S, Shioi A, Shoji T, et al. Angiotensin-converting enzyme gene polymorphism is associated with carotid arterial wall thickness in non-insulin-dependent diabetic patients. Circulation. 1996; 94: 704–707.
26. Kauma H, Paivansalo M, Savolainen MJ, Rantala AO, Kirma TR, Lilja M, Reunanen A, Kesaniemi YA. Association between angiotensin converting enzyme gene polymorphism and carotid atherosclerosis. J Hypertens. 1996; 14: 1183–1187.[Medline] [Order article via Infotrieve]
27. Dessi-Fulgheri P, Catalini R, Sarzani R, Sturbini S, Siragusa N, Guazzarotti F, Offidani M, Tamburrini P, Zingaretti O, Rappelli A. Angiotensin converting enzyme gene polymorphism and carotid atherosclerosis in a low-risk population. J Hypertens. 1995; 13(pt 2): 1593–1596.
28. Kakko S, Tamminen M, Paivansalo M, Kauma H, Rantala AO, Lilja M, Reunanen A, Kesaniemi YA, Savolainen MJ. Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima-media thickness. Eur J Clin Invest. 2001; 31: 558–559.[CrossRef][Medline] [Order article via Infotrieve]
29. Morrison AC, Brancati FL, Folsom AR, Smith L, Boerwinkle E. ß3-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. Hum Genet. 1999; 105: 314–319.[CrossRef][Medline] [Order article via Infotrieve]
30.
Bova I, Chapman J, Sylantiev C, Korczyn AD, Bornstein NM. The A 677V methylenetetrahydrofolate reductase gene polymorphism and carotid atherosclerosis. Stroke. 1999; 30: 2180–2182.
31. Mazza A, Motti C, Nulli A, Marra G, Gnasso A, Pastore A, Federici G, Cortese C. Lack of association between carotid intima-media thickness and methylenetetrahydrofolate reductase gene polymorphism or serum homocysteine in non-insulin-dependent diabetes mellitus. Metabolism. 2000; 49: 718–723.[CrossRef][Medline] [Order article via Infotrieve]
32. Kong C, Elatrozy T, Anyaoku V, Robinson S, Richmond W, Elkeles RS. Insulin resistance, cardiovascular risk factors and ultrasonically measured early arterial disease in normotensive type 2 diabetic subjects. Diabetes Metab Res Rev. 2000; 16: 448–453.[CrossRef][Medline] [Order article via Infotrieve]
33. Bonora E, Kiechl S, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M, Willeit J. Impaired glucose tolerance, type II diabetes mellitus and carotid atherosclerosis: prospective results from the Bruneck Study. Diabetologia. 2000; 43: 156–164.[CrossRef][Medline] [Order article via Infotrieve]
34.
Baldassarre D, Amato M, Bondioli A, Sirtori CR, Tremoli E. Carotid artery intima-media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerosis risk factors. Stroke. 2000; 31: 2426–2430.
35.
Davis PH, Dawson JD, Mahoney LT, Lauer RM. Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults: the Muscatine Study. Circulation. 1999; 100: 838–842.
36. Ferrières J, Elias A, Ruidavets J-B, Cantet C, Bongard V, Fauvel J, Boccalon H. Carotid intima-media thickness and coronary heart disease risk factors in a low-risk population. J Hypertens. 1999; 17: 743–748.[CrossRef][Medline] [Order article via Infotrieve]
37. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care. 1993; 16: 434–444.[Abstract]
38.
Crouse JR, Toole JF, McKinney WM, Dignan MB, Howard G, Kahl FR, McMahan MR, Harpold GH. Risk factors for extracranial carotid artery atherosclerosis. Stroke. 1987; 18: 990–996.
39.
Taniwaki H, Kawagishi T, Emoto M, Shoji T, Kanda H, Maekawa K, Nishizawa Y, Morii H. 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. Diabetes Care. 1999; 22: 1851–1857.
40.
D’Agostino RB Jr, Burke G, O’Leary D, Rewers M, Selby J, Savage PJ, Saad MF, Bergman RN, Howard G, Wagenknecht L, et al. Ethnic differences in carotid wall thickness. Stroke. 1996; 27: 1744–1749.
