Predictive value of low testosterone concentrations regarding coronary heart disease and mortality in men and women - evidence from the FINRISK97 study.

INTRODUCTION: The relevance of low testosterone concentrations for incident coronary heart disease (CHD) and mortality has been discussed in various studies. Here, we evaluate the predictive value of low baseline testosterone levels in a large population-based cohort. METHODS: We measured the serum levels of testosterone in 7671 subjects (3710 male, 3961 female) of the population-based FINRISK97 study. RESULTS: The median follow-up (FU) was 13.8 years. During the FU, a total of 779 deaths from any cause, and 395 incident CHD events were recorded. The age-adjusted baseline testosterone levels were similar in subjects suffering incident events during FU and those without incident events during FU (men: 15.80 vs. 17.01 nmol L-1 ; P = 0.69, women: 1.14 vs. 1.15 nmol L-1 ; P = 0.92). Weak correlations of testosterone levels were found with smoking (R = 0.09; P < 0.001), HDL cholesterol levels (R = 0.22, P < 0.001), systolic blood pressure (R = -0.05; P = 0.011), BMI (R = -0.23; P < 0.001) and waist-hip-ratio (R = -0.21; P < 0.001) in men, and with eGFR (R = -0.05; P = 0.009) in women. Kaplan-Meier analyses did not reveal a positive association of testosterone levels with incident CHD or mortality. Accordingly, also in Cox regression analyses, testosterone levels were not predictive for incident CHD or mortality - neither in men (HR 1.02 [95%CI: 0.70-1.51]; P = 0.79 for lowest versus highest quarter regarding CHD and HR 1.06 [95%CI: 0.80-1.39]; P = 0.67 regarding mortality), nor in women (HR 1.13 [95%CI: 0.69-1.85]; P = 0.56 for lowest versus highest quarter regarding CHD and HR 0.99 [95%CI: 0.71-1.39]; P = 0.80 regarding mortality). CONCLUSIONS: Low levels of testosterone are not predictive regarding future CHD or mortality - neither in men, nor in women.

Genetic predisposition to obesity, restrained eating and changes in body weight: a population-based prospective study.

OBJECTIVES: There is no consensus on whether cognitive control over food intake (that is, restrained eating) is helpful, merely ineffective or actually harmful in weight management. We examined the interplay between genetic risk of obesity, restrained eating and changes in body weight and size. METHODS: Participants were Finnish aged 25-74 years who attended the DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome study at baseline in 2007 and follow-up in 2014. At baseline (n=5024), height, weight and waist circumference (WC) were measured in a health examination and participants self-reported their weight at age 20 years. At follow-up (n=3735), height, weight and WC were based on measured or self-reported information. We calculated 7-year change in body mass index (BMI) and WC and annual weight change from age 20 years to baseline. Three-Factor Eating Questionnaire-R18 was used to assess restrained eating. Genetic risk of obesity was assessed by calculating a polygenic risk score of 97 known BMI-related loci. RESULTS: Cross-lagged autoregressive models indicated that baseline restrained eating was unrelated to 7-year change in BMI (ß=0.00; 95% confidence interval (CI)=-0.01, 0.02). Instead, higher baseline BMI predicted greater 7-year increases in restrained eating (ß=0.08; 95% CI=0.05, 0.11). Similar results were obtained with WC. Polygenic risk score correlated positively with restrained eating and obesity indicators in both study phases, but it did not predict 7-year change in BMI or WC. However, individuals with higher genetic risk of obesity tended to gain more weight from age 20 years to baseline, and this association was more pronounced in unrestrained eaters than in restrained eaters (P=0.038 for interaction). CONCLUSIONS: Our results suggest that restrained eating is a marker for previous weight gain rather than a factor that leads to future weight gain in middle-aged adults. Genetic influences on weight gain from early to middle adulthood may vary according to restrained eating, but this finding needs to be replicated in future studies.

Plasma levels of hepatocyte growth factor and placental growth factor predict mortality in a general population: a prospective cohort study.

