Publications
976 results found
Pinola P, Polonen J, Ronkainen J, et al., 2020, Polycystic ovary syndrome and leukocyte telomere length: results of cross-sectional and longitudinal analyses in a birth cohort study, 36th Virtual Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 85-85, ISSN: 0268-1161
Amaral A, Imboden M, Wielscher M, et al., 2020, Role of DNA methylation in the association of lung function with body mass index: A two-step epigenetic Mendelian randomisation study, BMC Pulmonary Medicine, Vol: 20, Pages: 1-8, ISSN: 1471-2466
BackgroundLow lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.MethodsWe used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.ResultsIn step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.ConclusionsTo our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function
Robinson O, Chadeau Hyam M, Karaman I, et al., 2020, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort, Aging Cell, Vol: 19, Pages: 1-13, ISSN: 1474-9718
Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.
Lee MA, McMahon G, Karhunen V, et al., 2020, Common variation at 16p11.2 is associated with glycosuria in pregnancy: findings from a genome-wide association study in European women, Human Molecular Genetics, Vol: 29, Pages: 2098-2106, ISSN: 0964-6906
Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.
NCD Risk Factor Collaboration NCD-RisC, 2020, Repositioning of the global epicentre of non-optimal cholesterol, Nature, Vol: 582, Pages: 73-77, ISSN: 0028-0836
High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular risk-changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and per
Toppila-Salmi S, Luukkainen AT, Xu B, et al., 2020, Maternal smoking during pregnancy affects adult onset of asthma in offspring: a follow up from birth to age 46 years, European Respiratory Journal, Vol: 55, Pages: 1-11, ISSN: 0903-1936
Rationale Environmental tobacco smoke (ETS) exposure increases asthma risk in children. There is limited knowledge of prenatal ETS for adult-onset asthma.Objectives To determine the association between prenatal ETS and adult onset asthma.Measurements and main results The questionnaire and clinical data of 5200 people, free of physician-diagnosed asthma by 31 years of age, who were included in the Northern Finland Birth Cohort 1966 Study was used. The association of maternal smoking during the last 3 months of pregnancy with onset of physician-diagnosed asthma and with lung function in adult offspring was studied using adjusted multivariate regression analyses. The cumulative incidence of physician-diagnosed asthma between the ages of 31 and 46 years was 5.1% among men and 8.8% among women. Gestational smoke exposure was associated with adult-onset asthma among offspring (adjusted OR 1.54, 95% CI 1.04–2.29), namely among offspring who reported either past non-diagnosed asthma (OR 9.63, 95% CI 2.28–40.67) or past cough with wheeze (3.21, 95% CI 1.71–6.05). A significant association was detected between gestational smoke exposure and the offspring's forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio at 31 years of age. In offspring with the haplotype rs11702779-AA of RUNX1, gestational smoke exposure was associated with adult-onset asthma (5.53, 95% CI 2.11–14.52, adjusted p-value for interaction 0.10).Conclusion Maternal smoking during pregnancy is associated with the cumulative incidence of asthma in offspring between the ages of 31 and 46 years. The association was accentuated in offspring who at age 31, reported having past respiratory problems and/or who had haplotype rs11702779-AA. A reduction in FEV1/FVC ratio was also observed at age 31 years in offspring with gestational smoke exposure. These results could reflect the early vulnerability of offspring's airways to ETS and its putative long-term effects.
