Effects of fat loss and low energy availability on the serum cardiometabolic profile of physique athletes.

Low energy availability (LEA) is a health concern for athletes, although it may paradoxically lead to improved cardiometabolic health in the general population. We investigated the associations between LEA, body composition, and serum cardiometabolic profile in 23 physique athletes (DIET) and 21 controls (CONT) during a 5-month pre-competition diet (MID), followed by 1 week of increased energy availability (COMP) and a 5-month weight regain period (POST). Quantification of 250 serum metabolome variables was conducted by NMR spectroscopy, body composition by dual-energy x-ray absorptiometry, dietary intake by food diaries, and exercise levels by training logs. Body fat percentage decreased from 19.5 ± 7.0% to 8.3 ± 5.3% (p < 0.001) in DIET through increased exercise levels and decreased energy intake, while CONT maintained those constant. In MID, DIET had increased (FDR < 0.01) HDL cholesterol, HDL particle size and number, and decreased (FDR < 0.05) VLDL lipids, serum triglycerides, and low-grade inflammation (glycoprotein acetyls) compared to baseline and CONT. The changes were associated with reduced android fat mass (-78 ± 13%) and energy intake (-28 ± 10%). In COMP, most of the metabolic changes found in MID persisted, except for altered triglycerides in all lipoprotein classes. After weight regain in POST, serum metabolome, body composition, energy intake, and exercise levels had reverted to baseline levels. In conclusion, fat loss and LEA may have beneficial yet transient effects on the serum cardiometabolic profile of lean individuals. Especially the HDL lipidome and lipoprotein triglycerides offer potential novel biomarkers for detecting LEA in athletes.

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Substantial fat mass loss reduces low-grade inflammation and induces positive alteration in cardiometabolic factors in normal-weight individuals.

The accumulation of fat, especially in visceral sites, is a significant risk factor for several chronic diseases with altered cardiometabolic homeostasis. We studied how intensive long-term weight loss and subsequent weight regain affect physiological changes, by longitudinally interrogating the lipid metabolism and white blood cell transcriptomic markers in healthy, normal-weight individuals. The current study examined 42 healthy, young (age: 27.5 ± 4.0 years), normal-weight (body mass index, BMI: 23.4 ± 1.7 kg/m2) female athletes, of which 25 belong to the weight loss and regain group (diet group), and 17 to the control group. Participants were evaluated, and fasting blood samples were drawn at three time points: at baseline (PRE); at the end of the weight loss period (MID: 21.1 ± 3.1 weeks after PRE); and at the end of the weight regain period (POST: 18.4 ± 2.9 weeks after MID). Following the weight loss period, the diet group experienced a ~73% reduction (~0.69 kg) in visceral fat mass (false discovery rate, FDR < 2.0 × 10-16), accompanied by anti-atherogenic effects on transcriptomic markers, decreased low-grade inflammation (e.g., as α1-acid glycoprotein (FDR = 3.08 × 10-13) and hs-CRP (FDR = 2.44 × 10-3)), and an increase in functionally important anti-atherogenic high-density lipoprotein -associated metabolites (FDR < 0.05). This occurred even though these values were already at favorable levels in these participants, who follow a fitness-lifestyle compared to age- and BMI-matched females from the general population (n = 58). Following the weight regain period, most of the observed beneficial changes in visceral fat mass, and metabolomic and transcriptomic profiles dissipated. Overall, the beneficial anti-atherogenic effects of weight loss can be observed even in previously healthy, normal-weight individuals.

The rs2516839 variation of USF1 gene is associated with 4-year mortality of nonagenarian women: The Vitality 90+ study.

Upstream transcription factor 1 (USF1) regulates the transcription of many genes related to cell and organism survival processes such as stress and immune response, regulation of cellular senesce, and carcinogenesis. In this study, our aim was to investigate the effect of USF1 single nucleotide variations (SNVs) on longevity in the Vitality 90+ study, a population-based study of nonagenarians (90 ±1 years of age) living in the area of Tampere municipality, Finland. Altogether 509 voluntary nonagenarians (115 males, 394 females) were genotyped using the 5'-nuclease assay for rs2774279G > A, rs2516839T > C, and rs2073658C > T SNVs. During the 4 years of follow-up, the total mortality rate was 64.2%. In the study, we found that the frequency of C-allele of rs2516839 among nonsurviving nonagenarians (52.5%) was higher than those who survived (41.2%; P = 0.0006, odds ratio = 1.575, 95% confidence interval [CI]: 1.215-2.041). Furthermore, carriage of this variation and its haplotypes had a significant gender by genotype interaction (P < 0.05) on mortality. Kaplan-Meier log-rank test during 4-years of follow-up showed significantly higher mortality rate in the case of CC genotype carriage than other genotype carriages in nonagenarian women (P < 0.0001). In addition, after adjusting for age in Cox regression analysis, cardiovascular disease, diabetes, infectious disease, dementia, and living place (nursing home or home), CC genotype of rs2516839T > C was found to be associated with shorter life expectancy in nonagenarian women (hazard ratio = 2.27; 95% CI, 1.34-3.85 P = 0.002). In conclusion, rs2516839 variation and related haplotypes of the USF1 gene are strongly related to all-cause mortality in Finnish nonagenarians, especially among women.

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.

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.

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.

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.

Type II antithrombin deficiency caused by a founder mutation Pro73Leu in the Finnish population: clinical picture.

BACKGROUND: It has been shown that some antithrombin (AT) activity assays do not correctly detect inherited type II AT deficiency, but erroneously classify these patients as normal. OBJECTIVES: Our aim was to investigate the mutations causing type II AT deficiency and to correlate the AT activity results with the genetic findings. PATIENTS/METHODS: A large population (n = 104; 42 families) of Finnish patients with known AT type II deficiency were interviewed for clinical data. Their AT activity was measured with five commercially available methods, and the SERPINC1 gene was genotyped. RESULTS: The mutations detected in type II AT-deficient patients were as follows: p.Pro73Leu (AT Basel) in 37 of 42 (88.1%) families; and p.Val30Glu, p.Arg425Cys and p.Pro439Ala in one family each. In two families, no mutation was detected. In the carriers of AT Basel two AT activity assays correctly identified most of the patients as AT-deficient, whereas three assays misclassified almost all of these patients as normal. Carriers of the founder mutation had, in addition to an elevated risk of venous thrombosis, a high risk of arterial thrombosis at young age, especially stroke. CONCLUSION: In Finland, a population with a strong founder effect, AT type II deficiency is caused predominantly by a single point mutation, p.Pro73Leu. The mutation is associated with a significant thrombotic risk. Reduced AT activity caused by this mutation cannot be detected by all available screening methods. This must be taken into account in the choice of laboratory method used for screening.

TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans.

Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, ß = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, ß = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, ß = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), ß = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

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.

Genetic polymorphism of the C-reactive protein (CRP) gene and a deep infection focus determine maximal serum CRP level in Staphylococcus aureus bacteremia.

C-reactive protein (CRP) is widely used in early detection of sepsis or organ dysfunction. Several single nucleotide polymorphisms (SNPs) in the CRP gene are shown to be associated with variability of basal CRP. To clarify the effect of these SNPs to CRP response in systemic infections, we compared genetic and clinical data on patients with Staphylococcus aureus bacteremia (SAB). Six SNPs in the CRP gene region (rs2794521, rs30912449, rs1800947, rs1130864, rs1205 and rs3093075) were genotyped in 145 patients and analyzed for associations with CRP and various clinical outcomes. We found that the rare minor A-allele of triallelic SNP rs30912449 (C > T > A) and presence of a deep infection focus were strongly associated to the higher maximal CRP during the first week of SAB. Median of the maximal CRP in patients who had the A-minor allele was 282 mg/L (interquartile range [IQR, defined as the difference between the third quartile and the first quartile], 169 mg/L) but only 179 mg/L (IQR, 148 mg/L) in patients without this allele (P = 0.004), and CRP in patients who had deep infection focus was higher 208 mg/L (IQR, 147 mg/L) than in other patients 114 mg/L (IQR, 121 mg/l) (P < 0.0001). Mortality, degree of leucocytosis, time to defervescence or number of deep infections were not affected by CRP gene SNPs. The maximal CRP during the first week in SAB was partly determined by variation in the CRP gene and partly by presence of deep infection focus. This finding suggests cautiousness in interpreting exceptionally high CRPs from SAB patients and comparison between patients.

Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci.

OBJECTIVE: To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN: We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom with an approximately 10-cM microsatellite marker map. Variance components linkage analysis was carried out with age, sex and country of origin as covariates. SUBJECTS: The GenomEUtwin consortium consists of twin cohorts from eight countries (Australia, Denmark, the Netherlands, Finland, Italy, Norway, Sweden and the United Kingdom) with a total data collection of more than 500,000 monozygotic and dizygotic (DZ) twin pairs. Variance due to early-life events and the environment is reduced within twin pairs, which makes DZ pairs highly valuable for linkage studies of complex traits. This study totaled 4401 European-originated twin families (10,535 individuals) from six countries (Australia, Denmark, the Netherlands, Finland, Sweden and the United Kingdom). RESULTS: We found suggestive evidence for a quantitative trait locus on 3q29 and 7q36 in the combined sample of DZ twins (multipoint logarithm of odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION: Linkage analysis of the combined data in this large twin cohort study provided evidence for suggestive linkage to BMI. In addition, two cohorts independently provided significant evidence of linkage to three new loci. The results of our study suggest a smaller environmental variance between DZ twins than full siblings, with a corresponding increase in heritability for BMI as well as an increase in linkage signal in well-replicated regions. The results are consistent with the possibility of locus heterogeneity for some genomic regions, and indicate a lack of major common quantitative trait locus variants affecting BMI in European populations.

Associations of vitamin D receptor, calcium-sensing receptor and parathyroid hormone gene polymorphisms with calcium homeostasis and peripheral bone density in adult Finns.

BACKGROUND: Thus far the search for osteoporosis candidate genes has focused less attention on the regulation of calcium homeostasis. Associations of vitamin D receptor (VDR) FokI, calcium-sensing receptor (CaSR) A986S and parathyroid hormone (PTH) BstBI polymorphisms with calcium homeostasis and peripheral bone density were investigated in adult Finns. METHODS: The subgroup of the population-based FINRISK survey consists of 339 healthy adults aged 31-43 years. Lifestyle data were assessed with questionnaires and food diaries. DNA was isolated from blood, and biochemical determinants of calcium metabolism were measured from blood and 24-hour urine samples. Bone mineral density (BMD) was measured using the DXA method at the distal forearm and by quantitative ultrasound (broadband ultrasound attenuation and speed of sound) at the calcaneus. Subjects were genotyped for VDR FokI, CaSR A986S and PTH BstBI polymorphisms. RESULTS: The CaSR 986S allele was associated with higher serum ionized calcium (p = 0.014). Forearm BMD was lowest for the PTH BstBI genotype bb in males (p = 0.023). VDR FokI and PTH BstBI polymorphisms showed a significant interaction on serum PTH (p = 0.010). The other gene-gene or diet-gene interactions studied showed no significant results. CONCLUSIONS: VDR, CaSR and PTH contribute to the genetic regulation of calcium homeostasis and peripheral bone density.

USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study.

AIMS/HYPOTHESIS: Genetic variants of upstream transcription factor 1 (USF1) have previously been associated with dyslipidaemias in family studies. Our aim was to further address the role of USF1 in metabolic syndrome and cardiovascular traits at the population level in a large Swedish male cohort (n=2,322) with multiple measurements for risk factors during 32 years of follow-up. METHODS: Participants, born in 1920-1924, were examined at 50, 60, 70 and 77 years of age. The follow-up period for cardiovascular events was 1970-2002. We genotyped three haplotype tagging polymorphisms capturing the major allelic variants of USF1. RESULTS: SNP rs2774279 was associated with the metabolic syndrome. The minor allele of rs2774279 was less common among individuals with metabolic syndrome than among healthy controls [p=0.0029 when metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III; p=0.0073 when defined according to the International Diabetes Federation (IDF)]. The minor allele of rs2774279 was also associated with lower BMI, lower fasting glucose values and higher HDL-cholesterol concentrations in longitudinal analyses. With SNP rs2073658, a borderline association with metabolic syndrome was observed (p=0.036, IDF), the minor allele being the risk-increasing allele. The minor allele of rs2073658 also associated with higher total and LDL-cholesterol, apolipoprotein B-100 and lipoprotein(a) concentrations in longitudinal analyses. Importantly, these trends with respect to the allelic variants prevailed throughout the follow-up time of three decades. CONCLUSIONS/INTERPRETATION: Our results suggest that USF1 variants associate with the metabolic syndrome at population level and influence the cardiovascular risk factors throughout adulthood in a consistent, longitudinal manner.

Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genome-wide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q.

The hepatic lipase gene C-480T polymorphism in the development of early coronary atherosclerosis: the Helsinki Sudden Death Study.

BACKGROUND: The T allele of the hepatic lipase (HL) C-480T polymorphism was previously found to be associated with lower post-heparin plasma HL activity, atherosclerosis and risk of coronary artery disease. We studied the association of HL C-480T polymorphism with the extent of atherosclerosis at vessel-wall level in an autopsy series of middle-aged men. MATERIALS AND METHODS: An autopsy cohort of 700 Caucasian Finnish men aged 33-70 years (mean 53 years), which comprised two autopsy series, collected 10 years apart during 1981-82 and 1991-92, were analysed. Areas of coronary wall covered with fatty streaks and fibrotic and complicated lesions were measured using computer-assisted planimetry and related to HL C-480T genotypes (CC, CT, and TT). RESULTS: There was a significant age-by-genotype interaction on the mean percentage area of fatty streaks (P = 0.01). The HL C-480T polymorphism was a significant explanatory factor for fatty streak area in men under 53 years of age with or without age, body mass index, hypertension, diabetes, smoking, alcohol consumption, apolipoprotein E genotype, and series number as covariates. Men carrying the TT genotype had two times larger areas of fatty streaks compared to the CC carriers (8.8% vs. 4.3%, P = 0.009). However, this association disappeared in men over 53 years. The areas of more advanced atherosclerotic lesions did not vary significantly among the genotype groups. CONCLUSIONS: Our results suggest that the HL C-480T polymorphism affects the formation of early coronary atherosclerotic lesions in men in their early middle age.

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.