LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our “modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.</p

Metabolic health and obesity: early determinants, trajectories and causal analysis:the Northern Finland Birth Cohort 1966 and 1986 studies

Abstract The obesity epidemic has grown over the last four decades in most European countries including Finland where 21.5% of women and 20% of men are now living with obesity. There is a large body of evidence establishing that the first years of life, including the foetal period, are critical for obesity and general health later in life. However, a better understanding of the link between early life determinants and the life-course trajectory of obesity is needed. In this thesis, associations between early life determinants and cardio-metabolically healthy obesity, defined as obesity in the absence of any cardiometabolic disorders, were investigated. The relationships between early life determinants and developmental body mass index (BMI) trajectories were explored. Finally, the associations between temperament traits and cardiovascular health and whether eating behaviours and fitness mediated the associations were examined. The research was conducted on data from the prospective Northern Finland Birth Cohorts 1966 (NFBC1966) and 1986 (NFBC1986) using association analyses, latent trajectory modelling and causal mediation analysis. The first study suggested that early life determinants such as age at adiposity rebound were associated with cardio-metabolically healthy obesity and that the association differed between males and females. In the second study, developmental BMI trajectories were modelled from NFBC1966 and NFBC1986. Adverse maternal factors were associated with unfavourable BMI trajectories. A different pattern of association between age at adiposity peak and BMI trajectories was found between the different cohorts, uncovering secular trends. The third study provided evidence that associations between temperament traits, established early in life, and cardiovascular health measures could be sex-specific. Furthermore, eating behaviours and mediators involved in the associations seemed to be associated with sex. The research undertaken in this thesis provides evidence to support the effect of early life determinants on life-course metabolic health and highlights the role of sex in these pathways. In addition, this work further advances the importance of psychological factors in relation to metabolic health with a specific focus on sex-specific temperament and behavioural mediators.Tiivistelmä Lihavuus on yleistynyt viimeisen neljän vuosikymmenen aikana useimmissa Euroopan maissa, myös Suomessa. Suomessa naisista 21,5 % ja miehistä 20 % on ylipainoisia. Aiempien tutkimusten mukaan ensimmäiset elinvuodet, sikiökausi mukaan luettuna, ovat tärkeitä myöhemmän lihavuuden ja yleisen terveyden kannalta. Tieto elämän varhaisvaiheisiin liittyvien tekijöiden ja lihavuuden kehityksen välisestä yhteydestä on kuitenkin puutteellista. Tämän väitöskirjan ensimmäisessä osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden yhteyttä kardiometabolisesti terveeseen lihavuuteen, joka määritellään lihavuudeksi ilman verenkiertoelimistön sairauksia tai niiden tunnettuja riskitekijöitä. Toisessa osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden ja painoindeksin kehityskaarten välisiä suhteita. Viimeisessä osatyössä tutkittiin temperamentin ja metabolisen terveyden, veren rasva-arvojen, välisiä yhteyksiä sekä näiden yhteyksien välittymistä syömiskäyttäytymisen ja fyysisen kunnon kautta. Tutkimus tehtiin Pohjois-Suomen syntymäkohorteissa 1966 (NFBC1966) ja 1986 (NFBC1986) käyttäen assosiaatioanalyysejä, latenttikasvukäyrämallinnusta sekä kausaalisuhdeanalyysejä. Ensimmäisessä osatyössä havaittiin, että elämän varhaisvaiheiden tekijät vaikuttivat kardiometabolisesti terveeseen lihavuuteen. Tällainen tekijä oli esimerkiksi ikä, jossa leikki-ikäisen lapsen painoindeksi on pienin ennen kuin se alkaa jälleen kasvaa (engl. adiposity rebound). Vaikutus oli kuitenkin erilainen miehillä ja naisilla. Toisessa tutkimuksessa painoindeksin kehityskaaret mallinnettiin NFBC1966 ja NFBC1986 -kohorteissa. Äidin tupakointi ja raskautta edeltänyt korkeampi painoindeksi olivat yhteydessä lapsen epäsuotuisaan painoindeksin kehityskaareen. Yhteys imeväisiän painoindeksin kasvukäyrän huipun ajoittumisen ja mallinnetun painoindeksin kehityskaaren välillä oli kohorteissa erilainen, mikä viittaa aikakaudellisiin ympäristön vaikutuksiin. Kolmannessa työssä tutkittiin erilaisia temperamenttipiirteitä, jotka myös ilmenivät varhaisella iällä. Työ osoitti, että temperamentti on yhteydessä veren rasva-arvoihin, mutta osin eri tavoin eri sukupuolilla. Lisäksi havaittiin miesten ja naisten välisiä eroja siinä, miten elintavat välittivät temperamenttipiirteiden ja veren rasva-arvojen välisiä yhteyksiä. Tämän väitöskirjan tulokset tarjoavat lisänäyttöä elämän varhaisvaiheen tekijöiden yhteyksistä metaboliseen terveyteen läpi elämän ja korostavat sukupuolten välisiä eroja. Tulokset vahvistavat käsitystä metaboliseen terveyteen vaikuttavien tekijöiden monimuotoisuudesta temperamentista terveyskäyttäytymiseen läpi elämän

