Kennet Harald

The early repolarization pattern in the general population: clinical correlates and heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

Expedited PublicationThe Early Repolarization Pattern in the General Population: Clinical Correlates and Heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. RESULTS ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). CONCLUSIONS ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.

An immune response network associated with blood lipid levels.

While recent scans for genetic variation associated with human disease have been immensely successful in uncovering large numbers of loci, far fewer studies have focused on the underlying pathways of disease pathogenesis. Many loci which are associated with disease and complex phenotypes map to non-coding, regulatory regions of the genome, indicating that modulation of gene transcription plays a key role. Thus, this study generated genome-wide profiles of both genetic and transcriptional variation from the total blood extracts of over 500 randomly-selected, unrelated individuals. Using measurements of blood lipids, key players in the progression of atherosclerosis, three levels of biological information are integrated in order to investigate the interactions between circulating leukocytes and proximal lipid compounds. Pair-wise correlations between gene expression and lipid concentration indicate a prominent role for basophil granulocytes and mast cells, cell types central to powerful allergic and inflammatory responses. Network analysis of gene co-expression showed that the top associations function as part of a single, previously unknown gene module, the Lipid Leukocyte (LL) module. This module replicated in T cells from an independent cohort while also displaying potential tissue specificity. Further, genetic variation driving LL module expression included the single nucleotide polymorphism (SNP) most strongly associated with serum immunoglobulin E (IgE) levels, a key antibody in allergy. Structural Equation Modeling (SEM) indicated that LL module is at least partially reactive to blood lipid levels. Taken together, this study uncovers a gene network linking blood lipids and circulating cell types and offers insight into the hypothesis that the inflammatory response plays a prominent role in metabolism and the potential control of atherogenesis.

Non-participation and mortality in different socioeconomic groups: the FINRISK population surveys in 1972–92

Background: Declining response rates pose a serious threat to the validity of estimates derived from epidemiological studies. If respondents and non-respondents differ systematically from each other, there can be a bias in the results of the study. A population-based cohort study was conducted to investigate disparities in socioeconomic structure between respondents and non-respondents and the contribution of these disparities to socioeconomic differences in total and cardiovascular mortality. Design: Data comprised 32 354 male and female participants and 4890 non-participants aged 35–74 years who belonged to the sample in one of the five FINRISK surveys in 1972, 1977, 1982, 1987 or 1992 in Finland. They were followed up for 9 years and 6 months. Results: It was found that the lower socioeconomic groups were over-represented among non-respondents both in men and women. When comparing the relative risk of death using the highest socioeconomic group of the participants as the reference group, it was found that although the socioeconomic gradient was similar for participants and non-participants—that is, lower groups had a higher risk of death—the risk was at a higher level among non-respondents. Conclusions: Basing analysis on participants does not distort the relative risk of death associated with socioeconomic position. However, it does underestimate the absolute risk.

The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study

Ron Do and colleagues find that a prudent diet high in raw vegetables may modify the increased genetic risk of cardiovascular disease conferred by the chromosome 9p21 SNP.

Fifteen-year changes in body mass index and waist circumference in Finnish adults

Background Obesity is an increasing health problem. Data on long-term obesity trends are most often based on the measurement of body mass index (BMI). Abdominal obesity, assessed by waist circumference may, however, be more closely related to health risks than overall obesity. The aim of this study was to investigate 15-year changes in general and abdominal obesity among adults in Finland, and furthermore, to assess whether obesity trends differ between educational groups. Design Four cross-sectional population surveys conducted at 5-year intervals between 1987 and 2002. Methods Altogether, 9025 men and 9950 women aged 25-64 years participated in these surveys. The weight, height, and waist circumferences of the participants were measured using a standardized protocol. Results Mean waist circumference increased by 2.7 cm in men and 4.3 cm in women in 15 years. Whereas the distribution of BMI values did not change much, a remarkable shift towards higher waist circumference values was observed in 15 years. In both sexes, mean and high values of waist circumference increased in all educational groups. However, the values remained highest among the subjects with the lowest education. Conclusions These results indicate that adverse changes in body shape have taken place from the late 1980s to the early 2000s. Given that one in five Finnish adults is defined as obese based on BMI, there is an even larger group of individuals at risk of obesity-related metabolic disorders because of abdominal obesity, particularly among low-educated individuals.

Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study

Objective To estimate how much changes in the main risk factors of cardiovascular disease (smoking prevalence, serum cholesterol, and systolic blood pressure) can explain the reduction in coronary heart disease mortality observed among working aged men and women in eastern Finland. Design Population based observational study. Setting Eastern Finland. Participants 34 525 men and women aged 30-59 years who participated in the national FINRISK studies between 1972 and 2012. Interventions Change in main cardiovascular risk factors through population based primary prevention. Main outcome measures Predicted and observed age standardised mortality due to coronary heart disease. Predicted change was estimated with a logistic regression model using risk factor data collected in nine consecutive, population based, risk factor surveys conducted every five years since 1972. Data on observed mortality were obtained from the National Causes of Death Register. Results During the 40 year study period, levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969-1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100 000 people) and 84% (114 to 17) among men and women aged 35-64 years, respectively. During the first 10 years of the study, changes in these three target risk factors contributed to nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than predicted. In the last 10 years of the study, about two thirds (69% in men and 66% in women) of the reduction could be explained by changes in the three main risk factors, and the remaining third by other factors. Conclusion Reductions in disease burden and mortality due to coronary heart disease can be achieved through the use of population based primary prevention programmes. Secondary prevention among high risk individuals and treatment of acute events of coronary heart disease could confer additional benefit.

Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry

Abstract Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist–hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006–0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

The validity of heart failure diagnoses obtained from administrative registers

Background: Population-based administrative registers could be used for identifying heart failure (HF) cases. However, the validity of the classification obtained from administrative registers is not known. Design: The validity of HF diagnoses obtained by record linkage of administrative databases in Finland was assessed against classification by three independent physicians. Methods: Data from the nationwide registers in Finland – the Hospital Discharge Register, Causes of Death Register, Drug Reimbursement Register, and pharmacy prescription data – were linked with the FINRISK 1997 survey data. Cases with hospitalizations before the survey date with HF as one of the discharge diagnoses, cases with special reimbursement for HF drugs before the survey date and cases with the use of furosemide before the survey date were classified as HF in the registers. All these cases, cases with baseline brain natriuretic peptide >100 pg/ml, and cases with use of digoxin were independently assessed by two physicians as HF/no HF. Discrepant cases were solved by a third physician. This classification was considered as the gold standard, against which the registers were assessed. Results: The specificity of the registers was 99.7% (95% CI 99.5–99.8%), positive predictive value 85.9% (95% CI 79.7–90.5%), negative predictive value 97.9% (95% CI 97.6–98.2%), and sensitivity 48.5% (95% CI 42.9–54.2%). Conclusions: Classification obtained from administrative registers has high specificity and can be used in follow-up studies with HF as an end point. Sensitivity is modest and administrative data should be used with caution for surveillance.

Socioeconomic Indicators and the Risk of Acute Coronary Heart Disease Events: Comparison of Population-Based Data from the United States and Finland

PURPOSE We wished to determine whether a gradient of association of low socioeconomic status with incidence of coronary heart disease was present in two population-based cohorts, one from United States and the other from Finland. METHODS Using data from the Atherosclerosis Risk in Communities (ARIC) cohort and the Finnish FINRISK cohort, we estimated, with Cox proportional hazard regression models, incidence of sudden cardiac death (SCD), non-sudden cardiac death (NSCD), and non-fatal myocardial infarction (NFMI) for strata of income and education (follow-up: 1987-2001). In both cohorts, incidence rates of the three outcomes increased across all socioeconomic status exposure categories. RESULTS Low education was associated with increased hazard of NFMI in both cohorts and with increased risk of SCD among ARIC women. Low income was significantly associated with increased hazard of all three outcomes among ARIC women and with increased hazard of cardiac death among ARIC men. In FINRISK, low income was significantly associated with increased risk of SCD only. Risk of SCD in the low income categories was similar for both cohorts. Smoking, alcohol consumption, and race (ARIC only) did not appreciably alter effect estimates in either cohort. CONCLUSIONS Indices of low SES show similar associations with increased risk of cardiac events in Finland and in United States.