Recent genome-wide association studies have identified genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRSs) constructed of these variants would predict incident cardiovascular disease (CVD) events. We genotyped 32 common single nucleotide polymorphisms in several Finnish cohorts, with up to 32,669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. We created GRSs separately for systolic BP and diastolic BP by multiplying the risk allele count of each single nucleotide polymorphism by the effect size estimated in published genome-wide association studies. We performed Cox regression analyses with and without adjustment for clinical factors, including BP at baseline in each cohort. The results were combined by inverse variance-weighted fixed-effects meta-analysis. The GRSs were strongly associated with systolic BP and diastolic BP, and baseline hypertension (all P
Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.
Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD.
We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n?=?27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n?=?694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11-1.45, P?=?3.4×10(-4)) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11-1.48, P?=?7.9×10(-4)). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01-1.26, P?=?0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P
Although sudden cardiac death (SCD) is heritable, its genetic underpinnings are poorly characterized. The QT interval appears to have a graded relationship to SCD, and 35% to 45% of its variation is heritable. We examined the relationship among recently reported common genetic variants, QT interval, and SCD.
We genotyped 15 common (minor allele frequency >1%) candidate single nucleotide polymorphisms (SNPs), based on association with the QT interval in prior studies, in individuals in 2 cohort studies (Health 2000, n = 6597; Mini-Finland, n = 801). After exclusions, we identified 116 incident SCDs from the remaining sample (n = 6808). We constructed a QT genotype score (QT(score)) using the allele copy number and previously reported effect estimates for each SNP. Cox proportional hazards models adjusting for age, sex, and geographical area were used for time to SCD analyses. The QT(score) was a continuous independent predictor of the heart rate-corrected QT interval (P
T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown.
To identify common genetic variants that affect the duration of the TPE interval in the general population.
We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study.
We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes.
The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.
The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the 2, 3, and 4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.
Cites: Am J Hum Genet. 1991 Aug;49(2):338-491867194
Apolipoprotein E (ApoE) is a major constituent of many lipoprotein particles. Previous genetic studies have focused on six genotypes defined by three alleles, denoted epsilon2, epsilon3, and epsilon4, encoded by two variable exonic sites that segregate in most populations. We have reported studies of the distribution of alleles of 20 biallelic variable sites in the gene encoding the ApoE molecule within and among samples, ascertained without regard to health, from each of three populations: African Americans from Jackson, Miss.; Europeans from North Karelia, Finland; and non-Hispanic European Americans from Rochester, Minn. Here we ask (1) how much variation in blood levels of ApoE (lnApoE), of total cholesterol (TC), of high-density lipoprotein cholesterol (HDL-C), and of triglyceride (lnTG) is statistically explained by variation among APOE genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles; (2) how much additional variation in these traits is explained by genotypes defined by combining the two variable sites that define these three alleles with one or more additional variable sites; and (3) what are the locations and relative allele frequencies of the sites that define multisite genotypes that significantly improve the statistical explanation of variation beyond that provided by the genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles, separately for each of the six gender-population strata. This study establishes that the use of only genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles gives an incomplete picture of the contribution that the variation in the APOE gene makes to the statistical explanation of interindividual variation in blood measurements of lipid metabolism. The addition of variable sites to the genotype definition significantly improved the ability to explain variation in lnApoE and in TC and resulted in the explanation of variation in HDL-C and in lnTG. The combination of additional sites that explained the greatest amount of trait variation was different for different traits and varied among the six gender-population strata. The role that noncoding variable sites play in the explanation of pleiotropic effects on different measures of lipid metabolism reveals that both regulatory and structural functional variation in the APOE gene influences measures of lipid metabolism. This study demonstrates that resequencing of the complete gene in a sample of >/=20 individuals and an evaluation of all combinations of the identified variable sites, separately for each population and interacting environmental context, may be necessary to fully characterize the impact that a gene has on variation in related traits of a metabolic system.
Evidence from prospective observational studies suggests that elevated circulating C-reactive protein (CRP) concentrations are associated with cancer risk, but it is unclear whether this association is causal. In order to examine this, we investigated whether genetic variants that are associated with circulating CRP concentrations are associated with cancer risk.
We pooled data from three population-based prospective Finnish studies: FINRISK 1992 (n = 5289), FINRISK 1997 (n = 7160) and Health 2000 (n = 6299). Cancer cases were identified from cancer registrations. Thirteen CRP-associated SNPs, identified from genome-wide association studies, were genotyped. We examined the associations of the SNPs and cancer risk using Cox, probit and instrumented probit regression models.
Compared to common allele homozygotes, individuals carrying one or two variant T alleles at rs1892534 had 1.05-fold (95% confidence interval (CI): 0.90, 1.23) and 1.2-fold (95% CI: 1.01, 1.42) increased overall cancer risk, respectively. Individuals with one or two variant A alleles at rs1169300 or rs2464196 had approximately 1.5- and 2-fold increased risk of lung cancer, respectively (p trend for both: 0.007). CRP SNPs were not associated with colorectal, prostate or breast cancer risk nor was CRP-associated with the probability of developing cancer in the instrumented probit analyses.
We found some evidence for an association of a small number of CRP-associated SNPs with the overall cancer risk and lung cancer risk. Our instrumental variable analyses provided no clear evidence for a causal association of CRP and cancer. These findings suggest that circulating CRP concentrations are unlikely to have a causal role in cancer.
Almost 100 genetic loci are known to affect serum cholesterol and triglyceride levels. For many of these loci, the biological function and causal variants remain unknown. We performed an association analysis of the reported 95 lipid loci against 216 metabolite measures, including 95 measurements on lipids and lipoprotein subclasses, obtained via serum nuclear magnetic resonance metabolomics and four enzymatic lipid traits in 8330 individuals from Finland. The genetic variation in the loci was investigated using a dense set of 440 807 directly genotyped and imputed variants around the previously identified lead single nucleotide polymorphisms (SNPs). For 30 of the 95 loci, we identified new metabolic or genetic associations (P
Association of estrogen receptor 1 (ESR1) gene variants and risk of coronary heart disease (CHD) and ischemic stroke was evaluated in the FINRISK-study. From 14,140 individuals, 2225 were selected for genotyping using a case-cohort design. Time-to-event analysis showed that the CC genotype of -397T/C ERS1 gene contributed to higher risk of CHD only in men (HR, 1.68, CI 1.03-2.74). The -351A/G polymorphism was not independently associated with CHD. Haplotype analysis of these two variants indicated that in men, haplotype TA conferred lower risk of CHD (HR=0.72, CI 0.55-0.95), whereas men with haplotype CA had 1.8 higher risk of CHD events (CI 1.21-2.77), compared to other haplotypes. No association was found with ischemic stroke. Our study suggests that the minor allele -397C of the ESR1 gene confers risk of CHD among Finnish men, both in homozygous state and as part of a haplotype with the -351A allele.