Showing papers by "Terho Lehtimäki published in 2011"

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children

Abstract: Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Abstract: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Genetic determinants of serum testosterone concentrations in men.

Abstract: Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as,300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with >= 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

Meta-analysis of Genome-Wide Association Studies From the CHARGE Consortium Identifies Common Variants Associated With Carotid Intima Media Thickness and Plaque

Abstract: Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

Fetal Growth and Preterm Birth Influence Cardiovascular Risk Factors and Arterial Health in Young Adults The Cardiovascular Risk in Young Finns Study

Abstract: Objective—Impaired fetal growth is associated with cardiovascular disease in adulthood. The mechanisms of this association remain poorly described. We aimed to determine the associations of impaired fetal growth and preterm birth with cardiovascular risk factors and arterial health in a large cohort of young adults. Methods and Results—Carotid intima-media thickness, brachial flow-mediated dilatation and cardiovascular risk factors were compared between young adults (24–45 years) born at term with impaired fetal growth (birth weight <10th percentile; n=207), born preterm (<37 weeks' gestation; n=253), and a control group born at term with normal fetal growth (birth weight 50–90th percentile; n=835), in the Cardiovascular Risk in Young Finns study. Compared with controls, those with impaired fetal growth had elevated triglycerides (P=0.006), C-reactive protein (P=0.004), low-density lipoprotein cholesterol, systolic blood pressure (both P=0.06), and intima-media thickness and impaired flow-mediated dilatat...

Cholesterol-lowering properties and safety of chitosan.

Abstract: Chitosan (CAS 9012-76-4) is derived by alkaline deacetylation from chitin, an abundant polymeric product of natural biosynthesis especially in crustaceans. It is available in a primary, unorganised structure, but also in a microcrystalline form. As a dietary supplement, chitosan has been claimed to control obesity and to lower serum cholesterol. A variety of chitosan products have been freely available worldwide in health stores and pharmacies. This review summarises the current knowledge about cholesterol-lowering and safety properties of chitosan and focuses its possible application for the treatment of hypercholesterolaemia. Chitosan behaves as a polycationic(+) cellulose-like fibrillar biopolymer that forms films with negatively charged surfaces. It is not specifically hydrolysed by digestive enzymes in man, but limited digestion of chitosan due to bacterial flora and to the unspecific enzymes might occur. Negatively charged molecules in stomach attach strongly to the positive charged tertiary amino group (-NH3 +) of chitosan. Therefore, chitosan reduces fat absorption from gastrointestinal tract by binding with anionic carboxyl groups of fatty and bile acids, and it interferes with emulsification of neutral lipids (i.e., cholesterol, other sterols) by binding them with hydrophobic bonds. In short-term animal studies the safety of chitosan has been good. There are only few studies with chitosan in humans. In man, dietary chitosan has been reported to reduce serum total cholesterol levels by 5.8-42.6 % and low-density lipoprotein levels by 15.1-35.1 %. In short-term trials up to 12 weeks, no clinically significant symptoms have been observed with chitosan compared to placebo. Mild and transitory nausea and constipation have been reported in 2.6-5.4 % of subjects. Although chitosan has been clinically well tolerated, it cannot be recommended to people allergic to crustaceans.

Childhood Environmental and Genetic Predictors of Adulthood Obesity: The Cardiovascular Risk in Young Finns Study

Abstract: Context: Obesity from childhood to adulthood is associated with adverse health later in life. Increased youth BMI is a risk factor for later obesity, but it is unknown whether identification of other risk factors, including recently discovered genetic markers, would help to identify children at risk of developing adult obesity. Objectives: Our objective was to examine the childhood environmental and genetic predictors of adult obesity. Design, Setting, and Participants: We followed 2119 individuals of the Cardiovascular Risk in Young Finns Study for up to 27 yr since baseline (1980, age 3–18 yr). Main Outcome Measure: We evaluated adult obesity [body mass index (BMI) ≥30 kg/m2]. Results: The independent predictors (P < 0.05) of adult obesity included childhood BMI, C-reactive protein (CRP), family income (inverse), mother's BMI, and polymorphisms near genes TFAP2B, LRRN6C, and FLJ35579. A risk assessment based on childhood BMI, mother's BMI, and family income was superior in predicting obesity compared wi...

