Timo Lakka

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures…

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci…

Knowledge on the association of plasma fatty acid (FA) composition in triacylglycerol (TG) and phospholipid (PL) fractions with cardiometabolic risk in population-based samples of children is lacking. We investigated the associations of proportions of FA in plasma TG and PL fractions as well as estimated desaturase and elongase activities with cardiometabolic risk in a population sample of 384 children aged 6-8 years. Plasma FA composition was analyzed by gas chromatography. Desaturase and elongase activities were estimated as product-to-precursor FA ratios. Cardiometabolic risk was assessed using a continuous cardiometabolic risk score (CRS) variable. Higher proportions of myristic and palmitoleic acids in plasma TG and PL were associated with a higher CRS. A lower proportion of linoleic acid in plasma TG was related to a higher CRS. Estimated stearoyl-CoA-desaturase and Δ6-desaturase activities in plasma TG and PL were directly associated with CRS, whereas estimated elongase activity in plasma TG and PL was inversely related to CRS. Greater proportions of myristic and palmitoleic acids and a smaller proportion of linoleic acid in plasma, as well as higher estimated stearoyl-CoA-desaturase and Δ6-desaturase activities and a lower estimated elongase activity, are associated with cardiometabolic risk factors among children. These findings reinforce the evidence that FA metabolism is closely associated with cardiometabolic risk, starting already from childhood.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men…

Objectives Methods Results Conclusions Low levels of physical activity (PA) have been associated with an increased risk of metabolic syndrome (MetS) in adults, but there are limited data on the relationships of PA and media time (MT) in children. We therefore studied these associations among children in the Physical Activity and Nutrition in Children (PANIC) Study. The subjects were 512 children 6-8 years of age examined at baseline of the PANIC Study in 2007-2009. Habitual physical activity (PA) and MT were assessed by the PANIC Physical Activity Questionnaire. We used a continuous metabolic risk score (MetSs) variable that was calculated by the following formula that included age-, sex-and height-adjusted variables standardized by Z-scores: waist circumference + fasting insulin + fasting glucose + systolic blood pressure + fasting triglycerides – fasting HDL cholesterol. Data were analyzed by ANOVA and statistical significance was defined as P<0.05.

  To examine the expression of possible secular trend in timing of the emergence of permanent teeth in Finnish children over the past few decades, considering the differences between genders.   Two age groups of Finnish children, one born in 1976-1985 (group 1980) and the other born in 1999-2002 (group 2000), were examined. Group 2000 comprised 483 children (235 girls and 248 boys) aged 6.4 to 8.5 years at the time of the examination, and the same children were examined at the age of 9.0 to 11.8 years. Altogether 405 children could be recalled, 196 girls and 209 boys. For comparison, matching age groups were selected from the group 1980 data (n  =  1579), resulting in a sample of 312 children (155 girls and 157 boys) aged 6.4 to 8.5 years and 393 children aged 9.0 to 11.8 years. The emergence stage of each permanent tooth was determined clinically (Grades 0-3), based on which the subjects were furthermore divided according to the emergence stage of the dentition.   Linear regression models showed that the permanent teeth of the first phase of the mixed dentition erupted earlier in group 2000 than in group1980, but the teeth of the second phase of the mixed dentition erupted later in group 2000. Girls showed more advanced tooth eruption than boys.   The longer duration of mixed dentition in group 2000 than in group 1980 makes the duration of combined follow-up and active treatment longer, and should be considered in timing of efficient orthodontic treatment.

ABSTRACT Background Observational studies suggest that higher levels of physical activity and cardiorespiratory fitness associate with improved cognition. However, evidence from randomised controlled trials (RCT) is limited. We hypothesised that increased regular exercise improves cognition in older individuals. The trial is registered: ISRCTN45977199 (http://isrctn.org).

To evaluate the lateral view photography of the face as a tool for assessing morphological properties (i.e. facial convexity) as a risk factor for sleep disordered breathing (SDB) in children and to test how reliably oral health and non-oral healthcare professionals can visually discern the lateral profile of the face from the photographs. The present study sample consisted of 382 children 6-8 years of age who were participants in the Physical Activity and Nutrition in Children (PANIC) Study. Sleep was assessed by a sleep questionnaire administered by the parents. SDB was defined as apnoeas, frequent or loud snoring or nocturnal mouth breathing observed by the parents. The facial convexity was assessed with three different methods. First, it was clinically evaluated by the reference orthodontist (T.I.). Second, lateral view photographs were taken to visually sub-divide the facial profile into convex, normal or concave. The photos were examined by a reference orthodontist and seven d...

