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Markus Juonala,
Paula Jääskeläinen,
Matthew A Sabin,
Jorma S A Viikari,
Mika Kähönen,
Terho Lehtimäki, Ilkka Seppälä,
Nina Hutri-Kähönen,
Leena Taittonen,
Eero Jokinen,
Tomi Laitinen,
Costan G Magnussen,
Olli T Raitakari
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ABSTRACT: OBJECTIVES: To investigate whether the body mass index (BMI) of a child's mother is associated with an increased future risk of type 2 diabetes, independent of genetic risk or childhood metabolic, behavioral, and environmental factors. STUDY DESIGN: The analyses were based on the Cardiovascular Risk in Young Finns Study including 1835 individuals aged 3-18 years at baseline with data on maternal BMI, childhood metabolic factors, as well as 34 newly identified type 2 diabetes susceptibility alleles. These subjects were then followed-up over 21-27 years. RESULTS: Maternal BMI (OR for 1-SD increase 1.54 [95% CI 1.12-2.11], P = .008) and child's systolic blood pressure (1.54 [1.01-2.35], P = .04) were significantly associated with increased odds for later type 2 diabetes, in a multivariable analysis adjusted for age, sex, type 2 diabetes genetic risk score, childhood BMI, insulin, lipids, dietary factors, socioeconomic status, and mother's age, and history of type 2 diabetes. A risk prediction model, which included maternal BMI status outperformed one which utilized only child's BMI data (area under the receiver operating characteristic curve 0.720 vs 0.623, P = .02). The inclusion of genetic risk score and other baseline risk variables did not additionally improve prediction (area under the receiver operating characteristic curve 0.720 vs 0.745, P = .40). CONCLUSIONS: Maternal BMI is a useful variable in determining offspring risk of developing type 2 diabetes.
The Journal of pediatrics 12/2012; · 4.02 Impact Factor
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Kari-Matti Mäkelä, Ilkka Seppälä,
Jussi A Hernesniemi,
Leo-Pekka Lyytikäinen,
Niku Oksala,
Marcus E Kleber,
Hubert Scharnagl,
Tanja B Grammer,
Jens Baumert,
Barbara Thorand, [......],
Markku Ahotupa,
Jorma S A Viikari,
Mika Kähönen,
Olli T Raitakari,
Mahir Karakas,
Wolfgang Koenig,
Bernhard O Boehm,
Bernhard R Winkelmann,
Winfried März,
Terho Lehtimäki
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ABSTRACT: BACKGROUND: -Oxidized low-density lipoprotein (oxLDL) may be a key factor in the development of atherosclerosis. We performed a genome-wide association study (GWAS) on oxLDL and tested the impact of the associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis, and cardiovascular events. METHODS AND RESULTS: -A discovery GWAS was performed on a population of young healthy Caucasian individuals (N=2,080), and the SNPs associated with a p value < 5 x 10(-8) were replicated in two independent samples (A: N=2,912; and B: N=1,326). Associations with cardiovascular endpoints were also assessed with two additional clinical cohorts (C: N=1,118; and D: N=808). We found 328 SNPs associated with oxLDL. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B (apoB) was the proxy SNP behind all associations (p=4.3 x 10(-136), effect size = 13.2 U/l per allele). This association was replicated in the two independent samples (A and B, p values = 2.5 x 10(-47) and 1.1 x 10(-11), effect sizes = 10.3 U/l and 7.8 U/l, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (CAD, hazard ratio [HR]=1.00 [0.94-1.06] per allele), three vessel CAD (HR=1.03 [0.94-1.13]) or myocardial infarction (HR=1.04 [0.96-1.12]). CONCLUSIONS: -This novel genetic marker is an important factor regulating oxLDL levels but not a major genetic factor for the studied cardiovascular end-points.
Circulation Cardiovascular Genetics 12/2012; · 6.11 Impact Factor
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ABSTRACT: AIMS: This study was set up to compare the accuracy, sensitivity and specificity of gene expression results between the Illumina HumanHT-12 v3 Expression BeadChip (GWE) and the TaqMan qRT-PCR low-density array (LDA) in atherosclerotic plaques. METHODS: Gene expression levels of 196 genes were determined from 22 atherosclerotic samples and 6 controls with both the GWE and the LDA. RESULTS: The accuracies of GWE in comparison to that of qRT-PCR for absolute fold changes (FC) 1.2, 1.6, 2.0 and 3.0 between cases and controls were 73.5%, 79.1%, 72.4% and 60.7%, respectively. The correlation of expression measurements between these methods was good (r = 0.87, y = 0.151 + 0.586x), and the Bland-Altman plot showed that for highly up- or down-regulated transcripts, GWE yields lower absolute FC values than LDA. CONCLUSION: Gene expression results obtained with the GWE are replicated with high accuracy in LDA, even for technically demanding atherosclerotic samples.
Atherosclerosis 11/2012; · 3.79 Impact Factor
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Mervi Oikonen,
Maria Wendelin-Saarenhovi,
Niina Siitonen,
Annele Sainio,
Markus Juonala,
Mika Kähönen,
Leo-Pekka Lyytikäinen, Ilkka Seppälä,
Terho Lehtimäki,
Jorma S A Viikari,
Hannu Järveläinen,
Olli T Raitakari
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ABSTRACT: Objectives. The tissue inhibitor of metalloproteinases 4 (TIMP4) is present in significant amounts in human atherosclerotic coronary artery lesions, but its relations with the early pathogenesis of atherosclerotic changes have not been clarified. We studied the associations of circulating TIMP4 with pre-clinical markers of atherosclerosis and traditional cardiovascular risk factors by using longitudinal data on carotid artery intima-media (cIMT) thickness in a population-based cohort of asymptomatic young adult Finns. Methods. Data on cIMT, plasma TIMP4, lipids, CRP, blood pressure, BMI, smoking status and daily alcohol intake were obtained from 980 24-39 year-old participants in 2001. The 6-year follow-up in cIMT measurements were performed in 2007 for 769 participants. Results. Plasma TIMP4 concentrations (mean ± SD) were 2.3 ± 1.7 ng/mL in men and 2.5 ± 1.8 ng/mL in women. Age, LDL-cholesterol, BMI and systolic blood pressure were directly associated with TIMP4 concentration. In a multivariable model, the independent determinants of TIMP4 included systolic blood pressure (p = 0.008) and daily smoking (p = 0.009), both being inversely associated with TIMP4. These two baseline variables explained 1.5% of the variation in TIMP4. TIMP4 was significantly and inversely associated with cIMT measured 6 years later (beta =- 0.0135, p = 0.01) explaining 0.7% of the variability of cIMT. Conclusion. In young apparently healthy adults, circulating TIMP4 concentration was independently and inversely associated with cIMT, a marker of vascular structure and function.
Scandinavian journal of clinical and laboratory investigation 09/2012; 72(7):540-6. · 1.38 Impact Factor
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M Jokela,
M Elovainio,
L Keltikangas-Järvinen,
G D Batty,
M Hintsanen, I Seppälä,
M Kähönen,
J S Viikari,
O T Raitakari,
T Lehtimäki,
M Kivimäki
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ABSTRACT: The causal role of obesity in the development of depression remains uncertain. We applied instrumental-variables regression (Mendelian randomization) to examine the association of adolescent and adult body mass index (BMI) with adult depressive symptoms. Participants were from the Young Finns prospective cohort study (n = 1731 persons, 2844 person-observations), with repeated measurements of BMI and depressive symptoms (modified Beck's Depression Inventory). Genetic risk score of 31 single nucleotide polymorphisms previously identified as robust genetic markers of body weight was used as a proxy for variation in BMI. In standard linear regression analysis, higher adult depressive symptoms were predicted by higher adolescent BMI (B = 0.33, CI = 0.06-0.60, P = 0.017) and adult BMI (B = 0.47, CI = 0.32-0.63, P < 0.001). These associations were replicated in instrumental-variables analysis with genetic risk score as instrument (B = 1.96, CI = 0.03-3.90, P = 0.047 for adolescent BMI; B = 1.08, CI = 0.11-2.04, P = 0.030 for adult BMI). The association for adolescent BMI was significantly stronger in the instrumented analysis compared to standard regression (P = 0.04). These findings provide additional evidence to support a causal role for high BMI in increasing symptoms of depression. However, the present analysis also demonstrates potential limitations of applying Mendelian randomization when using complex phenotypes.