BACKGROUND: Circulating levels of growth factors involved in leucocyte production and angiogenesis could be indicative of underlying aberrations of tissue homeostasis and therefore be utilized as predictors of risk for all-cause cardiovascular disease (CVD) or cancer mortality. METHODS: Baseline plasma levels of a range of growth factors were measured in two cohorts of the population-based FINRISK study (1997 Discovery cohort, N = 8444, aged 25-74; 2002 Replication cohort, N = 2951, aged 51-74 years) using a multiplexed bead array methodology and ELISA. Participants were followed up by linking them to registry data. RESULTS: In the Discovery cohort (653 deaths; 216 CVD-related, 231 cancer-related), fully adjusted Cox proportional hazard regression models showed that increased plasma hepatocyte growth factor (HGF) and placental growth factor (PlGF) were associated with higher risk of 10-year mortality (HR, 1.29 [95% confidence interval (CI), 1.18-1.41] and HR, 1.23 [95% CI, 1.14-1.32], respectively). In the Replication cohort (259 deaths; 83 CVD-related, 90 cancer-related), baseline HGF levels also predicted all-cause mortality (HR, 1.2 [95% CI, 1.08-1.32]; PlGF data not available). By including HGF levels in a CVD mortality model, 9% of all CVD deaths were correctly reclassified in the Discovery cohort (categorical net reclassification improvement [NRI] for events, P = 4.0 × 10-4 ). Moreover, adding HGF to all-cause and CVD mortality models resulted in an overall clinical NRI of 0.10-0.18 in the Discovery cohort and meta-analyses (P < 0.05 for all tests). CONCLUSION: Blood levels of HGF and PlGF may serve as new biomarkers for predicting increased risk of death in the general population.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Evaluation of HLA-DRB1 imputation using a Finnish dataset.

Owing to the vast amount of alleles, high-resolution human leukocyte antigen (HLA) typing is expensive and time-consuming. Scientists have attempted to develop computational approaches to define HLA alleles with high confidence. We tested the reliability of HLA*IMP and SNP2HLA for imputing HLA-DRB1 alleles in a Finnish material (n=161). The per-individual success rates varied between 16.68% and 25.4% using both softwares. One of the most prominent example was HLA-DRB1*01:01 allele showing approximately a 30% success rate while being the most common wrongly imputed allele. In Finland, isolation and migration history have shaped the gene pool narrower showing HLA haplotype frequencies typical to the Finnish population when compared to Europeans. The imputation success for HLA-DRB1 alleles was very low pointing to the importance of population-specific reference material.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene.

Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.

Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients.

Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.

Trends in population attributable fraction of acute coronary syndrome and ischaemic stroke due to diabetes in Finland.

AIMS/HYPOTHESIS: Cardiovascular disease (CVD) event rates are decreasing, but the prevalence of diabetes is increasing. The effect of these developments on the population attributable fraction (PAF) of CVD events due to diabetes is not known. METHODS: We used country-wide healthcare registers to identify all persons aged 25-80 years treated for diabetes in Finland during 1992-2002. These data were further linked to the National Cardiovascular Disease Register to identify the first CVD events (acute coronary syndrome and ischaemic stroke) among the individuals with and without diabetes. We calculated the annual PAF of the first CVD events due to diabetes separately for men and women. RESULTS: The number of men treated for diabetes each year almost doubled during the study period from 37,073 to 69,158 between 1992 and 2002. Among women, the number increased from 42,485 to 57,372. The annual number of first CVD events in the country declined among men with diabetes from 13,436 to 12,678 and among women with diabetes from 8,658 to 7,521 between 1992 and 2002. During the same period, the PAF due to diabetes of the first CVD events increased among men from 11.4% (95% CI 10.8, 12.0%) to 13.8% (95% CI 13.2, 14.5%) and decreased among women from 20.1% (95% CI 19.2, 21.0%) to 16.9% (95% CI 15.9, 17.8%). The trends in PAF were different between the sexes (p < 0.001 for the interaction year × sex). CONCLUSIONS/INTERPRETATION: Despite the very large increase in the prevalence of diabetes, the PAF of the first CVD events due to diabetes decreased in women and increased only slightly in men.

Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes.

OBJECTIVES: To examine whether interleukin-1 receptor antagonist (IL-1Ra) is a predictor for clinically incident diabetes in subjects with metabolic syndrome (MetS) and whether its predictive power is independent of C-reactive protein (CRP), an established marker of inflammation. We further examined whether genetic variants at the interleukin-1 (IL-1) locus would predict clinically incident diabetes. DESIGN: Two observational prospective cohort studies. SETTING: Two separate cohorts, Health 2000 and FINRISK 1997, followed up for an average of 7.1 and 10.8 years, respectively. SUBJECTS: Random population samples consisting of 5511 subjects aged 30-74 years in Health 2000 and 7374 subjects aged 25-74 years in FINRISK 1997. RESULTS: During follow-up, 141 cases of clinically incident diabetes were observed amongst subjects with MetS at baseline in Health 2000 and 248 cases in FINRISK 97. After adjustment for multiple traditional risk factors of diabetes, including age and body mass index, IL-1Ra was a significant (P < 0.01) predictor of incident diabetes amongst men in both cohorts and amongst women in FINRISK 1997. Further adjustment for CRP reduced the hazard ratios only slightly. Genetic analyses produced nominally significant associations for three single-nucleotide polymorphisms: rs3213448 in IL-1 receptor antagonist (IL1RN), rs1143634 in IL-1 beta (IL1B) and rs1800587 in IL-1 alpha (IL1A). The two latter variants had an interaction with gender (P = 0.023 and 0.002, respectively) suggesting the presence of gender-specific associations with the risk of clinically incident diabetes. CONCLUSIONS: IL-1Ra predicted the progression of MetS to clinically incident diabetes independently of CRP and other risk factors. Genetic variation in the IL-1 locus may have gender-specific associations with the risk of type 2 diabetes.

Case fatality rates after first acute coronary syndrome in persons treated for type 2 diabetes show an improving trend.

AIMS/HYPOTHESIS: We analysed whether the prognosis of a first acute coronary syndrome (ACS) in patients treated for type 2 diabetes has improved. We also compared the trends in patients with and without diabetes. METHODS: We used national registers to identify all patients with clinically known type 2 diabetes in Finland during the years 1988 to 2002 (n = 222,940). All first-ever ACS events (n = 43,412) among these patients were identified using the Hospital Discharge Register and the Causes of Death Register. From the National Cardiovascular Disease Register we identified all first ACS attacks (n = 191,403) among non-diabetic patients in the country. Finally, we calculated annual age-standardised case fatality rates for ACS for three time periods: prehospital, days 0 to 27 and days 28 to 364 after the first ACS. RESULTS: The case fatality rate of first ACS declined significantly in both sexes at all time points considered. The declining trends were not different between patients with type 2 diabetes and those without. Among men aged 35 to 74 years, 58.5% (95% CI 57.6-59.4%) with type 2 diabetes and 44.1% (95% CI 43.8-44.5%) without diabetes had died from cardiovascular causes 1 year after their first ACS. Among women of the same age, the corresponding figures were 54.2% (95% CI 53.0-55.4%) and 36.5% (95% CI 35.9-37.1%). Men generally had higher case fatality rates than women. However, except for prehospital deaths, diabetic women had the same or even higher case fatality rates than non-diabetic men. CONCLUSIONS/INTERPRETATION: The case fatality rates for first ACS show similar improving trends in patients with type 2 diabetes and in those without. However, case fatality rates have remained higher in patients with type 2 diabetes.

Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland.

