Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Chronotype and metabolic syndrome in midlife: findings from the Northern Finland Birth Cohort 1966.

Evening chronotype is known to be associated with various chronic diseases and cardiovascular risk factors. Metabolic syndrome is a group of conditions that together raise the risk of coronary heart disease, diabetes, stroke, and other serious health problems. Only a few studies have been published on the association between chronotype and metabolic syndrome in unselected population data, with conflicting results. The aim of this study was to evaluate the association between chronotype and metabolic syndrome at population level by using unselected Northern Finland Birth cohort 1966 (NFBC1966) database. The study population consists of participants with NFBC66 (n = 5,113, 57% female) at the age of 46 yr old. Chronotype was determined with shortened Morningness-Eveningness Questionnaires and expressed as morning (44%), intermediate (44%), and evening types (12%). Metabolic syndrome was determined according to the definition of International Diabetes Federation. One-way ANOVA, Kruskal-Walli's test, and χ2 tests were used to compare the chronotype groups, followed by logistic regression analysis (adjusted with alcohol consumption, smoking, marital status, level of education, and leisure-time physical activity). In women, the prevalence of metabolic syndrome was statistically significantly higher in the evening type group: 23, 24, and 34% for morning, intermediate, and evening groups, respectively (P < 0.001). In logistic regression analysis, evening chronotype was associated with higher risk of having metabolic syndrome (OR 1.5; CI 95% 1.2 to 2.0). In this population-based birth cohort study, the evening chronotype was independently associated with higher prevalence of metabolic syndrome in women.NEW & NOTEWORTHY Only a few studies have been conducted on the association between chronotype and metabolic syndrome in unselected population data, with conflicting results. In this population-based cohort study of 5,113 participants, the evening chronotype associated with metabolic syndrome in women when there was no such association in men. The result supports a previous South Korean population study of 1,620 participants, in which the association was also found in women, but not in men.

Women with a history of gestational diabetes mellitus present an accumulation of cardiovascular risk factors at age 46-A birth cohort study.

INTRODUCTION: The incidence of gestational diabetes mellitus (GDM) is globally increasing, and it has been associated with later type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, long-term population-based studies investigating common CVD risk factors years after pregnancy are lacking. To evaluate the future mortality and morbidity in cardiovascular and metabolic diseases, we conducted a thorough investigation of midlife risk factors in women with and without previous GDM. MATERIAL AND METHODS: A prospective population-based cohort study was conducted of 3173 parous women from the Northern Finland Birth Cohort, 1966. Study participants were obtained from the national register or patient records. Those with a GDM diagnosis formed the GDM cohort (n = 271), and those without a previous GDM diagnosis formed the control cohort (n = 2902). Clinical examinations were performed on participants at the age of 46 and included anthropometric measurements, oral glucose tolerance test (OGTT), biochemical measurements, and cardiovascular assessment. RESULTS: At the age of 46, women in the GDM cohort had a higher body mass index (BMI, 29.0 kg/m2 vs 26.3 kg/m2, p < 0.001) and greater waist circumference (94.1 cm vs 86.5 cm, p < 0.001) than the control cohort. In the GDM cohort, a higher incidence of impaired glucose tolerance (12.6% vs 7.3%, p = 0.002), more previously diagnosed and OGTT-detected type 2 diabetes (23.3% vs 3.9%, p < 0.001), lower high-density lipoprotein (1.53 mmol/L vs 1.67 mmol/L, p = 0.011), higher triglycerides (1.26 mmol/L vs 1.05 mmol/L, p = 0.002) and a higher fatty liver index (6.82 vs 2.47, p < 0.001), were observed even after adjusting for BMI, polycystic ovary syndrome, parity, level of education, physical activity, smoking, and alcohol consumption. The women in the GDM cohort also had more MetS (42.6% vs 21.9%, p < 0.001) and higher risk scores for CVD and fatal events (Framingham 4.95 vs 3.60, p < 0.001; FINRISK 1.71 vs 1.08, p < 0.001). CONCLUSIONS: Women with a previous diagnosis of GDM exhibit more risk factors for CVD in midlife and are at a higher risk for cardiovascular events later in life.