Genes Brain and Behavior 09/2012; · 3.48 Impact Factor
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Christian Hakulinen,
Markus Jokela,
Mirka Hintsanen,
Päivi Merjonen,
Laura Pulkki-Råback, Ilkka Seppälä,
Leo-Pekka Lyytikäinen,
Terho Lehtimäki,
Mika Kähönen,
Jorma Viikari,
Olli T Raitakari,
Liisa Keltikangas-Järvinen
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ABSTRACT: The serotonin system has been shown to be involved in the regulation of hostility, anger, and aggressive behavior. Previous molecular genetic studies suggest that the serotonin receptor 1B (HTR1B) rs6296 genotype might have a particular role in these types of behaviors. We examined whether HTR1B is related to hostility, anger, and aggressive behavior phenotypes over a lifespan and whether it modifies the connection between childhood aggressive behavior and adulthood hostility and anger. The participants were 967 women and men from a large population based sample (The Young Finns Study) with a 27-year follow-up. Childhood aggressive behavior was reported by the mother twice when the participants were 3 to 12 years of age. Adulthood hostility and anger were self-reported by the participants between ages 24 and 36. Childhood aggressive behavior predicted adulthood hostility over 27 years. HTR1B SNP rs6296 was associated with childhood aggressive behavior but not with adulthood anger or hostility. The HTR1B SNP rs6296 modified the association between childhood aggressive behavior and adulthood hostility. Aggressive behavior and hostility might form a life course pattern, and the HTR1B might contribute to a development of this pattern.
Journal of Behavioral Medicine 09/2012; · 3.10 Impact Factor
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Jonna Juhola,
Mervi Oikonen,
Costan G Magnussen,
Vera Mikkilä,
Niina Siitonen,
Eero Jokinen,
Tomi Laitinen,
Peter Würtz,
Samuel S Gidding,
Leena Taittonen, Ilkka Seppälä,
Antti Jula,
Mika Kähönen,
Nina Hutri-Kähönen,
Terho Lehtimäki,
Jorma S A Viikari,
Markus Juonala,
Olli T Raitakari
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ABSTRACT: Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension.
The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015).
Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension.
Circulation 06/2012; 126(4):402-9. · 14.74 Impact Factor
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Mervi Oikonen,
Maria Wendelin-Saarenhovi,
Leo-Pekka Lyytikäinen,
Niina Siitonen,
Britt-Marie Loo,
Antti Jula, Ilkka Seppälä,
Liisa Saarikoski,
Terho Lehtimäki,
Nina Hutri-Kähönen,
Markus Juonala,
Mika Kähönen,
Risto Huupponen,
Jorma S A Viikari,
Olli T Raitakari
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ABSTRACT: Serum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30-45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations.
In women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R(2) = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R(2) = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R(2) ∼ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT.
SUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.
Atherosclerosis 06/2012; 223(2):497-503. · 3.79 Impact Factor
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ABSTRACT: Background. Apolipoprotein A-I (apoA-I) and B (apoB) and multiple lipoprotein cardiovascular risk factors can be computationally estimated with our extended Friedewald approach (EFW) from classical inputs. Their impact on cardiovascular events and mortality in the working age population is not known. Methods. The working age (≤ 65 years, n = 5956) prospective population-based cohort (follow-up of 7.8 ± 0.9 years; 46,572 patient years, 409 non-fatal incident cardiovascular events, and 55 cardiovascular and 266 all-cause deaths) had their total serum cholesterol (TC), triglycerides (TG), and HDL-C measured. Continuous net reclassification improvement (NRI) was calculated. Results. In Cox models adjusted with cardiovascular risk factors, EFW-HDL(2)-C (HR 0.78, 95% CI 0.67-0.91; NRI 16.5%), apoA-I (HR 0.78, 95% CI 0.69-0.89; NRI 15.2%), apoB/apoA-I (HR 1.23, 95% CI 1.08-1.40; NRI 20.6%), and VLDL-TG (HR 1.15, 95% CI 1.05-1.25; NRI 20.1%) were associated with incident non-fatal cardiovascular events and improved risk prediction compared with TC, LDL-C, or non-HDL-C. Cardiovascular deaths could be best predicted with EFW apoB (HR 1.81, 95% CI 1.18-2.77; NRI 77.3%). Conclusions. EFW approach-derived HDL(2)-C, apoA-I, apoB/apoA-I, and VLDL-TG improve prediction of non-fatal cardiovascular events, and apoB of cardiovascular mortality, and can be utilized for risk estimation in a working age population without extra cost.