BACKGROUND AND OBJECTIVE: There are very few European cohort studies assessing the risk factors of end-stage renal disease (ESRD) in a community-based population. This study investigated the predictors of ESRD in Finland. DESIGN: Prospective cohort study. SETTING: Eastern Finland. SUBJECTS: A random sample of 25,821 men and women aged 25-64 years from the national population register participating in three independent cross-sectional population surveys in 1972, 1977 and 1982. Only the subjects without diagnosis of ESRD or chronic kidney disease based on the national register data were included in the study. MAIN OUTCOME MEASURE: Initiation of renal replacement therapy (dialysis or kidney transplantation) identified from the Finnish Registry for Kidney Diseases through December 31, 2006. RESULTS: A total of 94 cases with ESRD were identified during a mean follow-up period of 26.5 years. In a multivariate proportional subdistribution hazard regression analysis, taking into account death as a competing risk event, diabetes (hazard ratio [HR] 4.76, 95% confidence interval [CI] 2.32-9.79), hypertension (HR 2.21, 95% CI 1.19-4.12), obesity defined as body mass index > or =30 kg m(-2) (HR 2.02, 95 %CI 1.10-3.71) and male gender (HR 1.68, 95% CI 1.19-4.12) were independent risk factors for ESRD. CONCLUSION: The findings of the present study confirm that modifiable risk factors play a major role in the development of ESRD in the North-European population. People with diabetes, hypertension or obesity should be considered as the target groups when planning preventive measures to control the future epidemic of ESRD.

Common candidate gene variants are associated with QT interval duration in the general population.

OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Role of inflammation markers in the prediction of weight gain and development of obesity in adults - A prospective study.

BACKGROUND AND AIMS: There is a growing body of literature confirming the association between inflammation and obesity. Recent research suggests that inflammation may play a role in weight gain. The aim of the study was to analyse whether serum inflammatory markers predict weight gain or development of obesity in a prospective study design. METHODS AND RESULTS: The baseline study (DILGOM 2007) consists of a population-based sample of 5024 Finnish men and women aged 25-75 years, of whom 3735 participated in the follow-up study in 2014. Baseline data collection included a questionnaire on health behaviour, physical examinations and blood samples including serum high-sensitivity C-Reactive Protein (hs-CRP), Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6), Tumor Necrosis Factor Alpha (TNF-alpha) and high molecular weight adiponectin (HMW adiponectin). Indicators of obesity were weight, body mass index (BMI), waist circumference and body fat percentage (% body fat). At baseline hs-CRP, IL-1Ra, IL-6, TNF-alpha and HMW adiponectin associated strongly (p < 0.0001) with obesity indicators. After adjustment for several potential predictors of obesity, hs-CRP and IL-1Ra associated inversely with changes in obesity indicators during the 7-year follow-up. These associations disappeared, however, after further adjustment for baseline BMI. Only HMW adiponectin retained a modest positive association with the change in weight (p = 0.008), in BMI (p = 0.007) and in waist circumference (p = 0.002). CONCLUSION: These findings suggest that the inflammatory markers, although highly associated with obesity, do not predict weight gain in an adult population. This could translate into inflammation being a result of obesity rather than a contributing factor to it.

Chocolate, well-being and health among elderly men.

OBJECTIVE: We hypothesized that chocolate preference would be related to health and psychological well-being in old men. DESIGN, SETTING AND PARTICIPANTS: We have followed up a socio-economically homogenous group of men, born in 1919-1934, since the 1960s. In 2002-2003, a mailed questionnaire was used to assess the health and well-being (including questions related to positive life orientation, visual analogue scales and the Zung depression score) of survivors. In addition, candy preference was inquired. Those men who reported no candy consumption (n=108) were excluded from the analyses. OUTCOME MEASURES: Psychological well-being in old age. RESULTS: The response rate was 69% (1367 of 1991). Of the respondents, 860 and 399 preferred chocolate and other type of candy, respectively. The average age in both candy groups was 76 years. Of the respondents, 99% were home-dwelling, 96% were retired and 87% were presently married, without differences between the candy groups. Men preferring chocolate had lower body mass index and waist circumference, and they also reported more exercise and better subjective health (P=0.008) than other candy consumers. Variables related to psychological well-being were consistently better in those preferring chocolate. The differences were statistically significant in feeling of loneliness (P=0.01), feeling of happiness (P=0.01), having plans for the future (P=0.0002) and the Zung depression score (P=0.02). CONCLUSIONS: In this socioeconomically homogenous male cohort, chocolate preference in old age was associated with better health, optimism and better psychological well-being. SPONSORSHIP: The Academy of Finland, the Päivikki and Sakari Sohlberg Foundation, the Helsinki University Central Hospital and the Finnish Foundation for Cardiovascular Research.