Korpela N, Kaikkonen K, Auvinen J, et al., 2020, Early growth patterns and cardiac structure and function at midlife: northern Finland 1966 birth cohort study, Journal of Pediatrics, Vol: 221, Pages: 151-158.e1, ISSN: 0022-3476
ObjectivesTo evaluate the influence of early growth patterns that have previously been associated with later cardiometabolic risk on cardiac left ventricular (LV) structure and function in midlife.Study designA subpopulation of the Northern Finland Birth Cohort 1966 took part in follow-up, including echocardiography (n = 1155) at the age of 46 years. Body mass index (BMI) growth curves were modeled based on frequent anthropometric measurements in childhood. Age and BMI at adiposity peak (n = 482, mean age 9.0 months) and at adiposity rebound (n = 586, mean age 5.8 years) were determined. Results are reported as unstandardized beta (β) or OR with 95% CIs for 1 SD increase in early growth variable.ResultsEarlier adiposity rebound was associated with increased LV mass index (β = −4.10 g/m2 (−6.9, −1.3); P = .004) and LV end-diastolic volume index (β = −2.36 mL/m2 (−3.9, −0.84); P = .002) as well as with eccentric LV hypertrophy (OR 0.54 [0.38, 0.77]; P = .001) in adulthood in males. BMI at adiposity rebound was directly associated with LV mass index (β = 2.33 g/m2 [0.80, 3.9]; P = .003). Higher BMI at both adiposity peak and at adiposity rebound were associated with greater LV end-diastolic volume index (β = 1.47 mL/m2; [0.51, 2.4], β = 1.28 mL/m2 [0.41, 2.2], respectively) and also with eccentric LV hypertrophy (OR 1.41 [1.10, 1.82], OR 1.53 [1.23, 1.91], respectively) and LV concentric remodeling (OR 1.38 [1.02, 1.87], OR 1.40 [1.06, 1.83], respectively) in adulthood (P < .05 for all). These relationships were only partly mediated by adult BMI.ConclusionsEarly growth patterns in infancy and childhood contribute to cardiac structure at midlife.
Lowry E, Rautio N, Wasenius N, et al., 2020, Early exposure to social disadvantages and later life body mass index beyond genetic predisposition in three generations of Finnish birth cohorts, BMC Public Health, Vol: 20, ISSN: 1471-2458
BACKGROUND: The study aimed to explore the association between early life and life-course exposure to social disadvantage and later life body mass index (BMI) accounting for genetic predisposition and maternal BMI. METHODS: We studied participants of Helsinki Birth Cohort Study born in 1934-1944 (HBCS1934-1944, n = 1277) and Northern Finland Birth Cohorts born in 1966 and 1986 (NFBC1966, n = 5807, NFBC1986, n = 6717). Factor analysis produced scores of social disadvantage based on social and economic elements in early life and adulthood/over the life course, and was categorized as high, intermediate and low. BMI was measured at 62 years in HBCS1934-1944, at 46 years in NFBC1966 and at 16 years in NFBC1986. Multivariable linear regression analysis was used to explore associations between social disadvantages and BMI after adjustments for polygenic risk score for BMI (PRS BMI), maternal BMI and sex. RESULTS: The association between exposure to high early social disadvantage and increased later life BMI persisted after adjustments (β = 0.79, 95% CI, 0.33, 1.25, p < 0.001) in NFBC1966. In NFBC1986 this association was attenuated by PRS BMI (p = 0.181), and in HBCS1934-1944 there was no association between high early social disadvantage and increased later life BMI (β 0.22, 95% CI -0.91,1.35, p = 0.700). In HBCS1934-1944 and NFBC1966, participants who had reduced their exposure to social disadvantage during the life-course had lower later life BMI than those who had increased their exposure (β - 1.34, [- 2.37,-0.31], p = 0.011; β - 0.46, [- 0.89,-0.03], p = 0.038, respectively). CONCLUSIONS: High social disadvantage in early life appears to be associated with higher BMI in later life. Reducing exposure to social disadvantage during the life-course may be a poten
Palaniswamy S, Gill D, De Silva NM, et al., 2020, Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 111, Pages: 1036-1047, ISSN: 0002-9165
BackgroundObesity is associated with inflammation but the role of vitamin D in this process is not clear.ObjectivesWe aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation.MethodsNorthern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials.ResultsIn NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of
Bjerregaard LG, Wasenius N, Nedelec R, et al., 2020, Possible Modifiers of the Association Between Change in Weight Status From Child Through Adult Ages and Later Risk of Type 2 Diabetes, DIABETES CARE, Vol: 43, Pages: 1000-1007, ISSN: 0149-5992
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David A, 2020, A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin, Molecular Genetics and Genomic Medicine, Vol: 8, Pages: 1-9, ISSN: 2324-9269
BackgroundSevere hypercholesterolemia (HC, LDL‐C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL‐C.MethodsSummary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used.ResultsA 36‐SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL‐C trait and explained 8% of its variability (p = 10–41). After risk categorization, the risk of having HC was higher in the high‐ versus low‐risk group (RR = 4.17, p < 1 × 10−7). Compared to a 12‐SNP LDL‐C raising score (currently used in the United Kingdom), the PRS explained more LDL‐C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL‐C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL‐C raising score were reclassified to intermediate or high risk by the new PRS.ConclusionThe new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms.
Karjalainen MK, Holmes MV, Wang Q, et al., 2020, Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study, Atherosclerosis, Vol: 299, Pages: 56-63, ISSN: 0021-9150
Background and aimsApolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I concentrations inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. The aim was to assess the causal role of apoA-I using human genetics.MethodsWe identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations (p < 5 × 10−8) in 20,370 Finnish participants, and meta-analyzed our data with a previous GWAS of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts.ResultsApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; p = 1.5 × 10−9) but not with confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98,1.30 per 1-SD higher apoA-I), which was different from the observational association. Similar findings were observed using an independent ABCA1 variant in sensitivity analysis.ConclusionsGenetic evidence fails to support a cardioprotective role for apoA-I. This is in line with the cumulative evidence showing that HDL-related phenotypes are unlikely to have a protective role in CAD.
Fung E, Lui LT, Gustafsson F, et al., 2020, Predicting 10-year mortality in older adults using VO(2)max, oxygen uptake efficiency slope and frailty class, EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, ISSN: 2047-4873
Li C, Stoma S, Lotta LA, et al., 2020, Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length, American Journal of Human Genetics, Vol: 106, Pages: 389-404, ISSN: 0002-9297
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Merid SK, Novoloaca A, Sharp GC, et al., 2020, Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age, Genome Medicine: medicine in the post-genomic era, Vol: 12, Pages: 1-17, ISSN: 1756-994X
BackgroundPreterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.MethodsWe performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.ResultsWe identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10− 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.ConclusionsWe identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational a
Taivalantti M, Barnett JH, Halt A-H, et al., 2020, Depressive symptoms as predictors of visual memory deficits in middle-age, Journal of Affective Disorders, Vol: 264, Pages: 29-34, ISSN: 0165-0327
BackgroundDepression has been known to affect memory and other cognitive domains. The objective of this longitudinal cohort study was to investigate longitudinal associations between depressive symptoms at age 31 years and visual memory and new learning at the age of 46 years. We investigated whether depressive symptoms at age 31 predicted visual memory deficits at age 46 years, and whether changes in depressive symptoms between 31 and 46 years predicted visual memory at age 46.MethodsParticipants were members of the Northern Finland Birth Cohort 1966. Depressive symptoms were assessed with the Symptom Checklist-25 (SCL-25) on both occasions. Visual memory and new learning were assessed using Paired Associative Learning (PAL) test at the age 46 follow-up. PAL total errors adjusted and first trial memory score were used as outcomes and basic educational level, relationship status, physical activity and diet at baseline were considered as confounding factors in linear regression analysis.ResultsA total of 5029 (57% female) participants were included in the main analysis. No associations were found between depressive symptoms or change in depressive symptoms and visual memory and new learning scores. The result did not change following cut-offs 1.55 and 1.75 for depression.LimitationsSCL-25 only measures symptoms during the past week. Only one cognitive domain was assessed.ConclusionsContrary to our hypothesis, neither baseline depressive symptoms nor change in depressive symptoms predicted visual memory scores 15 years later. It appears that sub-clinical depressive symptoms do not effect this cognitive domain in the middle-aged population.
Ohukainen P, Kuusisto S, Kettunen J, et al., 2020, Data-driven multivariate population subgrouping via lipoprotein phenotypes versus apolipoprotein B in the risk assessment of coronary heart disease, Atherosclerosis, Vol: 294, Pages: 10-15, ISSN: 0021-9150
Background and aimsPopulation subgrouping has been suggested as means to improve coronary heart disease (CHD) risk assessment. We explored here how unsupervised data-driven metabolic subgrouping, based on comprehensive lipoprotein subclass data, would work in large-scale population cohorts.MethodsWe applied a self-organizing map (SOM) artificial intelligence methodology to define subgroups based on detailed lipoprotein profiles in a population-based cohort (n = 5789) and utilised the trained SOM in an independent cohort (n = 7607). We identified four SOM-based subgroups of individuals with distinct lipoprotein profiles and CHD risk and compared those to univariate subgrouping by apolipoprotein B quartiles.ResultsThe SOM-based subgroup with highest concentrations for non-HDL measures had the highest, and the subgroup with lowest concentrations, the lowest risk for CHD. However, apolipoprotein B quartiles produced better resolution of risk than the SOM-based subgroups and also striking dose-response behaviour.ConclusionsThese results suggest that the majority of lipoprotein-mediated CHD risk is explained by apolipoprotein B-containing lipoprotein particles. Therefore, even advanced multivariate subgrouping, with comprehensive data on lipoprotein metabolism, may not advance CHD risk assessment.
Bond TA, Karhunen V, Wielscher M, et al., 2020, Exploring the role of genetic confounding in the association between maternal and offspring body mass index: evidence from three birth cohorts, International Journal of Epidemiology, Vol: 49, Pages: 233-243, ISSN: 1464-3685
BACKGROUND: Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding. METHODS: We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (n ≤11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged individual participant data from all cohorts, enabling calculation of pooled estimates. RESULTS: Phenotypic covariance (equivalent here to Pearson's correlation coefficient) between maternal BMI and offspring phenotype was 0.15 [95% confidence interval (CI): 0.13, 0.17] for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW [-0.04 (95% CI: -0.09, 0.01)], but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results. CONCLUSIONS: Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI-offspring BMI association.
Taddei C, Jackson R, Zhou B, et al., 2020, National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio: an analysis of trends in Asian and Western countries, International Journal of Epidemiology, Vol: 49, Pages: 173-192, ISSN: 1464-3685
Background: Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease (CHD), multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio in Asian and Western countries.Methods: We pooled 458 population-based studies with 82.1 million participants in 23 Asian and Western countries. We estimated changes in mean total, HDL and non-HDL cholesterol, and mean total-to-HDL cholesterol ratio by country, sex and age group.Results: Since ~1980, mean TC increased in Asian countries. In Japan and South Korea, TC rise was due to rising HDL cholesterol, which increased by up to 0.17 mmol/L per decade in Japanese women; in China, it was due to rising non-HDL cholesterol. TC declined in Western countries, except in Polish men. The decline was largest in Finland and Norway, ~0.4 mmol/Lper decade. The decline in TC in most Western countries was the net effect of an increase in HDL cholesterol and a decline in non-HDL cholesterol, with the HDL cholesterol increase largest in New Zealand and Switzerland. Mean total-to-HDL cholesterol ratio declined in Japan, South Korea and most Western countries, by as much as ~0.7 per decade in Swiss men (equivalent to ~26% decline in CHD risk per decade). The ratio increased in China. Conclusions: HDL cholesterol has risen and total-to-HDL cholesterol ratio has declined in many Western countries, Japan and South Korea, with only weak correlation to changes in TC or non-HDL cholesterol.
Karjula S, Morin-Papunen L, Franks S, et al., 2020, Population-based data at ages 31 and 46 show decreased HRQoL and life satisfaction in women with PCOS symptoms., Journal of Clinical Endocrinology and Metabolism, Vol: 105, Pages: 1-13, ISSN: 0021-972X
CONTEXT: Polycystic ovary syndrome (PCOS) is associated with decreased health-related quality of life (HRQoL), but longitudinal data beyond the reproductive years are lacking, and the impact of isolated PCOS symptoms is unclear. OBJECTIVE: To study generic HRQoL using 15D, life satisfaction, and self-reported health status in women with PCOS symptoms at ages 31 and 46yr. DESIGN: A longitudinal assessment using the Northern Finland Birth Cohort 1966. SETTING: General community. PARTICIPANTS: The 15D data were available for women reporting isolated oligomenorrhea (OA;at age 31yr:214 and 46yr: 211), isolated hirsutism (H; 31yr:211 and 46yr:216), OA+H (PCOS; 31yr:74 and 46yr:75), or no PCOS symptoms (controls; 31yr:1382 and 46yr:1412). Data for life satisfaction and current health status were available for OA (31yr:329 and 46yr:247), H (31yr:323 and 46yr:238), PCOS (31yr:125 and 46yr:86), control (31yr:2182 and 46yr:1613) groups. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 15D HRQoL, questionnaires on life satisfaction, and self-reported health status. RESULTS: HRQoL was lower at ages 31 and 46 in women with PCOS or H compared with the controls. PCOS was an independent risk factor for low HRQoL, and the decrease in HRQoL in PCOS was comparable to that of women with other chronic conditions, like asthma, migraine, rheumatoid arthritis, and depression. The risk for low HRQoL in PCOS remained significant after adjusting for BMI, hyperandrogenism, and socioeconomic status. Mental distress was the strongest contributing factor to HRQoL. PCOS was also associated with a risk for low life satisfaction and a 4-fold risk for reporting a poor health status. CONCLUSIONS: Women with PCOS present with low HRQoL, decreased life satisfaction, and a poorer self-reported health status up to their late reproductive years. Assessments and interventions aiming to improve HRQoL in PCOS should be targeted beyond fertile age.