Health status and quality of life before critical illness: Northern Finland Birth Cohort 1966 study.

BACKGROUND: Previous findings support the claim intensive care unit (ICU) patients have a higher rate of comorbidities and reduction of health- and functional status compared with the normal population. AIM: In this prospective observational study, our aim was to determine those health-related factors at the age of 31 years which were associated with a later critical illness among previously un-hospitalized individuals by exploring data obtained from the Northern Finland Birth Cohort 1966 (NFBC1966). METHODS: NFBC1966 is a Finnish birth cohort, which includes 12,058 live births with expected dates of delivery during 1966. The study was conducted among cohort participants who had not been hospitalized for any reason before the cohort follow-up visit at the age of 31. The study group included NFBC1966 participants who were admitted to the ICU of the Oulu University Hospital. The control group included participants who were treated for any reason in regular hospital wards. The data considering the participants' health status and behavior at the age of 31 were collected from the NFBC1966 database. The gathering of ICU and hospitalization data was concluded on December 31, 2016. RESULTS: 849 NFBC1966 participants met the inclusion criteria: 69 were treated in the ICU (study group) and 780 on regular hospital wards (controls). In the study group, the rate of neurological diseases (26% vs. 16%, 95% CI: -21.8%, -0.2%), malignancy (3% vs. 0.7%, 95% CI: -9.7%, 0.0%), alcohol abuse (4.5% vs. 1%, 95% CI: -11.5%, -0.3%) and smoking (77% vs. 65%, 95% CI: -21.6%, -0.3%) were higher compared with the control group. The patients in the ICU group were also more prone to violent injuries, (17% vs. 7%, 95% CI: -20.2%, -1.9%), practiced less hard physical activity (65% vs. 78%, 95% CI: 2.1%, 25.3%) and had lower maximal muscle strength according to the hand grip test (30 vs. 34 kg, 95% CI: -8.2, 8.6 kg). CONCLUSIONS: In this study examining previously un-hospitalized patients, the main factors associated with future critical illness were neurological comorbidities, malignancy, alcohol misuse, smoking, low maximum muscle strength, and less frequent physical exercise compared with those with hospitalization not requiring ICU admission.

Cross-sectional analysis of depressive symptom profiles and serum C-reactive protein levels: data from the Northern Finland 1966 birth cohort.

PURPOSE: Individuals with depression exhibit significantly higher levels of systemic inflammation than those without depression, particularly among those with atypical depression. However, this association has been less convincing at the population level among individuals without a formal depression diagnosis but with suggestive symptoms. Our aim was to clarify this association. MATERIALS AND METHODS: In a large birth cohort sample of the Finnish general population, we examined the cross-sectional association between high-sensitivity C-reactive protein (hsCRP) levels in venous blood samples and atypical/non-atypical depressive symptoms using the Beck Depression Inventory-II to screen 5443 middle-aged participants. RESULTS: As expected, depressive symptoms associated to elevated hsCRP-levels compared to non-depressed. Participants with the atypical subtype of depressive symptoms (n = 84) had an odds ratio (OR) of 2.59 (95% CI 1.40-4.81) for elevated hsCRP levels compared to the non-depressed group. Similarly, our findings indicate that participants with non-atypical symptoms (n = 440) also showed an OR of 1.42 (95% CI 1.05-1.92) when compared to the non-depressed group (n = 4919). CONCLUSIONS: These results provide additional support for previous research linking depression and inflammation and add to the field with a unique and sizeable study population. Furthermore, the current results support the notion that different types of depressive symptoms may be associated with inflammatory markers in slightly different ways.

Body mass index in the middle-aged offspring of parents with severe mental illness.

