Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21.
OBJECTIVE
Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors.


RESULTS
A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574.


CONCLUSIONS
Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Clinical Physiology and Nuclear Medicine Unit, Skåne University Hospital, Malmö, Sweden.
Viktor
V
Hamrefors
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Bo
B
Hedblad
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
George
G
Hindy
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Department of Cardiology, Faculty of Medicine, Lund University, Lund, Sweden ; Department of Cardiology, Skåne University Hospital, Lund, Sweden ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
J Gustav
JG
Smith
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Peter
P
Almgren
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Gunnar
G
Engström
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Marketa
M
Sjögren
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Klas
K
Gränsbo
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Marju
M
Orho-Melander
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden ; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Olle
O
Melander
D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004522:Educational Status; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000209:etiology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012042:Registries / Q000706:statistics & numerical data; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D011795:Surveys and Questionnaires; D015996:Survival Rate; D013548:Sweden / Q000453:epidemiology