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Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

Type 2 diabetes (T2D) and cardiovascular disease (CVD) are highly prevalent complex diseases that result from lifestyle and genetic factors. Gene-lifestyle interactions are also believed to contribute to the etiology of these diseases. The aim of this thesis was to investigate gene-lifestyle interactions using the strongest T2D and CVD susceptibility genetic loci and to understand the causal nature of the associations of common cardio-metabolic biomarkers with T2D and coronary heart disease (CHD). The Malmö Diet and Cancer Study (MDCS), a population-based prospective study, was used and included around 30,000 individuals with comprehensive baseline dietary and lifestyle assessment between the years 1991-1996. The TCF7L2 genotype modified the association between fiber intake and the risk of T2D. The lower risk of T2D by higher fiber intake was restricted to individuals carrying the CC non-risk genotype (Pinteraction = 0.049). Similar interaction was observed with baseline levels of HbA1C (Pinteraction = 0.02). Other T2D associated genes were then investigated for links to WNT signaling pathway where TCF7L2 acts as a transcription factor. Of the 51 T2D associated gene loci 7 genes were annotated to the WNT pathway. Interaction analyses between single nucleotide polymorphisms (SNPs) in these loci and dietary fiber intake were significant for the TCF7L2, NOTCH2 and ZBED3 SNPs. Higher fiber intake associated with lower risk of T2D only among risk allele carriers of the NOTCH2 SNP (Pinteraction = 0.01) and only among homozygotes for the risk allele of the ZBED3 SNP (Pinteraction = 0.003). The interaction between TCF7L2 and fiber intake was further explored in relation to the metabolic syndrome in 4,606 individuals. Higher fiber intake was observed to be associated with lower prevalence of the metabolic syndrome only among non-risk CC genotype carriers (Pinteraction = 0.02) and similar interactions were observed on baseline levels of several traits related to the metabolic

GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD. SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881). METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change. A 13-SNP-myocardial-infarction-(MI)-genetic-risk-score was related to carotid atherosclerosis-markers in 4022 MDC-subjects. The MI-gene-score associated with carotid-bulb-intima-media-thickness (IMT) (beta=0.038 standard deviations of IMT per MI-gene-score-quintile; P-trend=0.005) and plaque (odds-ratio per MI-gene-score-quintile=1.11; 95% confidence interval (CI):1.04-1.18; P=0.001) in multivariable models. It was tested if eight blood-pressure-associated SNPs affected antihypertensive treatment-response in 3863 Swedish hypertensives from NORDIL. No robust associations were identified. Finally, interactions between life-style-factors and the CVD-SNP rs4977574 on chromosome 9p21 were evaluated in 24944 MDC-subjects during 15 years follow-up. There were interactions between rs4977574 and smoking on incident CAD (P=0.035) and CVD-mortality (P=0.012). The risk conferred by rs4977574 in never-smokers (n=9642; Hazard-ratio(HR) per risk-allele(CAD)=1.26; 95%CI:1.13-1.40; HR per risk-allele(CVD-mortality)=1.40; 95%CI:1.20-1.63) was attenuated in smokers (n=7000; HR per risk-allele(CAD)=1.05; 95%CI:0.95-1.16; HR per risk-allele(CVD-mortality)=1.08; 95%CI:0.94-1.23). CONCLUSIONS: CVD-genetics identifies subjects with markers of subclinical atherosclerosis, suggesting that early atherosclerosis-prevention may be targeted