BACKGROUND: People with severe mental illness (SMI) have an elevated risk of obesity but the causes and mechanisms are unclear. We explored the familial association between parental SMI and body mass index (BMI) in middle-aged offspring. Our objective was to determine if the offspring of either parent with SMI have an increased risk for obesity. METHODS: The Northern Finland Birth Cohort 1966 is a cohort study of offspring with expected date of birth in 1966. The data include originally 12 068 mothers and 12 231 children from the provinces of Lapland and Oulu in Finland. The final study sample included 5050 middle-aged offspring. Parental SMI was used as exposure in the study. BMI measured at the age of 46 years was used as a primary outcome. RESULTS: Risk for obesity was elevated in the offspring of mothers with SMI [overweight: adjusted odds ratio (OR) 1.93 (1.29-2.90), obese class I: 1.97 (1.20-3.25), obese classes II-III: 2.98 (1.67-5.33)]. For the offspring of either parent with SMI, statistically significant results were found in obese class I and obese classes II-III [overweight: adjusted OR 1.21 (0.94-1.54), obese class I: 1.52 (1.03-1.08), obese classes II-III: 1.53 (1.01-2.32)]. CONCLUSIONS: We found an elevated risk of obesity in the middle-aged offspring of either parent with SMI, especially in the offspring of mothers with SMI. Thus, there might be a common familial pathway leading to the co-occurrence of obesity and SMI.

Former long-term use of combined hormonal contraception and glucose metabolism disorders in perimenopausal women: A prospective, population-based cohort study.

INTRODUCTION: Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND METHODS: This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). RESULTS: Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. CONCLUSIONS: Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis.

BACKGROUND: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. METHODS: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). RESULTS: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. CONCLUSIONS: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Cardiometabolic Disorders in the Offspring of Parents With Severe Mental Illness.

OBJECTIVE: The elevated prevalence of cardiometabolic disorders is consistently reported in patients with severe mental illness (SMI). We explored the association between parental SMI and offspring cardiometabolic morbidity. Our hypothesis was that offspring of people with SMI have increased morbidity risk. METHOD: The Northern Finland Birth Cohort 1966 is a study of offspring whose date of birth was expected in 1966. The follow-up lasted until 2015 (49 years). The final study sample included 11,175 children. We used parental SMI as the exposure in the study. The following cardiometabolic disorders were used as outcome measures: diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, obesity, and cerebrovascular disorders. RESULTS: There were 139 (14.7%; hazard ratios [HR] = 1.63; 95% confidence interval [CI] = 1.36-1.94) children of parents with SMI who developed cardiometabolic disorder during follow-up and 957 (9.4%) in the comparison cohort. Statistically significant HRs were found in males (HR = 1.95; 95% CI =1.56-2.44), but not in females (HR = 1.29; 95% CI = 0.96-1.73). CONCLUSIONS: Having a cardiometabolic disorder was associated with male offspring of parents with SMI. Our findings suggest that there is an elevated risk of coronary artery disease, hyperlipidemia, obesity, and hypertension in the male offspring of parents with SMI. Our results suggest that the somatic health of offspring of parents with SMI should also be considered in addition to their mental health in clinical practice.

Nonalcoholic fatty liver disease and its prognosis associates with shorter leucocyte telomeres in a 21-year follow-up study.