Increased Mortality Despite Successful Multifactorial Cardiovascular Risk Reduction in Healthy Men: 40-Year Follow-Up of the Helsinki Businessmen Study Intervention Trial.

OBJECTIVES: In a 5-year multifactorial risk reduction intervention for healthy men with at least one cardiovascular disease (CVD) risk factor, mortality was unexpectedly higher in the intervention than the control group during the first 15-year follow-up. In order to find explanations for the adverse outcome, we have extended mortality follow-up and examined in greater detail baseline characteristics that contributed to total mortality. DESIGN: Long-term follow-up of a controlled intervention trial. SETTING: The Helsinki Businessmen Study Intervention Trial. PARTICIPANTS AND INTERVENTION: The prevention trial between 1974-1980 included 1,222 initially healthy men (born 1919-1934) at high CVD risk, who were randomly allocated into intervention (n=612) and control groups (n=610). The 5-year multifactorial intervention consisted of personal health education and contemporary drug treatments for dyslipidemia and hypertension. In the present analysis we used previously unpublished data on baseline risk factors and lifestyle characteristics. MAIN OUTCOME MEASURES: 40-year total and cause-specific mortality through linkage to nation-wide death registers. RESULTS: The study groups were practically identical at baseline in 1974, and the 5-year intervention significantly improved risk factors (body mass index, blood pressure, serum lipids and glucose), and total CVD risk by 46% in the intervention group. Despite this, total mortality has been consistently higher up to 25 years post-trial in the intervention group than the control group, and converging thereafter. Increased mortality risk was driven by CVD and accidental deaths. Of the newly-analysed baseline factors, there was a significant interaction for mortality between intervention group and yearly vacation time (P=0.027): shorter vacation was associated with excess 30-year mortality in the intervention (hazard ratio 1.37, 95% CI 1.03-1.83, P=0.03), but not in the control group (P=0.5). This finding was robust to multivariable adjustments. CONCLUSION: After a multifactorial intervention for healthy men with at least one CVD risk factor, there has been an unexpectedly increased mortality in the intervention group. This increase was especially observed in a subgroup characterised by shorter vacation time at baseline. Although this adverse response to personal preventive measures in vulnerable individuals may be characteristic to men of high social status with subclinical CVD, it clearly deserves further investigation.

Genome-wide analysis of nuclear magnetic resonance metabolites revealed parent-of-origin effect on triglycerides in medium very low-density lipoprotein in PTPRD gene.

AIM: The aim of the study was to explore the parent-of-origin effects (POEs) on a range of human nuclear magnetic resonance metabolites. MATERIALS & METHODS: We search for POEs in 14,815 unrelated individuals from Estonian and Finnish cohorts using POE method for the genotype data imputed with 1000 G reference panel and 82 nuclear magnetic resonance metabolites. RESULTS: Meta-analysis revealed the evidence of POE for the variant rs1412727 in PTPRD gene for the metabolite: triglycerides in medium very low-density lipoprotein. No POEs were detected for genetic variants that were previously known to have main effect on circulating metabolites. CONCLUSION: We demonstrated possibility to detect POEs for human metabolites, but the POEs are weak, and therefore it is hard to detect those using currently available sample sizes.

Thrombomodulin gene polymorphisms and haplotypes and the risk of cardiovascular events: a prospective follow-up study.

BACKGROUND: Thrombomodulin is an anticoagulant expressed during endothelial activation and damage. To address the potential role of allelic variants of thrombomodulin gene in the pathogenesis of cardiovascular diseases, we analyzed in a prospective follow-up study 8 single-nucleotide polymorphisms (SNPs) across the thrombomodulin locus, covering all common (>5%) haplotypes. METHODS AND RESULTS: Two separate, stratified random samples of men and women 25 to 74 years of age were examined in Finland in 1992 and 1997. The total sample size was 14 140 individuals, with 7 (1997 cohort) to 10 (1992 cohort) years of follow-up. Altogether, 662 individuals had a history of cardiovascular events already at baseline. During the follow-up, 401 incident coronary events and 148 incident ischemic strokes were observed. The alleles and common haplotypes of 8 SNPs were tested in Cox proportional hazards models using incident coronary events, incident ischemic strokes, and total mortality as end points. None of the SNPs or major SNP haplotypes showed consistent association with the end points analyzed in the combined data. CONCLUSIONS: Results from this prospective, population-based study suggest that common allelic variants of the thrombomodulin gene may not significantly contribute to the risk of cardiovascular events at the population level.

Neuregulin signaling pathway in smoking behavior.

Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine dependence and nicotine withdrawal. We comprehensively annotated the associated variants using expression (eQTL) and methylation quantitative trait loci (meQTL) analyses in a Finnish population sample. Among the 66 variants, we identified 25 eQTLs (in NRG1 and ERBB4), 22 meQTLs (in NRG3, ERBB4 and PSENEN), a missense variant in NRG1 (rs113317778) and a splicing disruption variant in ERBB4 (rs13385826). Majority of the QTLs in blood were replicated in silico using publicly available databases, with additional QTLs observed in brain. In conclusion, our results support the involvement of NSP in smoking behavior but not in alcohol use and abuse, and disclose functional potential for 56 of the 66 associated single-nucleotide polymorphism.

Associations of traffic related air pollutants with hospitalisation for first acute myocardial infarction: the HEAPSS study.

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death attributed to cardiovascular diseases. An association between traffic related air pollution and AMI has been suggested, but the evidence is still limited. OBJECTIVES: To evaluate in a multicentre study association between hospitalisation for first AMI and daily levels of traffic related air pollution. METHODS: The authors collected data on first AMI hospitalisations in five European cities. AMI registers were available in Augsburg and Barcelona; hospital discharge registers (HDRs) were used in Helsinki, Rome and Stockholm. NO2, CO, PM10 (particles <10 microm), and O3 were measured at central monitoring sites. Particle number concentration (PNC), a proxy for ultrafine particles (<0.1 microm), was measured for a year in each centre, and then modelled retrospectively for the whole study period. Generalised additive models were used for statistical analyses. Age and 28 day fatality and season were considered as potential effect modifiers in the three HDR centres. RESULTS: Nearly 27,000 cases of first AMI were recorded. There was a suggestion of an association of the same day CO and PNC levels with AMI: RR = 1.005 (95% CI 1.000 to 1.010) per 0.2 mg/m3 and RR = 1.005 (95% CI 0.996 to 1.015) per 10000 particles/cm3, respectively. However, associations were only observed in the three cities with HDR, where power for city-specific analyses was higher. The authors observed in these cities the most consistent associations among fatal cases aged <75 years: RR at 1 day lag for CO = 1.021 (95% CI 1.000 to 1.048) per 0.2 mg/m3, for PNC = 1.058 (95% CI 1.012 to 1.107) per 10000 particles/cm3, and for NO2 = 1.032 (95% CI 0.998 to 1.066) per 8 microg/m3. Effects of air pollution were more pronounced during the warm than the cold season. CONCLUSIONS: The authors found support for the hypothesis that exposure to traffic related air pollution increases the risk of AMI. Most consistent associations were observed among fatal cases aged <75 years and in the warm season.