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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-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 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 totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 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<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). 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.

Supplement: 2 Special Issue: SI Meeting Abstract: ESOC-1343

OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke. Haplotype analysis suggests that a shared genetic factor is of particular importance for intracerebral hemorrhage.

Background and Purpose - Impaired fibrinolytic function secondary to elevated plasminogen activator inhibitor-1 (PAI-1) levels has been implicated in ischemic stroke. PAI-1 levels are determined by genetic factors and environmental factors, triglyceride levels in particular. The aim of this study was to investigate the common functional 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene and the risk of stroke. Methods - A nested case-control study design was applied, using baseline data for 2 independent cohorts obtained at population-based surveys in northern Sweden. In study A, there were 113, and in study B, there were 275 individuals without major concomitant disease at baseline who later experienced a first-ever stroke. Blood samples obtained at baseline were analyzed for potential risk factors, including the 4G/5G polymorphism of the PAI-1 gene. Results - The 4G allele of the PAI-1 polymorphism was associated with an increased risk of future ischemic stroke in both studies (odds ratio [OR] of 4G homozygosity, 1.87, 95% CI, 1.12 to 3.15 in study A, OR of 4G homozygosity, 1.56, 95% CI, 1.12 to 2.16 in study B). Individuals with the combination of hypertriglyceridemia and 4G homozygosity were at the greatest risk of developing stroke. Multiple logistic regression analysis identified 4G homozygosity, systolic blood pressure, and diabetes as independent predictors of ischemic stroke. Conclusions - Identical findings in 2 independent studies strongly suggest a true and clinically important association between PAI-1 4G/5G genotype and risk of future ischemic stroke. The observed modification of the genotype effect by triglycerides may be interpreted as a gene-environment interaction. © 2005 American Heart Association. Inc.

67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals, ORLANDO, FLORIDA, OCT 23-28, 2003

BACKGROUND AND PURPOSE: Leptin, important for body weight regulation, may be involved in the pathogenesis of the insulin resistance syndrome, associated with cardiovascular disease. We tested to determine whether leptin is a risk marker for first-ever stroke in a nested case-referent study. METHODS: We identified 113 patients with first-ever stroke (94 with ischemic and 19 with hemorrhagic stroke) who, before the stroke, had participated in population-based health surveys in northern Sweden. Referents were matched for sex, age, date and type of health survey, and geographic region. Blood pressure (BP), body mass index (BMI), and presence of smoking, diabetes, and hypertension were recorded. Total cholesterol, insulin, and leptin were analyzed in stored samples. Risk markers for first-ever stroke were analyzed by conditional logistic regression analysis. RESULTS: Patients with hemorrhagic stroke had higher levels of BMI and systolic and diastolic BPs. Leptin levels were 72% and 59% higher in males and females, respectively, with hemorrhagic stroke versus referents. Patients with ischemic stroke more often had hypertension, diabetes mellitus, and higher fasting glucose and insulin levels. A diagnosis of hypertension and elevated systolic and diastolic BPs were significant risk markers for first-ever hemorrhagic stroke in univariate analysis. High leptin (OR=20.55; 95% CI, 1.12 to 376.7) levels together with hypertension (OR=16.28; 95% CI, 1.49 to 177.3) remained as significant risk markers in a multivariate model. The combination of high leptin and high systolic or diastolic BP were associated with a profoundly increased risk for hemorrhagic stroke (OR=22.11; 95% CI, 1.57 to 310.9). Diabetes, hypertension, and obesity (BMI >/=27), together with high levels of insulin, glucose, systolic and diastolic BP, were significant risk markers for first-ever ischemic stroke in univariate analysis. Hypertension (OR=2.10; 95% CI, 1.14 to 3.86) remained as an independent risk ma