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease, but not kidney disease or kidney function. We also observed associations with BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. Genetic approaches have advanced the understanding of biological pathways underlying inter-individual variation in BP. For example, studies of rare Mendelian BP disorders have identified multiple defects in renal sodium handling pathways4. More recently two genomewide association studies (GWAS), each of >25,000 individuals of European-ancestry, identified 13 loci associated with SBP, DBP, and hypertension5,6. We now report results of a new meta-analysis of GWAS data that includes staged follow-up genotyping to identify additional BP loci. Primary analyses evaluated associations between 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and SBP and DBP in 69,395 individuals of European ancestry from 29 studies (Supplementary Materials Sections 1–3, Supplementary Tables 1– 2). Following GWAS meta-analysis, we conducted a three-stage validation experiment that made efficient use of available genotyping resources, to follow up top signals in up to 133,661 additional individuals of European descent (Supplementary Fig. 1 and Supplementary Materials Section 4). Twenty-nine independent SNPs at 28 loci were significantly associated with SBP, DBP, or both in the meta-analysis combining discovery and follow up data (Fig. 1, Table 1, Supplementary Figs 2–3, Supplementary Tables 3–5). All 29 SNPs attained association P <5×10−9, an order of magnitude beyond the standard genome-wide significance level for a single stage experiment (Table 1). Sixteen of these 29 associations were novel (Table 1). Two associations were near the FURIN and GOSR2 genes; prior targeted analyses of variants in these genes suggested they Note added in proof: Since this manuscript was submitted, Kato et al published a BP GWAS in East Asians that identified a SNP highly correlated to the SNP we report at the NPR3-c5orf23 locus28. Author contributions Full author contributions and roles are listed in the Supplementary Materials Section 19. NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2012 May 01. Published in final edited form as: Nature. ; 478(7367): 103–109. doi:10.1038/nature10405. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript may be BP loci7,8. At the CACNB2 locus we validated association for a previously reported6 SNP rs4373814 and detected a novel independent association for rs1813353 (pairwise r2 =0.015 in HapMap CEU). Of our 13 previously reported associations5,6, only the association at PLCD3 was not supported by the current results (Supplementary Table 4). Some of the associations are in or near genes involved in pathways known to influence BP (NPR3, GUCY1A3-GUCY1B3, ADM, GNAS-EDN3, NPPA-NPPB, and CYP17A1; Supplementary Fig. 4). Twenty-two of the 28 loci did not contain genes that were a priori strong biological candidates. As expected from prior BP GWAS results, the effects of the novel variants on SBP and DBP were small (Fig. 1 and Table 1). For all variants, the observed directions of effects were concordant for SBP, DBP, and hypertension (Fig. 1, Table 1, Supplementary Fig. 3). Among the genes at the genome-wide significant loci, only CYP17A1, previously implicated in Mendelian congenital adrenal hyperplasia and hypertension, is known to harbour rare variants that have large effects on BP9. We performed several analyses to identify potential causal alleles and mechanisms. First, we looked up the 29 genome-wide significant index SNPs and their close proxies (r2>0.8) among cis-acting expression SNP (eSNP) results from multiple tissues (Supplementary Materials Section 5). For 13/29 index SNPs, we found association between nearby eSNP variants and expression level of at least one gene transcript (10−4 > p > 10−51, Supplementary Table 6). In 5 cases, the index BP SNP and the best eSNP from a genomewide survey were identical, highlighting potential mediators of the SNP-BP associations. Second, because changes in protein sequence are strong a priori candidates to be functional, we sought non-synonymous coding SNPs that were in high LD (r2 >0.8) with the 29 index SNPs. We identified such SNPsat 8 loci (Table 1, Supplementary Materials Section 6, Supplementary Table 7). In addition we performed