Leucocyte telomere length (LTL) has been associated with nonalcoholic fatty liver disease (NAFLD), but the evidence is imperfect. Furthermore, liver fibrosis has been shown to correlate with mortality and recent studies have also found associations with LTL and fibrosis suggesting that LTL may have additional prognostic value in liver diseases. Our objective was to study the association of LTL and NAFLD and evaluate the association of LTL in prognosis of NAFLD subjects. Study subjects (n = 847) were middle-aged hypertensive patients. All participants were evaluated for NAFLD and their LTL was measured at baseline. Outcomes were obtained from Finnish Causes-of-Death Register and the Care Register for Health Care in Statistics Finland to the end of 2014. An inverse association with NAFLD prevalence and LTL length was observed (p < .001 for trend). Shortest telomere tertile possessed statistically significantly more NAFLD subjects even with multivariate analysis (shortest vs. middle tertile HR 1.98 p = .006 and shortest vs. longest tertile HR 2.03 p = .007). For the study period, mortality of the study group showed statistically significant relation with telomere length in univariate but not for multivariate analysis. In subgroup analysis, LTL did not associate with prognosis of non-NAFLD subjects. However, LTL was inversely associated with overall mortality in the subjects with NAFLD in both univariate (HR 0.16 p = .007) and multivariate analysis (HR 0.20 p = .045). In middle-aged Caucasian cohort, shorter leucocyte telomeres associated independently with increased prevalence of NAFLD. Shorter LTL was not associated with mortality in non-NAFLD patients whereas it predicted mortality of NAFLD patients independently.

Association of long-term obesity and weight gain with periodontal pocketing: Results of the Northern Finland Birth Cohort 1966 study.

AIM: To investigate whether obesity, central obesity, and weight gain are associated with periodontal pocketing. MATERIALS AND METHODS: A never-smoking sub-population (n = 725) of the Northern Finland Birth Cohort 1966 was categorized based on body mass index (BMI; participants with normal weight, overweight, and obesity) and waist circumference (WC; participants without central obesity and with central obesity) at ages 31 and 46. The categories were combined to define whether the participants stayed in the respective BMI and WC categories or moved on to a higher category during follow-up. A periodontal examination was done at age 46. RESULTS: WC was more consistently associated with periodontal pocketing than BMI. The relative risks for the number of sites with periodontal pocket depth (PPD) ≥4 mm and bleeding PPD ≥4 mm in participants with central obesity both at age 31 and at age 46 were 1.7 (95% confidence interval [CI] 1.4-2.0) and 2.1 (95% CI 1.6-2.6). The corresponding values for participants who had no central obesity at age 31 but had central obesity at age 46 were 1.6 (95% CI 1.4-1.8) and 1.9 (95% CI 1.6-2.3). CONCLUSION: Of all the studied measures, central obesity appeared to be most strongly associated with the inflammatory condition of the periodontium.

Association of hyperglycaemia with periodontal status: Results of the Northern Finland Birth Cohort 1966 study.

AIM: To investigate the association of hyperglycaemia and changes in glycaemic control with periodontal status in non-diabetic individuals. MATERIALS AND METHODS: A sub-population (n = 647) of the Northern Finland Birth Cohort 1966 was studied. We categorized long-term glucose balance based on fasting plasma glucose (FPG) at ages 31 and 46: FPG <5.0 mmol/l (strict normoglycaemia), FPG 5.0-5.59 mmol/l (slightly elevated FPG) and FPG 5.6-6.9 mmol/l (prediabetes). Probing pocket depth (PPD) and alveolar bone level (BL) data were collected at age 46. Relative risks (RR, 95% CI) were estimated using Poisson regression models. RESULTS: Periodontal status was poorer in individuals whose glucose balance worsened from age 31 to 46 years than in those with a stable glucose balance. In the case of strict normoglycaemia at age 31 and slightly elevated FPG or prediabetes at age 46, the RRs for PPD ≥4 mm were 1.8 (95% CI 1.4-2.2) and 2.8 (95% CI 2.0-3.8) and for BL ≥5 mm 1.1 (95% CI 0.8-1.4) and 1.8 (95% CI 1.2-2.8), respectively. CONCLUSION: The results of this population-based cohort study suggest that impairment in glucose control in non-diabetic individuals is associated with periodontal pocketing and alveolar bone loss.

Alcohol consumption is associated with a later need for ICU admission: a Northern Finland Birth Cohort 1966-study.

