Publications by authors named "Lawrence J Beilin"

199 Publications

Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3.

Eur J Endocrinol 2021 Sep 1. Epub 2021 Sep 1.

S Wilson, Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia.

Objective Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental versus genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. Methods Heritability of thyroid stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9-16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7,522,526 single nucleotide polymorphisms as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n= 1115) followed by meta-analysis to maximise power for discovery. Results Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7-74.9%) for TSH, 67.5% (59.8-75.3%) for fT4, 59.7% (54.4-65.0%) for fT3 and 48.8% (40.6-56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. Conclusion Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.
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http://dx.doi.org/10.1530/EJE-21-0614DOI Listing
September 2021

Validation of a deficit-accumulation Frailty Index in the ASPREE study and its predictive capacity for disability-free survival.

J Gerontol A Biol Sci Med Sci 2021 Aug 2. Epub 2021 Aug 2.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria Australia.

Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterise a 67-item deficit-accumulation frailty index (FI) in 19,110 community-dwelling individuals in the ASPREE clinical trial. Participants aged 65 to 98 years were recruited from the U.S. and Australia, and were without diagnosed dementia and cardiovascular disease, and without major physical disability. The median FI score was 0.10 (IQR: 0.07; 0.14) at baseline, and the prevalence of frailty (FI> 0.21) increased from 8.1% to 17.4% after six years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r =-0.31) and grip strength (r = -0.46), and strongly associated with a modified Fried frailty phenotype (p<0.0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (HR:21.3, 95% CI:15.6-28.9). It added significantly to the predictive capacity of these outcomes above age, sex and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals, and provides important information about an individual's vulnerability to and risk of disease.
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http://dx.doi.org/10.1093/gerona/glab225DOI Listing
August 2021

Long-Term Blood Pressure Variability and Risk of Cognitive Decline and Dementia Among Older Adults.

J Am Heart Assoc 2021 Jul 26;10(13):e019613. Epub 2021 Jun 26.

Berman Center for Outcomes and Clinical Research Hennepin-Health Research InstituteHennepin Healthcare Minneapolis MN.

Background Blood pressure variability (BPV) in midlife increases risk of late-life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long-term, visit-to-visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow-up visits. Time-to-event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction =0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19-2.39) but not women (HR, 1.01; 95% CI, 0.72-1.42). For cognitive decline, similar increased risks were observed for men and women (interaction =0.15; men: HR, 1.36; 95% CI, 1.16-1.59; women: HR, 1.14; 95% CI, 0.98-1.32). Conclusions High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583; isrctn.com. Identifier: ISRCTN83772183.
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http://dx.doi.org/10.1161/JAHA.120.019613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403315PMC
July 2021

Relationship Between the Aldosterone-to-Renin Ratio and Blood Pressure in Young Adults: A Longitudinal Study.

Hypertension 2021 Aug 14;78(2):387-396. Epub 2021 Jun 14.

Medical School, The University of Western Australia (L.J.B., T.A.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17336DOI Listing
August 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Prenatal Testosterone Associates With Blood Pressure in Young Adults: A Prospective Cohort Study.

Hypertension 2021 May 29;77(5):1756-1764. Epub 2021 Mar 29.

From the Medical School, Royal Perth Hospital Campus (C.L-H, L.J.B., S.B., T.A.M.), the University of Western Australia, Perth.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16256DOI Listing
May 2021

Epigenome-Wide Association Study of Thyroid Function Traits Identifies Novel Associations of fT3 With KLF9 and DOT1L.

J Clin Endocrinol Metab 2021 04;106(5):e2191-e2202

Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Context: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.

Objective: To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.

Method: We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.

Results: We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.

Conclusions: This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
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http://dx.doi.org/10.1210/clinem/dgaa975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063248PMC
April 2021

Validation of fatty liver disease scoring systems for ultrasound diagnosed non-alcoholic fatty liver disease in adolescents.

Dig Liver Dis 2021 Jun 14;53(6):746-752. Epub 2020 Dec 14.