Maternal and infant prediction of the child BMI trajectories:studies across two generations of Northern Finland birth cohorts

Abstract Background/objective: Children BMI is a longitudinal phenotype, developing through interplays between genetic and environmental factors. Whilst childhood obesity is escalating, we require a better understanding of its early origins and variation across generations to prevent it. Subjects/methods: We designed a cross-cohort study including 12,040 Finnish children from the Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986) born before or at the start of the obesity epidemic. We used group-based trajectory modelling to identify BMI trajectories from 2 to 20 years. We subsequently tested their associations with early determinants (mother and child) and the possible difference between generations, adjusted for relevant biological and socioeconomic confounders. Results: We identified four BMI trajectories, ‘stable-low’ (34.8%), ‘normal’ (44.0%), ‘stable-high’ (17.5%) and ‘early-increase’ (3.7%). The ‘early-increase’ trajectory represented the highest risk for obesity. We analysed a dose-response association of maternal pre-pregnancy BMI and smoking with BMI trajectories. The directions of effect were consistent across generations and the effect sizes tended to increase from earlier generation to later. Respectively for NFBC1966 and NFBC1986, the adjusted risk ratios of being in the early-increase group were 1.08 (1.06–1.10) and 1.12 (1.09–1.15) per unit of pre-pregnancy BMI and 1.44 (1.05–1.96) and 1.48 (1.17–1.87) in offspring of smoking mothers compared to non-smokers. We observed similar relations with infant factors including birthweight for gestational age and peak weight velocity. In contrast, the age at adiposity peak in infancy was associated with the BMI trajectories in NFBC1966 but did not replicate in NFBC1986. Conclusions: Exposures to adverse maternal predictors were associated with a higher risk obesity trajectory and were consistent across generations. However, we found a discordant association for the timing of adiposity peak over a 20-year period. This suggests the role of residual environmental factors, such as nutrition, and warrants additional research to understand the underlying gene–environment interplay

Body size during adulthood, but not in childhood, associates with endometriosis, specifically in the peritoneal subtype:population-based life-course data from birth to late fertile age

Abstract Introduction: Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exist on body size during childhood and adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes. Material and methods: This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on (a) the World Health Organization’s International Statistical Classification of Diseases code documentation from national hospital discharge registers and (b) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth, and growth data up to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 years through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size were assessed using logistic regression models. Results: Body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (odds ratio [OR] 0.98, 95% CI 0.97–1.00) and 6% lower for every body mass index unit (OR 0.94, 95% CI 0.90–0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR 0.95, 95% CI 0.92–0.98), weight gain from age 14 to age 46 years (OR 0.97, 95% CI 0.93–1.00), body mass index (OR 0.90, 95% CI 0.82–0.98), waist circumference (OR 0.95, 95% CI 0.92–0.99), and waist-hip ratio (OR 0.41, 95% CI 0.21–0.78). Conclusions: This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence

The relationship of life-course patterns of adiposity with type 2 diabetes, depression, and their comorbidity in the Northern Finland Birth Cohort 1966

Abstract Objectives: Type 2 diabetes (T2D) and comorbid depression challenges clinical management particularly in individuals with overweight. We aim to explore the shared etiology, via lifecourse adiposity, between T2D and depression. Methods: We used data from birth until 46years from Northern Finland Birth Cohort 1966 (n = 6,372; 53.8% females). We conducted multivariate analyses on three outcomes: T2D (4.2%), depression (19.2%) and as comorbidity (1.8%). We conducted (i) Path analysis to clarify time-dependent body mass index (BMI) related pathways, including BMI polygenic risk scores (PRS); and (ii) Cox regression models to assess whether reduction of overweight between 7years and 31years influence T2D, depression and/or comorbidity. The models were tested for covariation with sex, education, smoking, physical activity, and diet score. Results: The odd ratios (OR) of T2D in individuals with depression was 1.68 [95% confidence interval (CI): 1.34–2.11], and no change in estimate was observed when adjusted for covariates. T2D and comorbidity showed similar patterns of relationships in the path analyses (P &lt; 0.001). The genetic risk for obesity (PRS BMI) did not show direct effect on T2D or comorbidity in adulthood but indirectly through measures of adiposity in early childhood and mid-adulthood in the path analysis (P &lt; 0.001). Having early-onset of overweight at 7years and 31years showed highest risk of T2D (OR 3.8, 95%CI 2.4–6.1) and comorbidity (OR 5.0, 95%CI 2.7–9.5), with mild-to-moderate attenuation with adjustments. Depression showed no significant associations. Conclusions: We found evidence for overweight since childhood as a risk factor for T2D and co-morbidity between T2D and depression, influenced moderately by lifestyle factors in later life. However, no shared early life adiposity related risk factors were observed between T2D and depression when assessed independently in this Finnish setting