41. Karter AJ, Gazzaniga JM, Cohen RD, Casper ML, Davis BD, Kaplan GA. Ischemic heart disease and stroke mortality in African-American, Hispanic, and non-Hispanic white men and women, 1985 to 1991. West J Med. 1998; 169: 139–145.[Medline] [Order article via Infotrieve]
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 A. Doria, J. Wojcik, R. Xu, E. V. Gervino, T. H. Hauser, M. T. Johnstone, D. Nolan, F. B. Hu, and J. H. Warram Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes JAMA, November 26, 2008; 300(20): 2389 - 2397. [Abstract] [Full Text] [PDF]
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 K. P Burdon, A. B Lehtinen, C. D Langefeld, J. J. Carr, S. S Rich, B. I Freedman, D. Herrington, and D. W Bowden Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study Diabetes and Vascular Disease Research, June 1, 2008; 5(2): 128 - 134. [Abstract] [PDF]
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 A. B. Lehtinen, C. Newton-Cheh, J. T. Ziegler, C. D. Langefeld, B. I. Freedman, K. R. Daniel, D. M. Herrington, and D. W. Bowden Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study Diabetes, April 1, 2008; 57(4): 1108 - 1114. [Abstract] [Full Text] [PDF]
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 J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]
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 A. B. Lehtinen, K. P. Burdon, J. P. Lewis, C. D. Langefeld, J. T. Ziegler, S. S. Rich, T. C. Register, J. J. Carr, B. I. Freedman, and D. W. Bowden Association of {alpha}2-Heremans-Schmid Glycoprotein Polymorphisms with Subclinical Atherosclerosis J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 345 - 352. [Abstract] [Full Text] [PDF]
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 J. M. Murabito, C.-Y. Guo, C. S. Fox, and R. B. D'Agostino Heritability of the Ankle-Brachial Index: The Framingham Offspring Study Am. J. Epidemiol., November 15, 2006; 164(10): 963 - 968. [Abstract] [Full Text] [PDF]
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H. Yokoyama, N. Katakami, and Y. Yamasaki Recent Advances of Intervention to Inhibit Progression of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes Mellitus Stroke, September 1, 2006; 37(9): 2420 - 2427. [Abstract] [Full Text] [PDF]
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D. W. Bowden, M. Rudock, J. Ziegler, A. B. Lehtinen, J. Xu, L. E. Wagenknecht, D. Herrington, S. S. Rich, B. I. Freedman, J. J. Carr, et al. Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes, July 1, 2006; 55(7): 1985 - 1994. [Abstract] [Full Text] [PDF]
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 B. I. Freedman, D. W. Bowden, M. M. Sale, C. D. Langefeld, and S. S. Rich Genetic Susceptibility Contributes to Renal and Cardiovascular Complications of Type 2 Diabetes Mellitus Hypertension, July 1, 2006; 48(1): 8 - 13. [Full Text] [PDF]
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K. P. Burdon, J. L. Bento, C. D. Langefeld, J. K. Campbell, J. J. Carr, L. M. Wagenknecht, D. M. Herrington, B. I. Freedman, S. S. Rich, and D. W. Bowden Association of Protein Tyrosine Phosphatase-N1 Polymorphisms With Coronary Calcified Plaque in the Diabetes Heart Study Diabetes, March 1, 2006; 55(3): 651 - 658. [Abstract] [Full Text] [PDF]
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F.A. Sayed-Tabatabaei, M.J.E. van Rijn, A.F.C. Schut, Y.S. Aulchenko, E.A. Croes, M.C. Zillikens, H.A.P. Pols, J.C.M. Witteman, B.A. Oostra, and C.M. van Duijn Heritability of the Function and Structure of the Arterial Wall: Findings of the Erasmus Rucphen Family (ERF) Study Stroke, November 1, 2005; 36(11): 2351 - 2356. [Abstract] [Full Text] [PDF]
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 K P Burdon, C D Langefeld, S R Beck, L E Wagenknecht, J J Carr, B I Freedman, D Herrington, and D W Bowden Association of genes of lipid metabolism with measures of subclinical cardiovascular disease in the Diabetes Heart Study J. Med. Genet., September 1, 2005; 42(9): 720 - 724. [Abstract] [Full Text] [PDF]
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 W.H. L. Kao, W.-C. Hsueh, D. L. Rainwater, D. H. O'Leary, I. G. Imumorin, M. P. Stern, and B. D. Mitchell Family History of Type 2 Diabetes Is Associated With Increased Carotid Artery Intimal-Medial Thickness in Mexican Americans Diabetes Care, August 1, 2005; 28(8): 1882 - 1889. [Abstract] [Full Text] [PDF]
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 B. I. Freedman, C. D. Langefeld, K. K. Lohman, D. W. Bowden, J. J. Carr, S. S. Rich, and L. E. Wagenknecht Relationship between Albuminuria and Cardiovascular Disease in Type 2 Diabetes J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2156 - 2161. [Abstract] [Full Text] [PDF]
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S. Moskau, A. Golla, C. Grothe, M. Boes, C. Pohl, and T. Klockgether Heritability of Carotid Artery Atherosclerotic Lesions: An Ultrasound Study in 154 Families Stroke, January 1, 2005; 36(1): 5 - 8. [Abstract] [Full Text] [PDF]
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J. L. Bento, N. D. Palmer, J. C. Mychaleckyj, L. A. Lange, C. D. Langefeld, S. S. Rich, B. I. Freedman, and D. W. Bowden Association of Protein Tyrosine Phosphatase 1B Gene Polymorphisms With Type 2 Diabetes Diabetes, November 1, 2004; 53(11): 3007 - 3012. [Abstract] [Full Text] [PDF]
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S.-H. H. Juo, H.-F. Lin, T. Rundek, E. A. Sabala, B. Boden-Albala, N. Park, M.-Y. Lan, and R. L. Sacco Genetic and Environmental Contributions to Carotid Intima-Media Thickness and Obesity Phenotypes in the Northern Manhattan Family Study Stroke, October 1, 2004; 35(10): 2243 - 2247. [Abstract] [Full Text] [PDF]
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 T. A. Manolio, E. Boerwinkle, C. J. O'Donnell, and A. F. Wilson Genetics of Ultrasonographic Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1567 - 1577. [Abstract] [Full Text] [PDF]
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V. A. Korshunov and B. C. Berk Flow-Induced Vascular Remodeling in the Mouse: A Model for Carotid Intima-Media Thickening Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2185 - 2191. [Abstract] [Full Text] [PDF]
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J. F. Meschia and T. C. Gerber Editorial Comment--Vascular Thickness and Calcification as Markers of Atherosclerotic Burden Stroke, October 1, 2003; 34(10): 2372 - 2373. [Full Text] [PDF]
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