Analysis of a cardiovascular disease genetic risk score in the Diabetes Heart Study
- 438 Downloads
It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g., lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes.
The composite risk score was analyzed for potential associations with subclinical CVD, self-reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex.
An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p = 1.23 × 10−4); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed.
These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes.
KeywordsType 2 diabetes Mortality Coronary artery calcification Genetic risk score
The authors thank the other investigators, the staff, and the participants of the DHS study for their valuable contributions. This study was supported by the National Institutes of Health through R01 HL67348 and R01 HL092301 (to DWB), R01 AR48797 (to JJC), and F31 AG044879 (to LMR).
Conflict of interest
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national, Wake Forest School of Medicine Institutional Review Board) and with the Helsinki Declaration of 1975, as revised in 2008 (5).
Informed consent was obtained from all patients for being included in the study.
- 2.Shah S, Casas JP, Gaunt TR, Cooper J, Drenos F, Zabaneh D, Swerdlow DI, Shah T, Sofat R, Palmen J et al (2013) Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies. Eur Heart J 34(13):972–981. doi: 10.1093/eurheartj/ehs243 PubMedCentralPubMedCrossRefGoogle Scholar
- 3.Voight B, Peloso G, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen M, Hindy G, Hólm H, Ding E, Johnson T et al (2012) Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380(9841):572–580. doi: 10.1016/s0140-6736(12)60312-2 PubMedCentralPubMedCrossRefGoogle Scholar
- 4.Ripatti S, Tikkanen E, Orho-Melander M, Havulinna A, Silander K, Sharma A, Guiducci C, Perola M, Jula A, Sinisalo J et al (2010) A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376(9750):1393–1400. doi: 10.1016/s0140-6736(10)61267-6 PubMedCentralPubMedCrossRefGoogle Scholar
- 6.Thanassoulis G, Peloso GM, Pencina MJ, Hoffmann U, Fox CS, Cupples LA, Levy D, D’Agostino RB, Hwang SJ, O’Donnell CJ (2012) A genetic risk score is associated with incident cardiovascular disease and coronary artery calcium: the Framingham heart study. Circ Cardiovasc Genet 5(1):113–121. doi: 10.1161/circgenetics.111.961342 PubMedCentralPubMedCrossRefGoogle Scholar
- 7.van Setten J, Isgum I, Smolonska J, Ripke S, de Jong PA, Oudkerk M, de Koning H, Lammers JW, Zanen P, Groen HJ et al (2013) Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction. Atherosclerosis 228(2):400–405. doi: 10.1016/j.atherosclerosis.2013.02.039 PubMedCrossRefGoogle Scholar
- 11.Wang W, Peng W, Zhang X, Lu L, Zhang R, Zhang Q, Wang L, Chen Q, Shen W (2010) Chromosome 9p21.3 polymorphism in a Chinese Han population is associated with angiographic coronary plaque progression in non-diabetic but not in type 2 diabetic patients. Cardiovasc Diabetol 9:33. doi: 10.1186/1475-2840-9-33 PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Qi L, Qi Q, Prudente S, Mendonca C, Andreozzi F, di Pietro N, Sturma M, Novelli V, Mannino GC, Formoso G et al (2013) Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes. JAMA 310(8):821–828. doi: 10.1001/jama.2013.276305 PubMedCrossRefGoogle Scholar
- 14.Bacci S, Rizza S, Prudente S, Spoto B, Powers C, Facciorusso A, Pacilli A, Lauro D, Testa A, Zhang YY et al (2011) The ENPP1 Q121 variant predicts major cardiovascular events in high-risk individuals: evidence for interaction with obesity in diabetic patients. Diabetes 60(3):1000–1007. doi: 10.2337/db10-1300 PubMedCentralPubMedCrossRefGoogle Scholar
- 15.Bowden D, Cox A, Freedman B, Hugenschimdt C, Wagenknecht L, Herrington D, Agarwal S, Register T, Maldjian J, Ng M et al (2010) Review of the Diabetes Heart Study (DHS) family of studies: a comprehensively examined sample for genetic and epidemiological studies of type 2 diabetes and its complications. Rev Diabet Stud RDS 7(3):188–201. doi: 10.1900/rds.2010.7.188 PubMedGoogle Scholar
- 18.Raffield L, Cox A, Hsu F-C, Ng M, Langefeld C, Carr J, Freedman B, Bowden D (2013) Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study. Cardiovasc Diabetol 12:95. doi: 10.1186/1475-2840-12-95 PubMedCentralPubMedCrossRefGoogle Scholar
- 20.Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs DR Jr, Sidney S, Bild DE, Williams OD, Detrano RC (2005) Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of multi-ethnic study of atherosclerosis (MESA) and coronary artery risk development in young adults (CARDIA) study. Radiology 234(1):35–43. doi: 10.1148/radiol.2341040439 PubMedCrossRefGoogle Scholar
- 21.Carr JJ, Crouse JR 3rd, Goff DC Jr, D’Agostino RB Jr, Peterson NP, Burke GL (2000) Evaluation of subsecond gated helical CT for quantification of coronary artery calcium and comparison with electron beam CT. AJR Am J Roentgenol 174(4):915–921. doi: 10.2214/ajr.174.4.1740915 PubMedCrossRefGoogle Scholar
- 24.Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J, Little DP, Strausberg R, Koester H, Cantor CR et al (2001) High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Natl Acad Sci USA 98(2):581–584. doi: 10.1073/pnas.021506298 PubMedCentralPubMedCrossRefGoogle Scholar
- 25.Fontaine-Bisson B, Renström F, Rolandsson O, Payne F, Hallmans G, Barroso I, Franks P (2010) Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population. Diabetologia 53(10):2155–2162. doi: 10.1007/s00125-010-1792-y PubMedCentralPubMedCrossRefGoogle Scholar
- 27.Folsom A, Kronmal R, Detrano R, O’Leary D, Bild D, Bluemke D, Budoff M, Liu K, Shea S, Szklo M et al (2008) Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 168(12):1333–1339. doi: 10.1001/archinte.168.12.1333 PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Erbel R, Mohlenkamp S, Moebus S, Schmermund A, Lehmann N, Stang A, Dragano N, Gronemeyer D, Seibel R, Kalsch H et al (2010) Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol 56(17):1397–1406. doi: 10.1016/j.jacc.2010.06.030 PubMedCrossRefGoogle Scholar
- 34.Elias-Smale SE, Proenca RV, Koller MT, Kavousi M, van Rooij FJ, Hunink MG, Steyerberg EW, Hofman A, Oudkerk M, Witteman JC (2010) Coronary calcium score improves classification of coronary heart disease risk in the elderly: the Rotterdam study. J Am Coll Cardiol 56(17):1407–1414. doi: 10.1016/j.jacc.2010.06.029 PubMedCrossRefGoogle Scholar
- 35.Hoff J, Quinn L, Sevrukov A, Lipton R, Daviglus M, Garside D, Ajmere N, Gandhi S, Kondos G (2003) The prevalence of coronary artery calcium among diabetic individuals without known coronary artery disease. J Am Coll Cardiol 41(6):1008–1012. doi: 10.1016/S0735-1097(02)02975-3 PubMedCrossRefGoogle Scholar
- 39.Wensley F, Gao P, Burgess S, Kaptoge S, Di Angelantonio E, Shah T, Engert JC, Clarke R, Davey-Smith G, Nordestgaard BG et al (2011) Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 342:d548. doi: 10.1136/bmj.d548 PubMedCrossRefGoogle Scholar