Early childhood growth and risk of adult cerebrovascular disease:the NFBC1966

Abstract Background: Low birth weight is associated with an increased risk of adulthood cerebrovascular disease (CVD). Not much is known about effects of early childhood growth. We studied whether the risk of adult CVD is associated with growth or nutritional factors during early childhood. Methods: Within the Northern Finland Birth Cohort 1966, 11 991 persons were followed from birth to 52 years of age. CVD diagnoses were extracted from national hospital and death registers with diagnostic coding based on the World Health Organization recommendations. Cox proportional hazard models were used to estimate associations of childhood growth variables, growth trajectories (by Latent Class Growth Modeling), and nutritional factors with adult CVD, for example, ischemic and hemorrhagic strokes. The analyses were adjusted for childhood socioeconomic status and birth weight. Results: A total of 453 (3.8%) CVDs were recorded during follow-up. Among females, groups with low early childhood weight and height had an increased risk for adulthood ischemic CVDs, with an adjusted hazard ratio of 1.97 (95% CI, 1.21–3.20) and 2.05 (CI, 1.11–3.81), respectively. In addition, females with body mass index over 1 SD at body mass index rebound had an increased risk for ischemic CVDs (adjusted hazard ratio, 1.90 [CI, 1.19–3.04]) compared with females with body mass index −1 to +1 SD. These associations were not found among males. Conclusions: The findings suggest that timing of weight gain during childhood is of significance for development of CVD risk among females

Accumulated exposure to unemployment is related to impaired glucose metabolism in middle-aged men:a follow-up of the Northern Finland Birth Cohort 1966

Abstract Aims: We explored whether registered unemployment is associated with impaired glucose metabolism in general population. Methods: Based on Northern Finland Birth Cohort 1966 at 46 years, we analyzed the oral glucose tolerance tests of 1970 men and 2544 women in relation to their preceding three-year employment records in three categories of unemployment exposure: no (employed), low (≤1-year) and high exposure (&gt;1-year). Results: Among men, pre-diabetes was found in 19.2% of those with no unemployment, 23.0% with low and 27.0% with high exposure, the corresponding figures for screen-detected type 2 diabetes were 3.8%, 3.8% and 9.2% (p &lt; 0.01). Among women, analogous figures for pre-diabetes were 10.0%, 12.6% and 16.2% and for screen-detected type 2 diabetes 1.7%, 3.4% and 3.6% (p &lt; 0.01). Men with high exposure to unemployment had a higher risk for pre-diabetes (OR 1.61, CI 95% 1.03–2.51) and screen-detected type 2 diabetes (OR 2.58 95% CI 1.23–5.44) than employed men, after adjustment for education, smoking, alcohol intake, physical activity and body mass index. Among women, associations were attenuated in the adjusted models. Conclusions: High exposure to unemployment may predispose to type 2 diabetes in middle-aged men. For clinicians, awareness of the patient’s unemployment status may be helpful in recognizing undiagnosed cases

Towards early risk biomarkers:serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood

Summary Background: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. Methods: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). Findings: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p&lt;0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p&lt;0·01) and males (AUC = 0·734‒0·889, all p&lt;0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p&lt;0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. Interpretation: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated

Possible modifiers of the association between change in weight status from child through adult ages and later risk of type 2 diabetes

Abstract Objective: We investigated the association between changes in weight status from childhood through adulthood and subsequent type 2 diabetes risks and whether educational attainment, smoking, and leisure time physical activity (LTPA) modify this association. Research design and methods: Using data from 10 Danish and Finnish cohorts including 25,283 individuals, childhood BMI at 7 and 12 years was categorized as normal or high using age- and sex-specific cutoffs (&lt;85th or ≥85th percentile). Adult BMI (20–71 years) was categorized as nonobese or obese (&lt;30.0 or ≥30.0 kg/m², respectively). Associations between BMI patterns and type 2 diabetes (989 women and 1,370 men) were analyzed using Cox proportional hazards regressions and meta-analysis techniques. Results: Compared with individuals with a normal BMI at 7 years and without adult obesity, those with a high BMI at 7 years and adult obesity had higher type 2 diabetes risks (hazard ratio [HR]girls 5.04 [95% CI 3.92–6.48]; HRboys 3.78 [95% CI 2.68–5.33]). Individuals with a high BMI at 7 years but without adult obesity did not have a higher risk (HRgirls 0.74 [95% CI 0.52–1.06]; HRboys 0.93 [95% CI 0.65–1.33]). Education, smoking, and LTPA were associated with diabetes risks but did not modify or confound the associations with BMI changes. Results for 12 years of age were similar. Conclusions: A high BMI in childhood was associated with higher type 2 diabetes risks only if individuals also had obesity in adulthood. These associations were not influenced by educational and lifestyle factors, indicating that BMI is similarly related to the risk across all levels of these factors

LongITools:dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases

Abstract The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our ”modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases