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The Lancet. Global Health Mar 2023Across the life course, socioeconomic disadvantage disproportionately afflicts those with genetic predispositions to inflammatory diseases. We describe how socioeconomic...
BACKGROUND
Across the life course, socioeconomic disadvantage disproportionately afflicts those with genetic predispositions to inflammatory diseases. We describe how socioeconomic disadvantage and polygenic risk for high BMI magnify the risk of obesity across childhood, and using causal analyses, explore the hypothetical impact of intervening on socioeconomic disadvantage to reduce adolescent obesity.
METHODS
Data were drawn from a nationally representative Australian birth cohort, with biennial data collection between 2004 and 2018 (research and ethics committee approved). We generated a polygenic risk score for BMI using published genome-wide association studies. We measured early-childhood disadvantage (age 2-3 years) with a neighbourhood census-based measure and a family-level composite of parent income, occupation, and education. We used generalised linear regression (Poisson-log link) to estimate the risk of overweight or obesity (BMI ≥85th percentile) at age 14-15 years for children with early-childhood disadvantage (quintiles 4-5) versus average (quintile 3) and least disadvantage (quintiles 1-2), for those with high and low polygenic risk separately.
FINDINGS
For 1607 children (n=796 female, n=811 male; 31% of the original cohort [N=5107]), polygenic risk and disadvantage were both associated with overweight or obesity; effects of disadvantage were more marked as polygenic risk increased. Of children with polygenic risk higher than the median (n=805), 37% of children living in disadvantage at age 2-3 years had an overweight or obese BMI by adolescence, compared with 26% of those with least disadvantage. For genetically vulnerable children, causal analyses indicated that early neighbourhood intervention to lessen disadvantage (to quintile 1-2) would reduce risk of adolescent overweight or obesity by 23% (risk ratio 0·77; 95% CI 0·57-1·04); estimates for improving family environments were similar (0·59; 0·43-0·80).
INTERPRETATION
Actions addressing socioeconomic disadvantage could mitigate polygenic risk for developing obesity. This study benefits from population-representative longitudinal data but is limited by sample size.
FUNDING
Australian National Health and Medical Research Council.
Topics: Child; Adolescent; Female; Male; Humans; Child, Preschool; Overweight; Cohort Studies; Pediatric Obesity; Body Mass Index; Genome-Wide Association Study; Socioeconomic Disparities in Health; Australia
PubMed: 36866486
DOI: 10.1016/S2214-109X(23)00094-3 -
Diabetologia Sep 2023Low birthweight is a risk factor for type 2 diabetes but it is unknown whether low birthweight is associated with distinct clinical characteristics at disease onset. We...
AIMS/HYPOTHESIS
Low birthweight is a risk factor for type 2 diabetes but it is unknown whether low birthweight is associated with distinct clinical characteristics at disease onset. We examined whether a lower or higher birthweight in type 2 diabetes is associated with clinically relevant characteristics at disease onset.
METHODS
Midwife records were traced for 6866 individuals with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Using a cross-sectional design, we assessed age at diagnosis, anthropomorphic measures, comorbidities, medications, metabolic variables and family history of type 2 diabetes in individuals with the lowest 25% of birthweight (<3000 g) and highest 25% of birthweight (>3700 g), compared with a birthweight of 3000-3700 g as reference, using log-binomial and Poisson regression. Continuous relationships across the entire birthweight spectrum were assessed with linear and restricted cubic spline regression. Weighted polygenic scores (PS) for type 2 diabetes and birthweight were calculated to assess the impact of genetic predispositions.
RESULTS
Each 1000 g decrease in birthweight was associated with a 3.3 year (95% CI 2.9, 3.8) younger age of diabetes onset, 1.5 kg/m (95% CI 1.2, 1.7) lower BMI and 3.9 cm (95% CI 3.3, 4.5) smaller waist circumference. Compared with the reference birthweight, a birthweight of <3000 g was associated with more overall comorbidity (prevalence ratio [PR] for Charlson Comorbidity Index Score ≥3 was 1.36 [95% CI 1.07, 1.73]), having a systolic BP ≥155 mmHg (PR 1.26 [95% CI 0.99, 1.59]), lower prevalence of diabetes-associated neurological disease, less likelihood of family history of type 2 diabetes, use of three or more glucose-lowering drugs (PR 1.33 [95% CI 1.06, 1.65]) and use of three or more antihypertensive drugs (PR 1.09 [95% CI 0.99, 1.20]). Clinically defined low birthweight (<2500 g) yielded stronger associations. Most associations between birthweight and clinical characteristics appeared linear, and a higher birthweight was associated with characteristics mirroring lower birthweight in opposite directions. Results were robust to adjustments for PS representing weighted genetic predisposition for type 2 diabetes and birthweight.
CONCLUSION/INTERPRETATION
Despite younger age at diagnosis, and fewer individuals with obesity and family history of type 2 diabetes, a birthweight <3000 g was associated with more comorbidities, including a higher systolic BP, as well as with greater use of glucose-lowering and antihypertensive medications, in individuals with recently diagnosed type 2 diabetes.
Topics: Humans; Diabetes Mellitus, Type 2; Birth Weight; Cross-Sectional Studies; Risk Factors; Genetic Predisposition to Disease; Glucose
PubMed: 37303007
DOI: 10.1007/s00125-023-05936-1 -
International Journal of Epidemiology Oct 2022We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general... (Observational Study)
Observational Study
BACKGROUND
We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general population.
METHODS
In this observational study, we identified 9560 UK Biobank participants diagnosed with COVID-19 during 2020. A polygenic risk score (PRS) for severe COVID-19 was derived and optimized using publicly available European and trans-ethnic COVID-19 genome-wide summary statistics. We estimated the risk of hospital or critical care admission within 28 days or death within 100 days following COVID-19 diagnosis, and assessed associations with socio-demographic factors, immunosuppressant use and morbidities reported at UK Biobank enrolment (2006-2010) and the PRS. To improve biological understanding, pathway analysis was performed using genetic variants comprising the PRS.
RESULTS
We included 9560 patients followed for a median of 61 (interquartile range = 34-88) days since COVID-19 diagnosis. The risk of severe COVID-19 increased with age and obesity, and was higher in men, current smokers, those living in socio-economically deprived areas, those with historic immunosuppressant use and individuals with morbidities and higher co-morbidity count. An optimized PRS, enriched for single-nucleotide polymorphisms in multiple immune-related pathways, including the 'oligoadenylate synthetase antiviral response' and 'interleukin-10 signalling' pathways, was associated with severe COVID-19 (adjusted odds ratio 1.32, 95% CI 1.11-1.58 for the highest compared with the lowest PRS quintile).
CONCLUSION
This study conducted in the pre-SARS-CoV-2-vaccination era, emphasizes the novel insights to be gained from using genetic data alongside commonly considered clinical and socio-demographic factors to develop greater biological understanding of severe COVID-19 outcomes.
Topics: Humans; Male; Antiviral Agents; COVID-19; COVID-19 Testing; Demography; Immunosuppressive Agents; Interleukin-10; Ligases; Risk Factors; SARS-CoV-2
PubMed: 35770811
DOI: 10.1093/ije/dyac137 -
The Journal of Adolescent Health :... Sep 2023Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics...
PURPOSE
Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics allow for studying G×E using individual genetic predispositions for overweight. We examine genetic influence on trajectories of overweight during adolescence and early adulthood and determine whether genetic predisposition is attenuated by higher socioeconomic status and having physically active parents.
METHODS
Latent class growth models of overweight were fitted using data from the TRacking Adolescents' Individual Lives Survey (n = 2720). A polygenic score for body mass index (BMI) was derived using summary statistics from a genome-wide association study of adult BMI (N = ∼700,000) and tested as predictor of developmental pathways of overweight. Multinomial logistic regression models were used to examine effects of interactions of genetic predisposition with socioeconomic status and parental physical activity (n = 1675).