BACKGROUND: Alcohol-related problems are common in intensive care unit (ICU) admitted patients. The aim of the present study is to assess the impact of alcohol consumption on the need of intensive care in 19 years follow-up period. METHODS: The study population consists of Northern Finland Birth Cohort 1966 participants, who responded alcohol-related questions at 31 years of age and Intensive Care Unit (ICU admissions from 1997 to 2016. RESULTS: There were a total of 8379 assessed people and 136 (1.6%) of them were later admitted to ICU. A total of 44 (32.4%) of the ICU-admitted persons had their alcohol consumption at the highest quartile of the cohort (P = 0.047). These patients had a lower number of malignancy-related admissions (3.6% versus 14.0%, P = 0.027), neurological admissions (14.3 versus 30.6%, P = 0.021), and were more often admitted due to poisonings (12.5% versus 5.0%, P = 0.07). There were no differences in 28-day post-ICU mortality but long-term mortality of ICU-admitted patients with lower alcohol consumption was higher than non-ICU-admitted population. CONCLUSION: Among ICU-admitted population, there was higher alcohol consumption at age of 31 years. People in the lower alcohol consumption quartiles were more often admitted to ICU due to malignancy-related causes and they had higher long-term mortality.

Type 1 and type 2 diabetes after gestational diabetes: a 23 year cohort study.

AIMS/HYPOTHESIS: The aim of this work was to examine the progression to type 1 and type 2 diabetes after gestational diabetes mellitus (GDM) in a 23 year follow-up study. METHODS: We carried out a cohort study of 391 women with GDM diagnosed by an OGTT or the use of insulin treatment during pregnancy, and 391 age- and parity-matched control participants, who delivered in 1984-1994 at the Oulu University Hospital, Finland. Diagnostic cut-off levels for glucose were as follows: fasting, ≥4.8 mmol/l; 1 h, ≥10.0 mmol/l; and 2 h, ≥8.7 mmol/l. Two follow-up questionnaires were sent (in 1995-1996 and 2012-2013) to assess the progression to type 1 and type 2 diabetes. Mean follow-up time was 23.1 (range 18.7-28.8) years. RESULTS: Type 1 diabetes developed (5.7%) during the first 7 years after GDM pregnancy and was predictable at a 2 h OGTT value of 11.9 mmol/l during pregnancy (receiver operating characteristic analysis: AUC 0.91, sensitivity 76.5%, specificity 96.0%). Type 2 diabetes increased linearly to 50.4% by the end of the follow-up period and was moderately predictable with fasting glucose (AUC 0.69, sensitivity 63.5%, specificity 68.2%) at a level of 5.1 mmol/l (identical to the fasting glucose cut-off recommended by the International Association of Diabetes and Pregnancy Study Groups [IADPSG) and WHO]). CONCLUSIONS/INTERPRETATION: All women with GDM should be intensively monitored for a decade, after which the risk for type 1 diabetes is minimal. However, the incidence of type 2 diabetes remains linear, and therefore individualised lifelong follow-up is recommended.

Maternal smoking during pregnancy affects adult onset of asthma in offspring: a follow up from birth to age 46†years.

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.

Early Growth Patterns and Cardiac Structure and Function at Midlife: Northern Finland 1966 Birth Cohort Study.

OBJECTIVES: To 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 DESIGN: A 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 (ß) or OR with 95% CIs for 1 SD increase in early growth variable. RESULTS: Earlier adiposity rebound was associated with increased LV mass index (ß = -4.10 g/m2 (-6.9, -1.3); P = .004) and LV end-diastolic volume index (ß = -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 (ß = 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 (ß = 1.47 mL/m2; [0.51, 2.4], ß = 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. CONCLUSIONS: Early growth patterns in infancy and childhood contribute to cardiac structure at midlife.

Overweight, obesity and hyperandrogenemia are associated with gestational diabetes mellitus: A follow-up cohort study.

