Coronary Artery Calcification and Its Relationship to Validated Genetic Variants for Diabetes Mellitus Assessed in the Heinz Nixdorf Recall Cohort

Objective—To examine the association between genomewide association study–based diabetes mellitus–related single-nucleotide polymorphisms (SNPs) and coronary artery calcification (CAC), a valid risk factor for coronary heart disease, in a large, unselected, population-based cohort. Methods and Results—We genotyped 11 validated genomewide association study–based diabetes SNPs in 4459 participants of the Heinz Nixdorf Recall Study. We applied generalized linear regression models to explore the impact of the diabetes SNPs on CAC and to jointly model the effect of the SNPs and CAC on diabetes status. We observed a significant association between cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) variant rs564398 and quantitative CAC (P=1.81×10−5 and adjusted P=4.02×10−4; odds ratio for the presence of CAC, 1.12 [95% CI, 1.02 to 1.25]). Moreover, we observed no strong impact of CAC on diabetes risk in the presence of the other genetic variants. Conclusion—We show that a genetic variant near CDKN2A/2B that has been reported to be strongly associated with diabetes is strongly associated with CAC. In contrast, variants near insulin-like growth factor-binding protein 2 (IGFBP2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), solute carreir family 30 (zinc transporter), member 8 (SLC30A8), hematopoietically-expressed homeobox (HHEX), and transcription factor 7-like2 (TCF7L2) were clearly associated with diabetes; no evidence for an association to CAC was observable. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations.

[1]  G. Schuler,et al.  ANRIL Expression Is Associated With Atherosclerosis Risk at Chromosome 9p21 , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[2]  A. Chakravarti,et al.  Understanding cardiovascular disease through the lens of genome-wide association studies. , 2009, Trends in genetics : TIG.

[3]  M. Wolfs,et al.  Type 2 Diabetes Mellitus: New Genetic Insights will Lead to New Therapeutics , 2009, Current genomics.

[4]  Mark I. McCarthy,et al.  Assessing the Combined Impact of 18 Common Genetic Variants of Modest Effect Sizes on Type 2 Diabetes Risk , 2008, Diabetes.

[5]  M. Permutt,et al.  Post Genome-Wide Association Studies of Novel Genes Associated with Type 2 Diabetes Show Gene-Gene Interaction and High Predictive Value , 2008, PloS one.

[6]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[7]  H. Stefánsson,et al.  The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm , 2008, Nature Genetics.

[8]  Nikolaos A Patsopoulos,et al.  Claims of sex differences: an empirical assessment in genetic associations. , 2007, JAMA.

[9]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[10]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[11]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[12]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[13]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[14]  Philippe Froguel,et al.  TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis , 2007, Journal of Molecular Medicine.

[15]  Jonathan C. Cohen,et al.  A Common Allele on Chromosome 9 Associated with Coronary Heart Disease , 2007, Science.

[16]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[17]  Richard A. Kronmal,et al.  Distribution of Coronary Artery Calcium by Race, Gender, and Age: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) , 2005, Circulation.

[18]  N. Kalinina,et al.  Smad Expression in Human Atherosclerotic Lesions Evidence for Impaired TGF-β/Smad Signaling in Smooth Muscle Cells of Fibrofatty Lesions , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[19]  S. Rane,et al.  Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice , 2003, Oncogene.

[20]  S. Lowe,et al.  Tumor suppression by Ink4a-Arf: progress and puzzles. , 2003, Current opinion in genetics & development.

[21]  D. Levy,et al.  Coronary artery calcification in type 2 diabetes and insulin resistance: the framingham offspring study. , 2002, Diabetes care.

[22]  D. Grönemeyer,et al.  Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle. , 2002, American heart journal.

[23]  L. Kuller,et al.  Coronary Artery Calcification in Older Adults to Age 99: Prevalence and Risk Factors , 2001, Circulation.

[24]  T. Mazzone,et al.  Increased prevalence of significant coronary artery calcification in patients with diabetes. , 2001, Diabetes care.

[25]  S. Haffner,et al.  Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? , 1990, JAMA.

[26]  S. Moebus,et al.  Association of impaired fasting glucose and coronary artery calcification as a marker of subclinical atherosclerosis in a population-based cohort—results of the Heinz Nixdorf Recall Study , 2008, Diabetologia.

[27]  S. Moebus,et al.  Baseline recruitment and analyses of nonresponse of the Heinz Nixdorf recall study: Identifiability of phone numbers as the major determinant of response , 2005, European Journal of Epidemiology.