Rezwan FI, Imboden M, Amaral AFS, et al., 2020, Association of adult lung function with accelerated biological aging, Aging-US, Vol: 12, Pages: 518-542, ISSN: 1945-4589
Lung function, strongly associated with morbidity and mortality, decreases with age. This study examines whether poor adult lung function is associated with age accelerations (AAs). DNA methylation (DNAm) based AAs, lifespan predictors (GrimAge and plasminogen activator inhibitor 1-PAI1) and their related age-adjusted measures were estimated from peripheral blood at two time points (8-to-11 years apart) in adults from two cohorts: SAPALDIA (n=987) and ECRHS (n=509). Within each cohort and stratified by gender (except for estimators from GrimAge and PAI1), AAs were used as predictors in multivariate linear regression with cross-sectional lung function parameters, and in covariate-adjusted mixed linear regression with longitudinal change in lung function and meta-analysed.AAs were found cross-sectionally associated with lower mean FEV1 (Forced Expiratory Volume in one second) (AA-residuals:P-value=4x10-4; Intrinsic Epigenetic AA:P-value=2x10-4) in females at the follow-up time point only, and the same trend was observed for FVC (Forced Vital Capacity). Both lifespan and plasma level predictors were observed strongly associated with lung function decline and the decline was stronger in the follow-up time points (strongest association between FEV1 and DNAmAge GrimAge:P-value=1.25x10-17).This study suggests that DNAm based lifespan and plasma level predictors can be utilised as important factors to assess lung health in adults.
Mutt SJ, Raza GS, Makinen MJ, et al., 2020, Vitamin D deficiency induces insulin resistance and re-supplementation attenuates hepatic glucose output via the PI3K-AKT-FOXO1 mediated pathway, Molecular Nutrition and Food Research, Vol: 64, Pages: 1-10, ISSN: 1613-4125
BackgroundPandemic vitamin D deficiency is associated with insulin resistance and type 2 diabetes. Vitamin D supplementation has been reported to have improved glucose homeostasis. However, its mechanism to improve insulin sensitivity remains unclear.Methods and resultsMale C57BL/6J mice are fed with/without vitamin D control (CD) or Western (WD) diets for 15 weeks. The vitamin‐D‐deficient lean (CDVDD) and obese (WDVDD) mice are further subdivided into two groups. One group is re‐supplemented with vitamin D for 6 weeks and hepatic insulin signaling is examined. Both CD and WD mice with vitamin D deficiency developed insulin resistance. Vitamin D supplementation in CDVDD mice significantly improved insulin sensitivity, hepatic inflammation, and antioxidative capacity. The hepatic insulin signals like pAKT, pFOXO1, and pGSK3β are increased and the downstream Pepck, G6pase, and Pgc1α are reduced. Furthermore, the lipogenic genes Srebp1c, Acc, and Fasn are decreased, indicating that hepatic lipid accumulation is inhibited.ConclusionThe results demonstrate that vitamin D deficiency induces insulin resistance. Its supplementation has significant beneficial effects on pathophysiological mechanisms in type 2 diabetes but only in lean and not in the obese phenotype. The increased subacute inflammation and insulin resistance in obesity cannot be significantly alleviated by vitamin D supplementation. This needs to be taken into consideration in the design of new clinical trials.
Korpela H, Miettunen J, Rautio N, et al., 2020, Early environmental factors and somatic comorbidity in schizophrenia and nonschizophrenic psychoses: A 50-year follow-up of the Northern Finland Birth Cohort 1966, European Psychiatry, Vol: 63, Pages: 1-10, ISSN: 0924-9338
Background.We studied the cumulative incidence of physical illnesses, and the effect of early environmental factors (EEFs) on somatic comorbidity in schizophrenia, in nonschizophrenic psychosis and among nonpsychotic controls from birth up to the age of 50 years.Methods.The sample included 10,933 members of the Northern Finland Birth Cohort 1966, of whom, 227 had schizophrenia and 205 had nonschizophrenic psychosis. Diagnoses concerning physical illnesses were based on nationwide registers followed up to the end of 2016 and classified into 13 illness categories. Maternal education and age, family type at birth and paternal socioeconomic status were studied as EEFs of somatic illnesses.Results.When adjusted by gender and education, individuals and especially women with nonschizophrenic psychosis had higher risk of morbidity in almost all somatic illness categories compared to controls, and in some categories, compared to individuals with schizophrenia. The statistically significant adjusted hazard ratios varied from 1.27 to 2.42 in nonschizophrenic psychosis. Regarding EEFs, single-parent family as the family type at birth was a risk factor for a higher somatic score among men with schizophrenia and women with nonschizophrenic psychosis. Maternal age over 35 years was associated with lower somatic score among women with nonschizophrenic psychosis.Conclusions.Persons with nonschizophrenic psychoses have higher incidence of somatic diseases compared to people with schizophrenia and nonpsychotic controls, and this should be noted in clinical work. EEFs have mostly weak association with somatic comorbidity in our study.
Leal Ayala LG, David A, Jarvelin MR, et al., 2019, Identification of disease-associated loci using machine learning for genotype and network data integration, Bioinformatics, Vol: 35, Pages: 5182-5190, ISSN: 1367-4803
MotivationIntegration of different omics data could markedly help to identify biological signatures, understand the missing heritability of complex diseases and ultimately achieve personalized medicine. Standard regression models used in Genome-Wide Association Studies (GWAS) identify loci with a strong effect size, whereas GWAS meta-analyses are often needed to capture weak loci contributing to the missing heritability. Development of novel machine learning algorithms for merging genotype data with other omics data is highly needed as it could enhance the prioritization of weak loci.ResultsWe developed cNMTF (corrected non-negative matrix tri-factorization), an integrative algorithm based on clustering techniques of biological data. This method assesses the inter-relatedness between genotypes, phenotypes, the damaging effect of the variants and gene networks in order to identify loci-trait associations. cNMTF was used to prioritize genes associated with lipid traits in two population cohorts. We replicated 129 genes reported in GWAS world-wide and provided evidence that supports 85% of our findings (226 out of 265 genes), including recent associations in literature (NLGN1), regulators of lipid metabolism (DAB1) and pleiotropic genes for lipid traits (CARM1). Moreover, cNMTF performed efficiently against strong population structures by accounting for the individuals’ ancestry. As the method is flexible in the incorporation of diverse omics data sources, it can be easily adapted to the user’s research needs.
Kettunen J, Holmes MV, Allara E, et al., 2019, Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition, PLoS Biology, Vol: 17, Pages: 1-19, ISSN: 1544-9173
Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (−0.02 SD LDL defined by particle size; 95% CI: −0.10 to 0.05 for CETP versus −0.24 SD, 95% CI −0.30 to −0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD
Ahola-Olli AV, Mustelin L, Kalimeri M, et al., 2019, Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts, Diabetologia, Vol: 62, Pages: 2298-2309, ISSN: 0012-186X
Aims/hypothesisMetabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults.MethodsNMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up.ResultsOut of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years).Conclusions/interpretationMetabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individua
Wang Q, Jokelainen J, Auvinen J, et al., 2019, Insulin resistance and systemic metabolic changes in oral glucose tolerance test in 5340 individuals: an interventional study, BMC Medicine, Vol: 17, Pages: 1-12, ISSN: 1741-7015
BackgroundInsulin resistance (IR) is predictive for type 2 diabetes and associated with various metabolic abnormalities in fasting conditions. However, limited data are available on how IR affects metabolic responses in a non-fasting setting, yet this is the state people are mostly exposed to during waking hours in the modern society. Here, we aim to comprehensively characterise the metabolic changes in response to an oral glucose test (OGTT) and assess the associations of these changes with IR.MethodsBlood samples were obtained at 0 (fasting baseline, right before glucose ingestion), 30, 60, and 120 min during the OGTT. Seventy-eight metabolic measures were analysed at each time point for a discovery cohort of 4745 middle-aged Finnish individuals and a replication cohort of 595 senior Finnish participants. We assessed the metabolic changes in response to glucose ingestion (percentage change in relative to fasting baseline) across the four time points and further compared the response profile between five groups with different levels of IR and glucose intolerance. Further, the differences were tested for covariate adjustment, including gender, body mass index, systolic blood pressure, fasting, and 2-h glucose levels. The groups were defined as insulin sensitive with normal glucose (IS-NGT), insulin resistant with normal glucose (IR-NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and new diabetes (NDM). IS-NGT and IR-NGT were defined as the first and fourth quartile of fasting insulin in NGT individuals.ResultsGlucose ingestion induced multiple metabolic responses, including increased glycolysis intermediates and decreased branched-chain amino acids, ketone bodies, glycerol, and triglycerides. The IR-NGT subgroup showed smaller responses for these measures (mean + 23%, interquartile 9–34% at 120 min) compared to IS-NGT (34%, 23–44%, P < 0.0006 for difference, corrected for multiple testing). No
Mitchell RN, Ashar FN, Jarvelin M-R, et al., 2019, Effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death, Journal of the American Heart Association, Vol: 8, Pages: 1-27, ISSN: 2047-9980
BackgroundSudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk.Methods and ResultsWe examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis.ConclusionsWhile individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.
Lumme J, Sebert S, Pesonen P, et al., 2019, Vitamin D levels in women with polycystic ovary syndrome: a population-based study, Nutrients, Vol: 11, Pages: 1-14, ISSN: 2072-6643
Background: Conflicting evidence supports a role for vitamin D in women with reproductive disorders such as polycystic ovary syndrome (PCOS) but studies on large, unselected populations have been lacking. Methods: We conducted a general population-based study from the prospective Northern Finland Birth Cohort 1966 (NFBC1966). Serum 25-hydroksyvitamin D (25(OH)D) levels were evaluated in women with self-reported PCOS (n = 280) versus non-symptomatic controls (n = 1573) at the age of 31 with wide range of endocrine and metabolic confounders. Results: The levels of 25(OH)D were similar among women with and without self-reported PCOS (50.35 vs. 48.30 nmol/L, p = 0.051). Women with self-reported PCOS presented with a higher body mass index (BMI), increased insulin resistance, and low-grade inflammation and testosterone levels compared to controls. The adjusted linear regression model showed a positive association between total 25(OH)D levels in self-reported PCOS (β = 2.46, 95% confidence interval (CI) 0.84 to 4.08, p = 0.003). The result remained after adjustment for BMI, testosterone, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hs-CRP) levels. Conclusion: In this population-based setting, PCOS was associated with higher vitamin D levels when adjusting for confounding factors, without distinct beneficial effects on metabolic derangements.
Karvonen R, Sipola M, Kiviniemi AM, et al., 2019, Postexercise heart rate recovery in adults born preterm, Journal of Pediatrics, Vol: 214, Pages: 89-95.e3, ISSN: 0022-3476
ObjectiveTo evaluate postexercise heart rate recovery (HRR) in adults born preterm.Study designWe studied the association between preterm birth and postexercise HRR in 545 adults (267 women) at 23.3 years of age (range 19.9-26.3 years). One hundred three participants were born early preterm (<34 completed weeks), 178 late preterm (34-36), and 264 were full term (control group). HRR was calculated as change in heart rate (HR) 30 seconds and 60 seconds after cessation of submaximal step test and maximum HR slope during the first minute after.ResultsMean peak HR was 159.5 bpm in the early preterm (P = .16 with controls), 157.8 bpm in the late preterm (P = .56), and 157.0 bpm in the control group. Mean HRR 30 seconds after exercise was 3.2 bpm (95% CI 1.1-5.2) lower in the early preterm group and 2.1 bpm (0.3-3.8) lower in the late preterm group than the full term controls. Mean 60s HRR was 2.5 (−0.1 to 5.1) lower in the early preterm group and 2.8 bpm (0.6-4.9) lower in the late preterm group. Mean maximum slope after exercise was 0.10 beats/s (0.02-0.17) lower in the early preterm group and 0.06 beats/s (0.00-0.12) lower in the late preterm group.ConclusionsOur results suggest reduced HRR after exercise in adults born preterm, including those born late preterm. This suggests altered reactivation of the parasympathetic nervous system, which may contribute to cardiovascular risk among adults born preterm.
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