INTRODUCTION: The aim of the study was to determine the association of body mass index (BMI), self-reported symptoms or diagnosis of polycystic ovary syndrome (PCOS), and hyperandrogenemia with the occurrence of gestational diabetes mellitus (GDM) through reproductive life. MATERIAL AND METHODS: A cohort of women born in 1966 were investigated at ages 14, 31 and 46. Women with self-reported PCOS symptoms (presence of both oligo-amenorrhea and hirsutism) at age 31 or with formally diagnosed polycystic ovaries (PCO)/PCOS by age 46 formed the group of self-reported PCOS (srPCOS, n = 222) and were compared with women without self-reported PCOS symptoms or diagnosis (n = 1357). We investigated also the association of hyperandrogenism (hirsutism or biochemical hyperandrogenism) at age 31 with the occurrence of GDM throughout reproductive life. RESULTS: Self-reported PCOS alone was not a risk factor for GDM, but combined with overweight at age 31 (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.22-4.86) or 46 (OR 3.04, 95% CI 1.58-5.83) srPCOS was associated with GDM when compared with normal weight controls. The association disappeared when comparing overweight srPCOS women with overweight controls. However, hyperandrogenemia at age 31, but not hirsutism, was associated with GDM even after adjustment for BMI. CONCLUSIONS: The increased risk of GDM in women with srPCOS was mostly attributed to overweight or obesity. Importantly, normal weight women with srPCOS did not seem to be at increased risk for developing GDM. However, hyperandrogenemia was associated with GDM even after adjustment for BMI. These findings strengthen the importance of weight management in reproductive-age women and suggest a noteworthy role of hyperandrogenemia in the pathophysiology of GDM.

Accumulated unhealthy behaviors and psychosocial problems in adolescence are associated with labor market exclusion in early adulthood - a northern Finland birth cohort 1986 study.

BACKGROUND: The relevance of health-related behaviors to exclusion from the labor market in early adulthood remains poorly studied in relation to the magnitude of the problem. We explored whether adolescents' accumulated unhealthy behaviors and psychosocial problems are associated with later labor market exclusion, and whether multisite musculoskeletal pain (MMSP) impacts these relations. METHODS: We gathered questionnaire data on unhealthy behaviors and psychosocial problems and MMSP among adolescents aged 15 to 16 belonging to the Northern Finland Birth Cohort 1986. The findings were combined with registry data on unemployment, employment and permanent work disability during a five-year follow-up between the ages of 25 and 29 (n = 6692). In the statistical modeling we used education, family leave and socioeconomic status of childhood family as potential confounders, as well as latent class and logistic regression analyses. RESULTS: The Externalizing behavior cluster associated with over one year of unemployment (RR 1.64, CI 1.25-2.14) and permanent work disability (OR 2.49, CI 1.07-5.78) in the follow-up among the men. The Sedentary cluster also associated with over one year (RR 1.41, CI 1.13-1.75) and under one year of unemployment (RR 1.25, CI 1.02-1.52) and no employment days (RR 1.93, CI 1.26-2.95) among the men. Obese male participants were at risk of over one year of unemployment (RR 1.50, CI 1.08-2.09) and no employment days (RR 1.93, CI 1.07-3.50). Among the women, the Multiple risk behavior cluster related significantly to over one year of unemployment (RR 1.77, CI 1.37-2.28). MMSP had no influence on the associations. CONCLUSIONS: Unhealthy behavior patterns and psychosocial problems in adolescence have long-term consequences for exclusion from the labor market in early adulthood, especially among men. Simultaneously supporting psychological well-being and healthy behaviors in adolescence may reduce labor market inclusion difficulties in the early phase of working life.

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study.

BACKGROUND: Low 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: To 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 with BMI.

The association between diabetes and cognitive changes during aging.

BACKGROUND: Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age. METHODS: to address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles. RESULTS: 11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results. CONCLUSION: Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings.