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1.
BMJ Glob Health ; 6(11)2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34725039

RESUMO

INTRODUCTION: South Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D. METHODS: This cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40-70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values. RESULTS: There were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference -1.10 kg (95% CI -1.70 to -1.06), p<0.001). The adjusted mean difference for waist circumference was -1.9 cm (95% CI -2.5; to 1.3), p<0.001). No overall difference was observed for blood pressure or HbA1c. People who attended multiple intervention sessions had a dose-dependent effect on waist circumference, blood pressure and HbA1c, but not on weight. CONCLUSION: An intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c. TRIAL REGISTRATION NUMBER: EudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.

2.
Nat Commun ; 12(1): 6618, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34785669

RESUMO

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34841466

RESUMO

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 18% of women. Besides metabolic and fertility aspects, attention has lately been directed towards the detrimental effect of PCOS on psychological health. The objective of the study was to investigate whether women with PCOS are at higher risk for psychotic disorders. The study population derives from the Northern Finland Birth Cohort 1966 (N = 5889 women). The women with PCOS were identified by two simple questions on oligo-amenorrhea and hirsutism at age 31. Women reporting both symptoms were considered PCOS (N = 124) and asymptomatic women as controls (N = 2145). The diagnosis of psychosis was traced using multiple national registers up to the year 2016. Symptoms of psychopathology were identified using validated questionnaires at age 31. Women with PCOS showed an increased risk for any psychosis by age 50 (HR [95% CI] 2.99, [1.52-5.82]). Also, the risk for psychosis after age 31 was increased (HR 2.68 [1.21-5.92]). The results did not change after adjusting for parental history of psychosis, nor were they explained by body mass index or hyperandrogenism at adulthood. The scales of psychopathology differed between women with PCOS and non-PCOS controls showing more psychopathologies among the affected women. PCOS cases were found to be at a three-fold risk for psychosis, and they had increased psychopathological symptoms. PCOS should be taken into consideration when treating women in psychiatric care. More studies are required to further assess the relationship between PCOS and psychotic diseases.

4.
J Epidemiol ; 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34776498

RESUMO

BACKGROUND: The EU LifeCycle Project was launched in 2017 to combine, harmonise, and analyse data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview over the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. METHODS: Data on cognitive, behavioural and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. RESULTS: The mental health data in LifeCycle contain longitudinal and cross-sectional data for ages 0-18+ years, covering domains across a wide range of behavioural and psychopathology indicators and outcomes (including executive function, depression, ADHD and cognition). These data span a unique combination of qualitative data collected through behavioural/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of brain imaging (MRI, foetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. CONCLUSION: Mental health data harmonized through the LifeCycle project can be used to study life course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

5.
Transl Psychiatry ; 11(1): 455, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34482360

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with obesity, however, the potential causality between the traits remains unclear. We examined both genetic and prenatal evidence for causality using Mendelian Randomisation (MR) and polygenic risk scores (PRS). We conducted bi-directional MR on ADHD liability and six obesity-related traits using summary statistics from the largest available meta-analyses of genome-wide association studies. We also examined the shared genetic aetiology between ADHD symptoms (inattention and hyperactivity) and body mass index (BMI) by PRS association analysis using longitudinal data from Northern Finland Birth Cohort 1986 (NFBC1986, n = 2984). Lastly, we examined the impact of the prenatal environment by association analysis of maternal pre-pregnancy BMI and offspring ADHD symptoms, adjusted for PRS of both traits, in NFBC1986 dataset. Through MR analyses, we found evidence for bidirectional causality between ADHD liability and obesity-related traits. PRS association analyses showed evidence for genetic overlap between ADHD symptoms and BMI. We found no evidence for a difference between inattention and hyperactivity symptoms, suggesting that neither symptom subtype is driving the association. We found evidence for association between maternal pre-pregnancy BMI and offspring ADHD symptoms after adjusting for both BMI and ADHD PRS (association p-value = 0.027 for inattention, p = 0.008 for hyperactivity). These results are consistent with the hypothesis that the co-occurrence between ADHD and obesity has both genetic and prenatal environmental origins.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Obesidade/genética , Gravidez
6.
Sci Rep ; 11(1): 19365, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588469

RESUMO

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

7.
Environ Res ; 204(Pt A): 111980, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474033

RESUMO

The ubiquitous presence of legacy and emerging persistent organic pollutants (POPs) in the environmental matrices poses a potential hazard to the humans and creating public health concerns. The present study aimed to evaluate dioxins, dioxin-like polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and chlorinated paraffins (CPs) concentrations in serum of women (postpartum, pregnant and non-pregnant) from Northern Norway to better understand their exposure and contamination status as well as temporal trends across 2007-2009 (MISA 1) to 2019 (MISA 2). Sixty-two blood samples from the MISA 1 cohort and 38 samples from MISA 2 were randomly selected in this study (n = 100). Ninety samples from postpartum (MISA 1) and pregnant women (MISA 2) were randomly combined into 9 pools, with 9-11 individual samples contributing to each pool keeping the groups of pregnant and postpartum women. Remaining 10 samples from non-pregnant women (MISA 2) were allocated into separate group. Geometric mean, minimum and maximum were used to describe the serum concentrations of pooled POPs in MISA cohort. Mann-Whitney U test and independent sample t-test were applied for trend analysis of blood levels of POPs between MISA 1 and MISA 2. We found the serum concentrations of selected POPs in this study to be at lower range. Serum concentrations of dibenzo-p-dioxins (PCDDs) (p = 0.010), polychlorinated dibenzofurans (PCDFs) (p = 0.002), dioxins-like PCBs (p = 0.001), hexachlorobenzene (HCB) (p < 0.001) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) (p = 0.002) were decreased between the studied time. In contrast, the serum concentrations of medium chain chlorinated paraffins showed an increasing trend between 2007 and 2009 and 2019 (p = 0.019). Our findings report a particular concern of emerging contaminant medium chain chlorinated paraffin exposure to humans. Future observational studies with repeated measurements of chlorinated paraffins in general populations worldwide and large sample size are warranted.

8.
Pediatr Res ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429512

RESUMO

BACKGROUND: We evaluated pubertal growth and pubertal timing of participants born preterm compared to those born at term. METHODS: In the ESTER Preterm Birth Study, we collected growth data and measured final height of men/women born very or moderately preterm (<34 gestational weeks, n = 52/55), late preterm (34-<37 weeks, 94/106), and term (≥37 weeks, 131/151), resulting in median 9 measurements at ≥6 years. Timing of menarche or voice break was self-reported. Peak height velocity (PHV, cm/year) and age at PHV (years) were compared with SuperImposition by Translation And Rotation (SITAR) model (sexes separately). RESULTS: Age at PHV (years) and PHV (cm/year) were similar in all gestational age groups. Compared to term controls, insignificant differences in age at PHV were 0.1 (95% CI: -0.2 to 0.4) years/0.2 (-0.1 to 0.4) for very or moderately/late preterm born men and -0.0 (-0.3 to 0.3)/-0.0 (-0.3 to 0.2) for women, respectively. Being born small for gestational age was not associated with pubertal growth. Age at menarche or voice break was similar in all the gestational age groups. CONCLUSIONS: Timing of pubertal growth and age at menarche or voice break were similar in participants born preterm and at term. IMPACT: Pubertal growth and pubertal timing were similar in preterm and term participants in a relatively large cohort with a wide range of gestational ages. Previous literature indicates that small for gestational age is a risk for early puberty in term born children. This was not shown in preterm children. While our study had limited power for children born very preterm, all children born preterm were not at increased risk for early puberty.

10.
iScience ; 24(8): 102893, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34401672

RESUMO

Here, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, that is, CNV association with complex human traits such as 1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 (ENSE00003720745) as a pleiotropic locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D) and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define metabolomic signatures for variants in TSPAN8.

11.
Int J Epidemiol ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34405869

RESUMO

BACKGROUND: Quantitative lipoprotein analytics using nuclear magnetic resonance (NMR) spectroscopy is currently commonplace in large-scale studies. One methodology has become widespread and is currently being utilized also in large biobanks. It allows the comprehensive characterization of 14 lipoprotein subclasses, clinical lipids, apolipoprotein A-I and B. The details of these data are conceptualized here in relation to lipoprotein metabolism with particular attention on the fundamental characteristics of subclass particle numbers, lipid concentrations and compositional measures. METHODS AND RESULTS: The NMR methodology was applied to fasting serum samples from Northern Finland Birth Cohorts 1966 and 1986 with 5651 and 5605 participants, respectively. All results were highly consistent between the cohorts. Circulating lipid concentrations in a particular lipoprotein subclass arise predominantly as the result of the circulating number of those subclass particles. The spherical lipoprotein particle shape, with a radially oriented surface monolayer, imposes size-dependent biophysical constraints for the lipid composition of individual subclass particles and inherently restricts the accommodation of metabolic changes via compositional modifications. The new finding that the relationship between lipoprotein subclass particle concentrations and the particle size is log-linear reveals that circulating lipoprotein particles are also under rather strict metabolic constraints for both their absolute and relative concentrations. CONCLUSIONS: The fundamental structural and metabolic relationships between lipoprotein subclasses elucidated in this study empower detailed interpretation of lipoprotein metabolism. Understanding the intricate details of these extensive data is important for the precise interpretation of novel therapeutic opportunities and for fully utilizing the potential of forthcoming analyses of genetic and metabolic data in large biobanks.

12.
Environ Int ; 156: 106766, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34271428

RESUMO

BACKGROUND: Occupational exposure to pesticides has been reported among general population worldwide. However, little is known about the associations between non-occupational exposure to pesticides, and biological markers of health and their response by sex. OBJECTIVES: We aimed to assess the associations between non-occupational overall pesticide exposure, length of exposure and specific pesticides reported with 35 biological markers of health representing cardiometabolic, haematological, lung function, sex hormones, liver and kidney function profiles, and vitamin D in Finnish cohort. METHODS: 31-year cross-sectional examination of the Northern Finland Birth Cohort 1966 provided blood samples for biomarker measurements in 1997-1998. Number of subjects varied between 2361 and 5037 for given exposures and certain outcome associations. Multivariable regression analyses were performed to examine associations between overall pesticide exposure (OPE), length of pesticide exposure in months (PEM), in years (PEY), and specific pesticides use (PEU) or not with cardiometabolic [SBP, DBP, TC, LDL, HDL, triglycerides, fasting glucose, insulin, HOMA-IR, HOMA-B, HOMA-S, hs-CRP], hematological [WBC, RBC, Hb, HCT, MCV, MCH, MCHC, platelets], lung function (FVC, FEV1), sex hormones [luteinizing hormone (LH), testosterone (TT), sex-hormone binding globulin (SHBG)], liver and kidney function profiles [total protein, albumin, globulin, ALP, ALT, GGT, urea, creatinine], and vitamin D adjusting for sex, BMI, socioeconomic position (SEP) and season of pesticide use. RESULTS: This cohort study on up to 5037 adults with non-occupational OPE, PEM, PEY and PEU differed by sex and SEP. In regression analyses, all the exposures were positively associated with total cholesterol and low-density lipoprotein cholesterol, and PEU was negatively associated with high-density lipoprotein cholesterol in females. OPE and PEM were positively associated with haematocrit in females and PEU with platelets in males. PEU was negatively associated with mean corpuscular haemoglobin. OPE and PEM were positively associated with LH in males. OPE was negatively associated with total protein and albumin in males. DISCUSSION: In Finnish young adults, non-occupational overall pesticide exposure, length of exposure and specific pesticides were associated with multiple biological markers of health. The biological markers seem to be indicative of adverse effects of pesticides and warrant for further studies to replicate the findings and determine the underlying mechanisms.


Assuntos
Exposição Ocupacional , Praguicidas , Biomarcadores , Estudos de Coortes , Estudos Transversais , Feminino , Finlândia , Humanos , Masculino , Praguicidas/toxicidade
13.
Sci Adv ; 7(29)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34261659

RESUMO

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (n = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