Division by total body weight is the usual way to standardise peak oxygen uptake (peak VO2) for body size. However, this method systematically underestimates cardiopulmonary fitness in obese individuals. Our aim was to analyse whether lean-mass is a better base for a body mass-independent standard of cardiopulmonary fitness. A population based sample of 578 men (body mass index (BMI) 19-47 kg/m(2)) and 592 women (BMI 16-49 kg/m(2)) 57-78 years of age. Peak VO2 was assessed by respiratory gas analysis during a maximal exercise test on a cycle ergometer. We studied the validity of the weight-ratio and the lean mass-ratio standards in a linear regression model. The weight-ratio standard implies an increase of peak VO2 per additional kg body weight with 20.7 ml/min (95% confidence interval (CI): 20.3-21.1) in women and 26.9 ml/min (95% CI: 26.4-27.5) in men. The observed increase per kg is only 8.5 ml/min (95% CI: 6.5-10.5) in men and 10.4 ml/min (95% CI: 7.5-13.4) in women. For the lea...

To test the hypothesis that waist and hip circumferences together provide additional information on the progression of preclinical atherosclerosis beyond either of them alone in elderly women. A 12-year follow-up study. A population-based sample of 102 women 60-70 years of age at baseline. Waist and hip circumferences and body mass index (BMI) were assessed and carotid intima-media thickness (IMT) was quantified noninvasively by ultrasonography. There was a significant increase in the 12-year carotid IMT progression across the thirds of waist circumference (0.080, 0.277, 0.279 mm, P=0.02 for difference) and hip circumference (0.030, 0.342, 0.260 mm, P=0.001 for difference) adjusted for conventional risk factors (age, smoking, systolic blood pressure, serum low-density lipoprotein and high-density lipoprotein cholesterol, blood glucose). The association of waist circumference with IMT progression was not significant after further adjustment for hip circumference or BMI. Further adjus...

We investigated the role of the angiotensinogen (AGT) gene M235T polymorphism in determining blood pressure (BP) response to moderate intensity exercise in a 6-yr randomized controlled trial in 140 middle-aged men. Sitting, supine, and standing blood pressures were measured annually. Of the randomized men, 86% participated in the trial for 6 yr. Submaximal cardiorespiratory fitness increased by 16% in the exercise group. In the M homozygotes, sitting systolic BP decreased by 1.0 mmHg in the exercise but increased by 14.6 mmHg in the reference group (P = 0.007 for net effect). Sitting and supine diastolic BP decreased by 6.2 and 3.3 mmHg in the exercise but increased by 2.8 and 3.2 mmHg in the reference group (P = 0.026 and 0.024 for net effects), respectively. Regular moderate intensity exercise attenuates aging-related increase in systolic BP and decreases diastolic BP among the M homozygotes of the AGT gene M235T polymorphism.

In the exercise testing measures of cardiorespiratory fitness need to be scaled by body size or composition to enable comparison between individuals. Traditionally used weight-proportional measures are potentially confounded by body adiposity that hampers their interpretation and applicability in the clinical assessment of cardiorespiratory fitness. We aimed to find the most appropriate measure of body size or composition for scaling of measures of cardiorespiratory fitness among children. We assessed body weight and height, maximal workload (WMAX ) and maximal oxygen uptake (VO2 MAX ) using cycle ergometer exercise test with respiratory gas analysis and body lean mass (LM) and fat mass (FM) by dual-energy X-ray absorptiometry and by bioimpedance analysis among 38 children. The data were analysed using Pearson's coefficients for correlation and stepwise linear regression models. Lean mass (r > 0·54) and height (r > 0·51) had stronger positive correlations with absolute WMAX and VO2 MAX than weight (r > 0·30) in girls and boys. None of the measures of body size or composition correlated with LM-proportional WMAX or VO2 MAX in girls or boys. Only LM correlated positively with height-proportional WMAX (r = 0·65) and VO2 MAX (r = 0·71) in boys. FM correlated negatively with weight-proportional WMAX (r < -0·58) and VO2 MAX (r < -0·64) in girls and boys. FM was even stronger determinant of weight-proportional WMAX (β = -0·68) and VO2 MAX (β = -0·61) than exercise performance in multivariate linear regression models. While assessing cardiorespiratory fitness, LM is the most appropriate measure of body size or composition for scaling of WMAX and VO2 MAX , because scaling by body weight introduces confounding by body adiposity.

Evidence suggests that dietary supplementation of L-arginine, the precursor of nitric oxide, may protect arteries against atherosclerosis. We tested the hypothesis that dietary arginine intake is associated with a decreased risk of acute coronary events in Finnish men aged 42-60 y. We investigated this association in a prospective cohort study of men who were free of prior coronary artery disease and who were examined in 1984-1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The dietary arginine intake of 1981 men was assessed by a 4-d food intake record during the baseline phase of the KIHD. Men in the highest quintile of dietary arginine intake (>or= 5691 mg/d) did not have a significantly lower risk of acute coronary events than did men in the 4 lower quintiles (relative risk after adjustment for potential coronary risk factors: 1.28; 95% CI: 0.85, 1.94). The covariates were age; examination years; body mass index; systolic blood pressure; serum total, HDL, ...

Type 2 diabetes mellitus (DM) is a common chronic disease. Cardiovascular disease is the most prevalent complication of DM. In the past decade, the associations of physical activity, physical fitness, and changes in lifestyle with the risk of type 2 DM have been assessed by a number of prospective epidemiologic studies and clinical trials. Several studies also evaluate the joint associations of physical activity, body mass index, and glucose levels with the risk of type 2 DM. The results of 21 prospective studies and four clinical trials demonstrated that moderate or high levels of physical activity or physical fitness, as well as changes in lifestyle (dietary modification and enhanced physical activity) could prevent type 2 DM.

We studied the associations of clustering of metabolic risk factors with plasma levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) in healthy prepubertal children. The subjects were a representative population sample of 492 children 6-8 years of age. We assessed body fat percentage (dual-energy X-ray absorptiometry), body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, ALT, GGT, and high-sensitivity C-reactive protein (hsCRP) and calculated a continuous metabolic syndrome score variable. We also used factor analysis to examine whether high-normal liver enzymes are a feature of metabolic syndrome among children. Children with overweight or obesity, defined by International Obesity Task Force (IOTF) criteria, had a 2.1-times higher risk of having ALT and a 4.5-times higher risk of having GGT in the highest fifth of its distribution than normal weight children. Children in the highest sex-specific third of metabolic syndrome score, body fat percentage, waist circumference, and insulin had a two to three times higher risk of being in the highest fifth of ALT and GGT. Moreover, children in the highest third of glucose and hsCRP had a 2.5-fold risk of being in the highest fifth of GGT. First-order factor analysis yielded three factors; the first included insulin, glucose, and triglycerides; the second waist circumference, insulin, GGT, and hsCRP; and the third HDL-C, triglycerides, waist circumference, and insulin. Second-order factor analysis yielded a single metabolic syndrome factor, explaining 64.1% of the variance. Clustering of metabolic risk factors, particularly excess body fat, is associated with high-normal levels of ALT and GGT in prepubertal children. High-normal levels of liver enzymes, especially GGT, and systemic low-grade inflammation could be considered features of metabolic syndrome among children. Subtle changes in liver function may play an important role in the pathogenesis of metabolic syndrome beginning in childhood.

Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), stimulate the release of C-reactive protein (CRP). We investigated the association between the TNF-alpha G-308A polymorphism and plasma CRP levels. Subjects were 456 White (225 men, 231 women) and 232 Black (83 men, 149 women) healthy adults who underwent a 20-week standardized exercise program in the HERITAGE Family Study. The TNF-alpha gene promoter polymorphism was determined using PCR amplification followed by NcoI digestion. Plasma CRP was measured using a high-sensitivity assay. Genotype frequencies were in Hardy-Weinberg equilibrium. After adjustment for age, smoking, alcohol consumption, maximal oxygen uptake and, in women, hormone use, the AA homozygotes for the G-308A polymorphism had higher baseline CRP levels than other genotypes in White and Black men (P<0.001 and P = 0.044, respectively) and in Black women (P = 0.032). Body mass index partly explained these associations in Blacks. The exercise program results provided further evidence for an association with the polymorphism. Among those with high CRP at baseline (> or = 3.0 mg/L), regular exercise decreased CRP less in AA homozygotes than in other genotypes (P = 0.043). The AA genotype of the TNF-alpha G-308A polymorphism is associated with higher plasma CRP levels and less favorable CRP response to regular exercise.

Systolic blood pressure (SBP) during exercise has been found to predict a future diagnosis of hypertension, coronary heart disease, and cardiovascular disease death. No studies have been conducted to show a relationship between SBP during exercise test and stroke. The aim of the present study was to study the associations between SBP rise, percent maximum SBP at 2 minutes after exercise, and the risk of stroke in a population-based sample of men with no prior coronary heart disease. SBP was measured every 2 minutes during and after the exercise test. The subjects were a population-based sample of 1026 men without clinical coronary heart disease, antihypertensive medication, or prior stroke at baseline. During an average follow-up of 10.4 years, there were 46 cases of stroke (38 ischemic strokes). Men with SBP rise >19.7 mm Hg per minute of exercise duration had a 2.3-fold increased risk of any stroke and a 2.3-fold increased risk of ischemic stroke compared with men whose SBP rise was <16.1 mm Hg/min. Similarly, percent maximum SBP at 2 minutes after exercise (SBP at 2 minutes' recovery divided by maximum SBP) was associated (highest tertile) with a 4.6-fold increased risk of any stroke and a 5.2-fold increased risk of ischemic stroke. SBP rise during exercise and percent maximum SBP at 2 minutes after exercise were directly and independently associated with the risk of all stroke and ischemic stroke. Exercise SBP testing may be recommended as an additional tool in the prediction of future stroke.

The aim of the study was to describe the levels and to create reference values of cardiorespiratory fitness, expressed as maximal oxygen consumption (VO(2max) ), maximal metabolic equivalents (METs) and maximal workload in aging men and women. We measured VO(2max) directly by a breath-by-breath method during a maximal exercise stress test on a bicycle ergometer with a linear workload increase of 20 W/min in a representative population sample of 672 men and 677 women aged 57-78 years. We presented the age and sex-specific categories of cardiorespiratory fitness (very low, low, medium, high and very high) based on variable distribution and non-linear regression models of VO(2max) , maximal METs and maximal workload. The linear age-related decrement of VO(2max) was -0.047 L/min/year (-2.3%) and -0.404 mL/kg/min/year (-1.6%) in men and -0.027 L/min/year (-1.9%) and -0.328 mL/kg/min/year (-1.6%) in women. After exclusion of diseased individuals, the rate of VO(2max) decrement remained similar. The number of chronic diseases (0, 1, 2 or ≥3) was inversely associated with VO(2max) in men (P<0.001) and women (P<0.001). The present study provides clinically useful reference values of cardiorespiratory fitness for primary and secondary prevention purposes in aging people.

Previous studies have suggested that higher levels of regular physical activity and cardiorespiratory fitness are associated with a reduced risk of coronary heart disease. We investigated the independent associations of physical activity during leisure time and maximal oxygen uptake (a measure of cardiorespiratory fitness) with the risk of acute myocardial infarction. During the period 1984 to 1989, we performed base-line examinations in 1453 men 42 to 60 years old who did not report having cardiovascular disease or cancer. Physical activity was assessed quantitatively with a detailed questionnaire, and maximal oxygen uptake was measured directly by exercise testing. During an average follow-up of 4.9 years, 42 of the 1166 men with normal electrocardiograms at base line had a first acute myocardial infarction. After adjustment for age and the year of examination, the relative hazard (risk) of myocardial infarction in the third of subjects with the highest level of physical activity (> 2.2 hours per week) was 0.31 (95 percent confidence interval, 0.12 to 0.85; P = 0.02), as compared with the third with the lowest level (P = 0.04 for linear trend over all three groups). The relative hazard in the third with the highest maximal oxygen uptake (> 2.7 liters per minute) was 0.26 (95 percent confidence interval, 0.10 to 0.68; P = 0.006) (P = 0.006 for linear trend), after adjustment for age, the year and season when the examination was performed, weight, height, and the type of respiratory-gas analyzer used. After up to 17 confounding variables were controlled for, the relative hazards for the third of subjects with the highest level of physical activity (0.34; 95 percent confidence interval, 0.12 to 0.94; P = 0.04) and maximal oxygen uptake (0.35; 95 percent confidence interval, 0.13 to 0.92; P = 0.03), as compared with the values in the lowest third, were significantly (P < 0.05) less than 1.0. Higher levels of both leisure-time physical activity and cardiorespiratory fitness had a strong, graded, inverse association with the risk of acute myocardial infarction, supporting the idea that lower levels of physical activity and cardiorespiratory fitness are independent risk factors for coronary heart disease.

Several vascular risk factors have been linked to cognitive decline. However, little is known about the association between the atherosclerotic process and cognitive impairment. We investigated whether carotid intima-media thickness (IMT) predicts the risk of cognitive impairment and whether the putative impairment is specific for some cognitive domains. A 12-year population-based follow-up study was performed for a total of 91 women, aged 60-70 years at baseline. Ultrasonographically assessed carotid artery IMT and the Mini-Mental State Examination test were performed at baseline and 12-year follow-up. A detailed cognitive evaluation for memory and cognitive speed was performed in 2003. The mean of left and right carotid bifurcation IMT was used in the analyses for association with the risk for poor cognitive speed and memory. Increased IMT at baseline was an independent predictor for poor memory (beta = -5.004, 95% confidence interval = -7.74 to -2.27; p = 0.001) and cognitive speed (beta = 2.562, 95% confidence interval = 1.19-4.94; p = 0.035) at 12-year follow-up after adjustment for age, education, depression, plasma LDL cholesterol, systolic blood pressure, cardiovascular disease, hormone replacement therapy, smoking, alcohol consumption and physical activity. The risk for poor memory (p = 0.023 for linear trend) and cognitive speed (p = 0.070 for linear trend) increased with increasing IMT tertiles. Carotid IMT predicts an increased risk for cognitive impairment, particularly poor memory and cognitive speed, in elderly women.