RESULTS
A three-class model of developmental pathways of overweight fitted the data best ("non-overweight", "adolescent-onset overweight", and "persistent overweight"). The polygenic score for BMI and socioeconomic status distinguished the persistent overweight and adolescent-onset overweight trajectories from the non-overweight trajectory. Only genetic predisposition differentiated the adolescent-onset from the persistent overweight trajectory. There was no evidence for G×E.
DISCUSSION
Higher genetic predisposition increased the risk of developing overweight during adolescence and young adulthood and was associated with an earlier age at onset. We did not find that genetic predisposition was offset by higher socioeconomic status or having physically active parents. Instead, lower socioeconomic status and higher genetic predisposition acted as additive risk factors for developing overweight.
Topics: Adult; Adolescent; Humans; Young Adult; Longitudinal Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Overweight; Body Mass Index; Pediatric Obesity; Risk Factors; Seizures
PubMed: 37318409
DOI: 10.1016/j.jadohealth.2023.04.028 -
Diabetic Medicine : a Journal of the... Oct 2021Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information...
AIMS
Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown.
METHODS
We used data from 15,671 diabetes-free participants of European ancestry aged 45 years and older from the prospective population-based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk.
RESULTS
At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group.
CONCLUSIONS
Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk.
Topics: Aged; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Life Style; Male; Middle Aged; Multifactorial Inheritance; Obesity; Risk; White People
PubMed: 34245042
DOI: 10.1111/dme.14639 -
Frontiers in Physiology 2021It is estimated that 30% of pregnant women worldwide are overweight or obese, leading to adverse health effects for both mother and child. Women with obesity during...
It is estimated that 30% of pregnant women worldwide are overweight or obese, leading to adverse health effects for both mother and child. Women with obesity during pregnancy are at higher risk for developing both metabolic and mental disorders, such as diabetes and depression. Numerous studies have used rodent models of maternal obesity to understand its consequences on the offspring, yet characterization of changes in the dams is rare, and most rodent models rely solely on a high fat diet to induce maternal obesity, without regarding genetic propensity for obesity. Here we present the influence of both peripartum high energy diet (HE) and obesity-proneness on maternal health using selectively bred diet-resistant (DR) and diet-induced obese (DIO) rat dams. Outbred Sprague-Dawley rats were challenged with HE diet prior to mating and bred according to their propensity to gain weight. The original outbred breeding dams (F0) were maintained on low-fat chow during pregnancy and lactation. By comparison, the F1 dams consuming HE diet during pregnancy and lactation displayed higher gestational body weight gain ( < 0.01), and HE diet caused increased meal size and reduced meal frequency ( < 0.001). Sensitivity to the hormone amylin was preserved during pregnancy, regardless of diet. After several rounds of selective breeding, DIO and DR dams from generation F3 were provided chow or HE during pregnancy and lactation and assessed for their postpartum physiology and behaviors. We observed strong diet and phenotype effects on gestational weight gain, with DIO-HE dams gaining 119% more weight than DR-chow ( < 0.001). A high-resolution analysis of maternal behaviors did not detect main effects of diet or phenotype, but a subset of DIO dams showed delayed nursing behavior ( < 0.05). In generation F6/F7 dams, effects on gestational weight gain persisted ( < 0.01), and we observed a main effect of phenotype during a sucrose preference test ( < 0.05), with DIO-chow dams showing lower sucrose preference than DR controls ( < 0.05). Both DIO and DR dams consuming HE diet had hepatic steatosis ( < 0.001) and exhibited reduced leptin sensitivity in the arcuate nucleus ( < 0.001). These data demonstrate that both diet and genetic obesity-proneness have consequences on maternal health.
PubMed: 35222059
DOI: 10.3389/fphys.2021.772707 -
Nature Communications Oct 2022Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations...
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
Topics: Alleles; Cholesterol, LDL; Genome-Wide Association Study; Humans; Lipids; Whole Genome Sequencing
PubMed: 36220816
DOI: 10.1038/s41467-022-33510-7 -
Nutrients Nov 2022Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In... (Review)
Review
Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In addition to short-term adverse outcomes, such as hypertensive pregnancy disorders and fetal macrosomia, in the long term, GDM results in excess cardiometabolic morbidity in both the mother and child. Recent data suggest that women with GDM are characterized by notable phenotypic and genotypic heterogeneity and that frequencies of adverse obstetric and perinatal outcomes are different between physiologic GDM subtypes. However, as of yet, GDM treatment protocols do not differentiate between these subtypes. Mapping the genetic architecture of GDM, as well as accurate phenotypic and genotypic definitions of GDM, could potentially help in the individualization of GDM treatment and assessment of long-term prognoses. In this narrative review, we outline recent studies exploring genetic risk factors of GDM and later type 2 diabetes (T2D) in women with prior GDM. Further, we discuss the current evidence on gene-lifestyle interactions in the development of these diseases. In addition, we point out specific research gaps that still need to be addressed to better understand the complex genetic and metabolic crosstalk within the mother-placenta-fetus triad that contributes to hyperglycemia in pregnancy.
Topics: Female; Humans; Pregnancy; Diabetes Mellitus, Type 2; Diabetes, Gestational; Fetal Macrosomia; Life Style; Risk Factors
PubMed: 36432486
DOI: 10.3390/nu14224799 -
Saudi Journal of Biological Sciences Oct 2023Obesity is a polygenic disorder which has become a global epidemic in recent years. Aim of the present study was to assess the theranostic potential of probiotics ( and...
Obesity is a polygenic disorder which has become a global epidemic in recent years. Aim of the present study was to assess the theranostic potential of probiotics ( and local herbs (fenugreek seeds, aloe vera) on the body weight, biochemical (liver and kidney functions) and histology of some internal organs (liver, kidney, ovary, small intestine) in obese rats. In present study, nanoemulsions of probiotics and local herbs were formulated by high energy method and characterized by FTIR and UV analysis. One hundred and sixty (1 6 0) female wistar rats were divided into sixteen groups. A high-fat diet was given to induce obesity in them. Obese rats were treated with different doses of probiotics, local herbs and their combination. Weekly body weight was monitored. Rats were dissected after fifteen weeks; blood and organs were harvested for biochemical analysis and histology. Results demonstrated a protective effect of nanoemulsion of probiotics and local herbs on the central vein, glomerulus, villi and normal ovulatory function of obese rats. Rats treated with a combination of probiotics and local herbs (fenugreek seeds, aloe vera) exhibited improved levels of bilirubin (4 mg/dl to15 mg/dl), AST from (110 U/L to 18 U/L) and ALT from (52 U/L to 10U/L). Similar renoprotective effects were recorded on the overall renal function tests (RFT). A combination of probiotics and local herbs in post treatment rats improved urea (63 mg/dl to 22 mg/dl) and creatinine (0.2 mg/dl to 0.8 mg/dl) levels. It was therefore evident that a combination of probiotics and local herbs has the potential to reverse the effects of obesity on the biochemical parameters and histological architecture of liver, kidney, small intestine and ovary. The overall results indicated that probiotics have positive effects of their own, but when combined with local herbs, they produced highly effective results in obese rats and therefore can be used as a complementary option in obese individuals.
PubMed: 37680978
DOI: 10.1016/j.sjbs.2023.103790 -
BMC Cancer Jun 2020Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship.
METHODS
We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset.
RESULTS
Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding).
CONCLUSIONS
Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.
Topics: Cholesterol, LDL; Genetic Predisposition to Disease; Genome-Wide Association Study; Glioma; Humans; Hypersensitivity; Mendelian Randomization Analysis; Obesity; Polymorphism, Single Nucleotide; Risk Factors; Telomere Homeostasis; Triglycerides
PubMed: 32493226
DOI: 10.1186/s12885-020-06967-2