14.
Diabetologia ; 64(8): 1749-1759, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34110438

RESUMO

AIMS/HYPOTHESIS: The gut microbiome is hypothesised to be related to insulin resistance and other metabolic variables. However, data from population-based studies are limited. We investigated associations between serologic measures of metabolic health and the gut microbiome in the Northern Finland Birth Cohort 1966 (NFBC1966) and the TwinsUK cohort. METHODS: Among 506 individuals from the NFBC1966 with available faecal microbiome (16S rRNA gene sequence) data, we estimated associations between gut microbiome diversity metrics and serologic levels of HOMA for insulin resistance (HOMA-IR), HbA1c and C-reactive protein (CRP) using multivariable linear regression models adjusted for sex, smoking status and BMI. Associations between gut microbiome diversity measures and HOMA-IR and CRP were replicated in 1140 adult participants from TwinsUK, with available faecal microbiome (16S rRNA gene sequence) data. For both cohorts, we used general linear models with a quasi-Poisson distribution and Microbiome Regression-based Kernel Association Test (MiRKAT) to estimate associations of metabolic variables with alpha- and beta diversity metrics, respectively, and generalised additive models for location scale and shape (GAMLSS) fitted with the zero-inflated beta distribution to identify taxa associated with the metabolic markers. RESULTS: In NFBC1966, alpha diversity was lower in individuals with higher HOMA-IR with a mean of 74.4 (95% CI 70.7, 78.3) amplicon sequence variants (ASVs) for the first quartile of HOMA-IR and 66.6 (95% CI 62.9, 70.4) for the fourth quartile of HOMA-IR. Alpha diversity was also lower with higher HbA1c (number of ASVs and Shannon's diversity, p < 0.001 and p = 0.003, respectively) and higher CRP (number of ASVs, p = 0.025), even after adjustment for BMI and other potential confounders. In TwinsUK, alpha diversity measures were also lower among participants with higher measures of HOMA-IR and CRP. When considering beta diversity measures, we found that microbial community profiles were associated with HOMA-IR in NFBC1966 and TwinsUK, using multivariate MiRKAT models, with binomial deviance dissimilarity p values of <0.001. In GAMLSS models, the relative abundances of individual genera Prevotella and Blautia were associated with HOMA-IR in both cohorts. CONCLUSIONS/INTERPRETATION: Overall, higher levels of HOMA-IR, CRP and HbA1c were associated with lower microbiome diversity in both the NFBC1966 and TwinsUK cohorts, even after adjustment for BMI and other variables. These results from two distinct population-based cohorts provide evidence for an association between metabolic variables and gut microbial diversity. Further experimental and mechanistic insights are now needed to provide understanding of the potential causal mechanisms that may link the gut microbiota with metabolic health.

15.
Eur J Endocrinol ; 185(2): 279-288, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081616

RESUMO

Objective: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. Design: The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (<34 gestational weeks, VMPT), 127 born late preterm (at 34-36 weeks, LPT), and 184 born full term (≥37 weeks, controls) were included in the analysis (mean age: 23.2 years). Methods: We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L). Results: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject's birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). Conclusions: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.


Assuntos
Biomarcadores , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Crianças Adultas/estatística & dados numéricos , Androgênios/sangue , Biomarcadores/análise , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Finlândia/epidemiologia , Idade Gestacional , Hirsutismo/sangue , Hirsutismo/diagnóstico , Hirsutismo/epidemiologia , Humanos , Recém-Nascido , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/etiologia , Gravidez , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fatores de Risco , Testosterona/sangue , Adulto Jovem
16.
Stroke ; 52(8): 2680-2684, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34078102

RESUMO

BACKGROUND AND PURPOSE: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals. METHODS: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy. RESULTS: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals. CONCLUSIONS: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.

17.
Diabetes Care ; 44(9): 1992-1999, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34116986

RESUMO

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10-2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS: Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Metilação de DNA , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Epigenoma , Feminino , Proteínas Ativadoras de GTPase , Humanos , Gravidez , Estudos Prospectivos , Fatores de Transcrição/genética
18.
Genome Med ; 13(1): 104, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154662

RESUMO

BACKGROUND: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. METHODS: We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000). RESULTS: We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. CONCLUSIONS: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

19.
J Clin Endocrinol Metab ; 106(11): e4621-e4633, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34153097

RESUMO

CONTEXT: The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. OBJECTIVE: To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 years is associated with insulin resistance, insulin secretion and AGM by age 46. DESIGN: Prospective study including 5889 females followed at ages 31 and 46 years. SETTING: General community. PARTICIPANTS: Women with HA were compared with normoandrogenic women at ages 31 and 46 years. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic ß-cell function (HOMA-B). RESULTS: At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 highest FAI quartiles at ages 31 (Q4: OR = 3.76; 95% CI, 2.24-6.32) and 46 (Q4: OR = 2.79; 95% CI, 1.74-4.46) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: Q4: OR = 0.28; 95% CI, 0.17-0.44). CONCLUSION: Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.

20.
Eur J Nutr ; 60(8): 4541-4553, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34137914

RESUMO

PURPOSE: Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations. METHODS: We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D [25(OH)D] at ages 31 (1997) and 46 (2012-2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D z score adjusted for sex, season, latitude and technical effect was used in the analysis. RESULTS: We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below < 50 nmol/L was halved. The changes were found for both sexes and were more pronounced in winter compared to summer months. Regular VitD supplementation had a significant positive effect on 25(OH)D at the age of 46, as well as had the dietary intake of fortified dairy products and fish, and the previous 25(OH)D concentration. However, the intake of fat-spreads albeit VitD-fortified, did not predict 25(OH)D. CONCLUSION: Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population.


Assuntos
Suplementos Nutricionais , Deficiência de Vitamina D , Adulto , Animais , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estações do Ano , Vitamina D , Deficiência de Vitamina D/epidemiologia , Vitaminas
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