analyses testing for differences in genetic effect according to body mass index (BMI) or sex, and analyses of copy number variants, pathway enrichment, and metabolomic data, but we did not find any statistically significant results (Supplementary Materials Sections 7–9, Supplementary Tables 8–10). We evaluated whether the BP variants we identified in Europeans were associated with BP in individuals of East Asian (N=29,719), South Asian (N=23,977), and African (N=19,775) ancestries (Table 1, Supplementary Tables 11–13). We found significant associations in individuals of East Asian ancestry for SNPs at 9 loci and in individuals of South Asian ancestry for SNPs at 6 loci; some have been reported previously (Supplementary Tables 12 and 15). The lack of significant association for individual SNPs may reflect small sample sizes, differences in allele frequencies or LD patterns, imprecise imputation for some ancestries using existing reference samples, or a genuinely different underlying genetic architecture. Because of limited power to detect effects of individual variants in the smaller non-European samples, we created genetic risk scores for SBP and DBP incorporating all 29 BP variants weighted according to effect sizes observed in the European samples. In each non-European ancestry group, risk scores were strongly associated with SBP (P=1.1×10−40 in East Asian, P=2.9×10−13 in South Asian, P=9.8×10−4 in African ancestry individuals) and DBP (P=2.9×10−48, P=9.5×10−15, and P=5.3×10−5, respectively; Supplementary Table 13). We also created a genetic risk score to assess association of the variants in aggregate with hypertension and with clinical measures of hypertensive complications including left ventricular mass, left ventricular wall thickness, incident heart failure, incident and prevalent stroke, prevalent coronary artery disease (CAD), kidney disease, and measures of kidney function, using results from other GWAS consortia (Table 2, Supplementary Materials Sections 10–11, Supplementary Table 14). The risk score was weighted using the average of Page 2 Nature. Author manuscript; available in PMC 2012 May 01. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript SBP and DBP effects for the 29 SNPs. In an independent sample of 23,294 women10, an increase of 1 standard deviation in the genetic risk score was associated with a 21% increase in the odds of hypertension (95% CI 19%–28%; Table 2, Supplementary Table 14). Among individuals in the top decile of the risk score, the prevalence of hypertension was 29% compared with 16% in the bottom decile (odds ratio 2.09, 95% CI 1.86–2.36). Similar results were observed in an independent hypertension case-control sample (Table 2). In our study, individuals in the top compared to bottom quintiles of genetic risk score differed by 4.6 mm Hg SBP and 3.0 mm Hg DBP, differences that approach population-averaged BP treatment effects for a single antihypertensive agent11. Epidemiologic data have shown that differences in SBP and DBP of this magnitude, across the population range of BP, are associated with an increase in cardiovascular disease risk3. Consistent with this and in line with findings from randomized trials of BP-lowering medication in hypertensive patients12,13, the genetic risk score was positively associated with left ventricular wall thickness (P=6.0×10−6), occurrence of stroke (P=3.3×10−5) and CAD (P=8.1×10−29). The same genetic risk score was not, however, significantly associated with chronic kidney disease or measures of kidney function, even though these renal outcomes were available in a similar sample size as for the other outcomes (Table 2). The absence of association with kidney phenotypes could be explained by a weaker causal relation of BP with kidney phenotypes than with CAD and stroke. This finding is consistent with the mismatch between observational data that show a positive association of BP with kidney disease, and clinical trial data that show inconsistent evidence of benefit of BP lowering on kidney disease prevention in patients with hypertension14. Thus, several lines of evidence converge to suggest that BP elevation may in part be a consequence rather than a cause of sub-clinical kidney disease. Our discovery meta-analysis (Supplementary Fig. 2) suggests an excess of modestly significant (10−5

Genetic Variants and Blood Pressure in a Population-Based Cohort The Cardiovascular Risk in Young Finns Study

Abstract: Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2357). Blood pressure was measured at baseline in 1980 (age 3–18 years) and in follow-ups in 1983, 1986, 2001, and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped, and 3 genetic risk scores associated with systolic and diastolic blood pressures and their combination were derived for all of the participants. Effects of the genetic risk score were 0.47 mm Hg for systolic and 0.53 mm Hg for diastolic blood pressures (both P P =0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood ( P

Metabolic syndrome in childhood and increased arterial stiffness in adulthood: the Cardiovascular Risk In Young Finns Study.

Abstract: OBJECTIVE. We conducted the present study to examine the associations of two different paediatric metabolic syndrome (MetS) definitions and recovery from childhood MetS with arterial pulse wave velocity (PWV), an index of arterial stiffness, measured in adulthood. METHODS. A total of 945 subjects participated in the base-line study in 1986 (then aged 9-18 years) and the adult follow-up in 2007 (then aged 30-39 years). Cardiovascular risk factor data were available at both base-line and follow-up. In the follow-up study, arterial PWV was measured using a whole-body impedance cardiography device. RESULTS. Subjects suffering from MetS in childhood (prevalence 11.1%-14.1%) had higher arterial PWV after 21-year follow-up when compared with those not afflicted by the syndrome in childhood (P < 0.007). An increasing number of the MetS components in childhood were associated with increased PWV in adulthood (P for trend = 0.005). Subjects who recovered from the MetS during the 21-year follow-up period had lower PWV than those with persistent MetS (P < 0.001). CONCLUSION. MetS in childhood predicted increased arterial stiffness in adulthood, and recovery from childhood MetS was associated with decreased arterial PWV in adulthood. The current results emphasize the importance of the prevention and controlling of MetS risk factors both in childhood and adulthood.

Serotonin and early cognitive development: variation in the tryptophan hydroxylase 2 gene is associated with visual attention in 7-month-old infants

Abstract: Background: Allelic variation in the promoter region of a gene that encodes tryptophan hydroxylase isoform 2 (TPH2), a rate-limiting enzyme of serotonin synthesis in the central nervous system, has been associated with variations in cognitive function and vulnerability to affective spectrum disorders. Little is known about the effects of this gene variant on cognition during development and about possible intermediate developmental steps that lead to the adult phenotype. Here, we examined the hypothesis that the TPH2 -703 may act during early stages of development and bias the acquisition of elementary cognitive processes involved in attention and emotion regulation. Methods: Seven-month-old infants (n = 66) were genotyped for the TPH2 -703 G/T polymorphism (rs4570625) and tested for the efficiency of attention shifts from a stimulus at fixation to a new stimulus in the visual periphery. Results: Compared to TPH2 G/G homozygotes, infants with the T-carrier genotype exhibited a significantly higher number of missing attention shifts. This genotype effect tended to be particularly pronounced when infants had to disengage from an affectively salient stimulus before shifting attention to the peripheral stimulus. The results also showed that TPH2 genotype was indirectly associated, via its effect on attention disengagement, with temperamental emotion regulation (soothability). Conclusions: Together, these results implicate serotonin system genes in early cognitive development and suggest variations in the early-emerging cognitive capacities as a potential developmental precursor of individual differences in emotion regulation and vulnerability to affective disorders.

Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study

Abstract: Background : Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect. Methods : A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P�3.11058), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis. Results: rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking. Conclusions Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.

Pentraxin 3 (PTX3) is associated with cardiovascular risk factors: the Health 2000 Survey.

Abstract: Pentraxin 3 (PTX3) is a novel candidate immunoinflammatory marker that has been reported to be associated with cardiometabolic risk factors and to predict adverse outcomes in individuals with cardiovascular disease (CVD). Despite being a member of the same pentraxin protein family as C-reactive protein (CRP), PTX3 probably reflects different aspects of CVD pathogenesis. In this study, we assessed plasma PTX3 correlates and determinants in the Health 2000 Survey population, which comprised n = 403 insulin-resistant subjects, n = 845 hypercholesterolaemic subjects and n = 311 hypertensive subjects, all aged between 46 and 76 years. In insulin-resistant subjects the PTX3 concentration was found to correlate directly with age, pulse pressure and indoleamine 2,3-dioxygenase (IDO) enzyme activity and inversely with total and low-density lipoprotein (LDL) cholesterol. In hypercholesterolaemic subjects, the PTX3 concentration correlated directly with HDL cholesterol, systolic blood pressure and pulse pressure, whereas in hypertensive subjects, the PTX3 concentration correlated directly with systolic blood pressure, pulse pressure and IDO activity. No correlation was observed between the concentrations of PTX3 and CRP, adiposity indicators or indicators of subclinical atherosclerosis in any of the subject groups. PTX3 concentration variations were attributed to variations in LDL cholesterol and IDO activity in insulin-resistant subjects and to pulse pressure in hypercholesterolaemic and hypertensive subjects. These results indicate that, in individuals at high risk of CVD, the PTX3 concentration is associated with cardiovascular risk factors but not with subclinical atherosclerosis.

Genetic Variants of TSLP and Asthma in an Admixed Urban Population

Abstract: Background: Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. Objectives: To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. Methodology and Main Results: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR)=1.50; 95% confidence interval (95% CI): 1.09–2.05, p=0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR=2.00, 95% CI: 1.04–3.83, p=0.04) but not significant in never-smokers (OR=1.34; 95% CI: 0.93–1.94, p=0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR=1.58, 95% CI: 1.10–2.27, p=0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR=1.15, 95% CI: 1.07–1.23, p=0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR=1.21, 95% CI: 1.08–1.34, p=0.003; never-smokers: OR=1.06, 95% CI: 0.94–1.17, p=0.33). Conclusions: Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction.

Characterization of systemic metabolic phenotypes associated with subclinical atherosclerosis

Abstract: Detailed molecular phenotyping gives insight into disease mechanisms and can individualize medical practice for improved risk assessment and treatment. We show in an epidemiological study (n = 4309) that the multi-metabolic profiles obtained by serum NMR metabonomics inherently associate with the extent of atherosclerosis already in preclinical stages. Data-driven analysis of the spectral profiles of healthy, young adults revealed three distinct metabolic phenotypes associated with high carotid intima-media thickness (IMT), a surrogate marker of cardiovascular disease. The phenotypes were characterized by varying combinations of well-known metabolic disturbances like elevated VLDL and LDL and low HDL levels. Low IMT was also associated with distinct metabolic phenotypes with lipoprotein as well as other biochemical characteristics partly opposing those found for the high IMT phenotypes. Profiles of low-molecular-weight metabolites quantified from the experimentation were also characteristic for the metabolic phenotypes and substantiate developments toward the use of multi-metabolic risk phenotypes. The methodology can be taken as a direct extension for the routine analytics used for the risk assessment of atherosclerosis; quantification of metabolites will complement and might even replace conventional lipid measurements. Serum NMR metabonomics is therefore anticipated as a rational option for comprehensive cardiovascular risk assessment.

Serotonin receptor 2A gene moderates the effect of childhood maternal nurturance on adulthood social attachment.

Abstract: The ability to form and maintain attachment relations with other people is crucial for mental health and well-being. The origins of attachment behaviors are often assumed to be in early experiences with other people, especially with primary caregivers. Preliminary evidence suggests that serotonergic system may be involved in attachment behaviors. We examined whether the T102C variant of the serotonin receptor 2A gene moderates the effect of childhood maternal nurturance on social attachment in adulthood. The participants were 1070 women and men from the Young Finns Study with 27-year follow-up and two measurement times for the outcomes (n = 1836 person observations). Mothers reported their relationship quality with their children (participants) in childhood or adolescence. Social attachment was assessed by participant's self-reports on two measures (reward dependence scale of the Temperament and Character Inventory and the Relationship Questionnaire). High childhood maternal nurturance predicted high reward dependence and low avoidant attachment in carriers of the T/T genotype but not in the T/C or C/C genotype groups, while low maternal nurturance was associated with low reward dependence and high avoidant attachment in T/T genotype carriers but not in C allele carriers. Our result suggests that T/T genotype carriers were more influenced by their childhood nurturing environment, than their C allele carrying counterparts, thus providing evidence for differential susceptibility to childhood nurturing environment associated with the HTR2A gene.

Association of Known Loci With Lipid Levels Among Children and Prediction of Dyslipidemia in Adults

Abstract: Background—Recent genome-wide association studies have found 95 distinct genetic loci associated with high-density (HDL-C) and low-density (LDL-C) lipoprotein cholesterol, total cholesterol (TC), a...