Annals of medicine 04/2012; · 3.52 Impact Factor
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Jussi A Hernesniemi, Ilkka Seppälä,
Leo-Pekka Lyytikäinen,
Nina Mononen,
Niku Oksala,
Nina Hutri-Kähönen,
Markus Juonala,
Leena Taittonen,
Erin N Smith,
Nicholas J Schork, [......],
Sarah S Murray,
Tomi Laitinen,
Antti Jula,
Johannes Kettunen,
Samuli Ripatti,
Reijo Laaksonen,
Jorma Viikari,
Mika Kähönen,
Olli T Raitakari,
Terho Lehtimäki
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ABSTRACT: Genome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis--i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE)--beyond classical risk factors.
We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30-45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46-76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS(24SNP/CAD)) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.
CIMT or CAE did not significantly associate with GRS(24SNP/CAD) before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.
Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.
PLoS ONE 01/2012; 7(1):e28931. · 4.09 Impact Factor
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Mervi Oikonen,
Emmi Tikkanen,
Jonna Juhola,
Tarja Tuovinen, Ilkka Seppälä,
Markus Juonala,
Leena Taittonen,
Vera Mikkilä,
Mika Kähönen,
Samuli Ripatti, [......],
Frank Kee,
Christopher Newton-Cheh,
Leena Peltonen,
Nicholas J Schork,
Sarah S Murray,
Gerald S Berenson,
Wei Chen,
Sathanur R Srinivasan,
Veikko Salomaa,
Olli T Raitakari
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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<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 years onward (β=0.68 mm Hg; 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<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood; individuals with several susceptibility alleles have, on average, a 0.5-mm Hg higher blood pressure, and this trajectory continues from childhood to adulthood.
Hypertension 12/2011; 58(6):1079-85. · 6.21 Impact Factor
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Markus Juonala,
Jonna Juhola,
Costan G Magnussen,
Peter Würtz,
Jorma S A Viikari,
Russell Thomson, Ilkka Seppälä,
Jussi Hernesniemi,
Mika Kähönen,
Terho Lehtimäki,
Mikko Hurme,
Risto Telama,
Vera Mikkilä,
Carita Eklund,
Leena Räsänen,
Mirka Hintsanen,
Liisa Keltikangas-Järvinen,
Mika Kivimäki,
Olli T Raitakari
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ABSTRACT: 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.
Our objective was to examine the childhood environmental and genetic predictors of adult obesity.
We followed 2119 individuals of the Cardiovascular Risk in Young Finns Study for up to 27 yr since baseline (1980, age 3-18 yr).
We evaluated adult obesity [body mass index (BMI) ≥ 30 kg/m(2)].
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 with the approach using data only on BMI (C-statistics 0.751 vs. 0.772, P = 0.0015). Inclusion of data on childhood CRP and novel genetic variants for BMI did not incrementally improve C-value (0.779, P = 0.16). A nonlaboratory risk score (childhood BMI, mother's BMI, and family income) predicted adult obesity in all age groups between 3-18 yr (P always <0.001).
Childhood BMI, CRP, family income (inversely), mother's BMI, and polymorphisms near genes FLJ35779, TFAP2B, and LRRN6C are independently related to adulthood obesity. However, because genetic risk markers and CRP only marginally improve the prediction, our results indicate that children at high risk of adult obesity can be identified using a simple non-laboratory-based risk assessment.
The Journal of clinical endocrinology and metabolism 07/2011; 96(9):E1542-9. · 6.50 Impact Factor
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Emma Raitoharju, Ilkka Seppälä,
Mari Levula,
Pekka Kuukasjärvi,
Jari Laurikka,
Kjell Nikus,
Ari-Pekka J Huovila,
Niku Oksala,
Norman Klopp,
Thomas Illig,
Reijo Laaksonen,
Pekka J Karhunen,
Jari Viik,
Rami Lehtinen,
Markku Pelto-Huikko,
Matti Tarkka,
Mika Kähönen,
Terho Lehtimäki
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ABSTRACT: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI.
To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk.
Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples.
A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P<0.001 and OR=1.43, P<0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations.
The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.
Atherosclerosis 05/2011; 218(1):127-33. · 3.79 Impact Factor