A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol

Abstract: Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

Relation of positive T wave in lead aVR to risk of cardiovascular mortality.

Abstract: We examined the prevalence and prognostic impact of a positive T wave in lead aVR (aVRT+) on a standard electrocardiogram in the general population. Data were collected from a large nationally representative (random sample) health examination survey conducted in Finland from 2000 through 2001. The survey consisted of 6,354 subjects (2,876 men and 3,478 women) ≥30 years who participated in the field health examination including standard electrocardiographic (ECG) recording at rest. The prevalence of aVRT+ (defined as positive or isoelectric T wave in lead aVR) was 2.2%. During the median follow-up of 98.5 months (interquartile range 96.6 to 99.6), there were 214 (3.5%) cardiovascular (CV) deaths. In Cox regression analysis after adjustment for age and gender, relative risks for CV and total mortalities associated with aVRT+ were 3.24 (95% confidence interval [CI] 2.32 to 4.54, p <0.001) and 1.91 (95% CI 1.47 to 2.49, p <0.001), respectively. In the fully adjusted model controlling for other risk factors, CV morbidity, and ECG findings, the relative risk for CV mortality for aVRT+ was 2.94 (95% CI 2.07 to 4.18, p <0.001). In conclusion, aVRT+, an easily recognized ECG finding, predicts risk for CV mortality in the general population. This finding could aid in screening for risk of total and CV mortalities.

Is 5-HTTLPR linked to the response of selective serotonin reuptake inhibitors in MDD?

Abstract: The role of a functional polymorphism in the transcriptional control region of serotonin transporter gene (5-HTTLPR, SERTPR) has been studied intensively in major depression and in the response to selective serotonin inhibitors (SSRIs) in major depression. The findings have been contradictory, although majority of the studies indicate that the short allele is associated with poor response to SSRIs in major depression. In the present study, we evaluated the association of 5-HTTLPR with treatment response to SSRI medication in Finnish Caucasian MDD patients. A secondary purpose was to study the possible association of this particular polymorphism with major depressive disorder. The aim of the study was to replicate the previous findings in this area. Primary outcomes of the treatment were remission, defined by an exit score of seven or less, and response, defined by a reduction of at least 50% on the MADRS. We had also a control population of 375 healthy blood donors, as a secondary objective was to evaluate the possible association of this particular polymorphism with major depressive disorder. Twenty-nine of the 85 (34.1%) patients reached the remission and 58.8% achieved the predefined response criteria. The l/l genotype of 5-HTTLPR was presented in 51.7% of those patients who achieved remission vs. 25.0% in the non-remitters (P = 0.03). The result remained statistically significant after adjusting for age, gender, medication and MADRS points at the study entry. However, the small sample size limits the reliability of this result.

Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study

Abstract: Eur J Clin Invest 2011; 41 (9): 951–957 Abstract Background Increased levels of C-reactive protein (CRP) and serum amyloid A (SAA) are associated with an increased risk of cardiovascular disease. It is hypothesized that dysregulation of the autonomic nervous system (ANS) leads to increased inflammation via the cholinergic anti-inflammatory pathway. Heart rate variability (HRV) is a marker of ANS function. HRV has been shown to be associated with CRP levels. Currently, there are no studies addressing the relationship between HRV and SAA. Design The purpose of this study was to compare the associations between HRV, CRP and SAA in healthy young adults. CRP and SAA concentrations and short-term HRV indices [high frequency (HF), low frequency (LF), total spectral component of HRV, root mean square differences of successive R-R intervals, the standard deviation of all R-R intervals and ratio between LF and HF) were measured in 1601 men and women aged 24–39 taking part in the Cardiovascular Risk in Young Finns study. Results A significant inverse correlation (P 0·05) after adjusting for age, sex, body mass index, cholesterol levels, leptin and other common traditional cardiovascular risk factors. Conclusions Reduced HRV indices are independently associated with increased CRP levels, but not with SAA levels. This association supports the hypothesis that dysregulation of the ANS may lead to increased inflammation early in adulthood.