Menzies Institute for Medical Research, University of Tasmania. Electronic address:

Background And Aims: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in young populations. However, there are inadequate data regarding diagnosis of NAFLD. We aimed to validate three scoring systems against a previous standard of suprailiac skinfold thickness for diagnosing NAFLD in population-based adolescents.

Methods: Seventeen-year-old adolescents (n = 899), participating in the Raine Study, attended a cross-sectional follow-up. NAFLD was diagnosed using liver ultrasound. Scores for Fatty liver index (FLI), Hepatic Steatosis Index (HSI) and Zhejiang University index (ZJU index) were calculated. Diagnostic accuracy of these diagnostic tests was evaluated through discrimination and calibration.

Results: NAFLD was diagnosed 9% in males and 15% in females. The three scoring systems demonstrated better discrimination performance for NAFLD in males (AUC was FLI:0.82, HSI: 0.83 and ZJU index: 0.83) compared to females (AUC was FLI: 0.67, HSI: 0.67 and ZJU index: 0.67). Suprailiac skinfold performed better than the scoring systems (overall AUC: 0.82; male AUC:0.88; female AUC:0.73). FLI had best calibration performance.

Conclusion: Suprailiac skinfold thickness was a better predictor of ultrasound-diagnosed NAFLD than the three diagnostic scoring systems investigated. The higher performance characteristics of the algorithmic scoring systems in males compared with females may have implications for use in population assessments.
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http://dx.doi.org/10.1016/j.dld.2020.11.037DOI Listing
June 2021

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Genome Med 2020 11 25;12(1):105. Epub 2020 Nov 25.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.

Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.

Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P = 1; childhood P = 2.00 × 10; adolescence P = 2.10 × 10).

Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
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http://dx.doi.org/10.1186/s13073-020-00810-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687793PMC
November 2020

Practical Guidance for Food Consumption to Prevent Cardiovascular Disease.

Heart Lung Circ 2021 Feb 3;30(2):163-179. Epub 2020 Nov 3.

Medical School, University of Western Australia, Perth, WA, Australia.

This dietary guidance, informed by best contemporary evidence, aims to assist medical practitioners and allied health professionals in advising patients for the primary and secondary prevention of cardiovascular disease (CVD). While differing in some details from other current guidelines, the core messages accord with those published in 2019 by the American College of Cardiology/American Heart Association and the European Society of Cardiology/European Atherosclerosis Society; the National Lipid Association in 2014 and the NH&MRC Australian Dietary Guidelines in 2013. These were assessed through the Appraisal of Guidelines for Research and Evaluation (AGREE II) and the levels of evidence and classes of a recommendation developed using the GRADE system. Recommendations with high levels of evidence include increased consumption of plant based foods comprising mainly complex, fibre enriched carbohydrates (wholegrains, fruits and vegetables) while limiting intake of refined starches; partial replacement of saturated fats with monounsaturated or polyunsaturated fats and oils; reduced salt intake; achievement and maintenance of healthy weight; and low-to-moderate consumption of alcohol. Additional guidance but with moderate levels of evidence includes increased consumption of fish (and fish oils where indicated); reduction in sugar-sweetened beverages and added sugars; avoidance of butter and cream especially in those at increased CVD risk but encouragement of yoghurt; allow moderate consumption of lean meat but limit intake of processed meats; and limit cholesterol-rich foods such as eggs and crustaceans for those at increased CVD risk. Guidance has been formulated qualitatively on food categories of commonly eaten foods while avoiding prescriptive quantitative measures that are less readily translatable. This approach accords with current guidelines such as the American College of Cardiology/American Heart Association 2019 guidelines and is understandable and readily implemented.
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http://dx.doi.org/10.1016/j.hlc.2020.08.022DOI Listing
February 2021

Long-Term Blood Pressure Variability and Risk of Cardiovascular Disease Events Among Community-Dwelling Elderly.

Hypertension 2020 12 2;76(6):1945-1952. Epub 2020 Nov 2.

Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia (E.K.C., R.W., A.M.T., J.R., R.L.W., J.J.M., C.M.R.).

High office blood pressure variability (OBPV) in midlife increases the risk of cardiovascular disease (CVD), but the impact of OBPV in older adults without previous CVD is unknown. We conducted a post hoc analysis of ASPREE trial (Aspirin in Reducing Events in the Elderly) participants aged 70-years and older (65 for US minorities) without history of CVD events at baseline, to examine risk of incident CVD associated with long-term, visit-to-visit OBPV. CVD was a prespecified, adjudicated secondary end point in ASPREE. We estimated OBPV using within-individual SD of mean systolic BP from baseline and first 2 annual visits. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% CI for associations with CVD events. In 16 475 participants who survived to year 2 without events, those in the highest tertile of OBPV had increased risk of CVD events after adjustment for multiple covariates, when compared with participants in the lowest tertile (HR, 1.36 [95% CI, 1.08-1.70]; =0.01). Similar increased risk was observed for ischemic stroke (HR, 1.56 [95% CI, 1.04-2.33]; =0.03), heart failure hospitalization, or death (HR, 1.73 [95% CI, 1.07-2.79]; =0.02), and all-cause mortality (HR, 1.27 [95% CI, 1.04-1.54]; =0.02). Findings were consistent when stratifying participants by use of antihypertensive drugs, while sensitivity analyses suggested the increased risk was especially for individuals whose BP was uncontrolled during the OBPV estimation period. Our findings support increased OBPV as a risk factor for CVD events in healthy older adults with, or without hypertension, who have not had such events previously. Registration- URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01038583; URL: https://www.isrctn.com; Unique identifiers: ISRCTN83772183.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666049PMC
December 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Changing dietary approaches to prevent cardiovascular disease.

Curr Opin Lipidol 2020 12;31(6):313-323

Medical School, University of Western Australia, Perth, Australia.

Purpose Of Review: We have focused on recent research relevant to effects of dietary patterns and major food groups on cardiovascular outcomes, taking into account guidelines and position statements from expert authorities, with an emphasis on important changes in recommendations, some of which remain controversial.

Recent Findings: Major findings include: refocusing on qualitative patterns of food consumption replacing quantitative prescriptive advice on nutrients; increasing intake of plant foods; substituting saturated fats with polyunsaturated and monounsaturated oils; reducing salt intake; regular consumption of fish with a focus on omega-3 enrichment; not restricting dairy foods, other than butter and cream, with encouragement of some fermented products; reducing cholesterol intake for those at increased cardiovascular risk and diabetes, allowing 7-eggs weekly; restricting processed meats and allowing moderate lean meat consumption; preference for fiber-rich complex carbohydrates and reduced sugar intake; maintaining healthy bodyweight; and although water is the preferred beverage, allowing moderate alcohol consumption to national guidelines and avoiding alcohol in specific cardiovascular disorders.

Summary: The new approach that focuses on healthier patterns of food intake is more readily understood by health practitioners and translatable to consumers and patients.
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http://dx.doi.org/10.1097/MOL.0000000000000709DOI Listing
December 2020

Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents.

JHEP Rep 2020 Dec 24;2(6):100150. Epub 2020 Jul 24.

Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, WA, Australia.

Background & Aims: Remnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors.

Methods: Adolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed.

Results: NAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR.

Conclusions: There is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were associated with the severity of hepatic steatosis and markers of cardiometabolic risk, lower serum RLP-C might reflect reduced cardiovascular risk.

Lay Summary: Remnant lipoprotein cholesterol (RLP-C) is a part of the blood cholesterol that is linked with heart disease and non-alcoholic fatty liver disease (NAFLD) in adults. In the Raine Study, teenagers with high RLP-C levels had more severe fat accumulation in their liver. Thus, RLP-C might be the hidden link between NAFLD and future risk of heart disease.
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http://dx.doi.org/10.1016/j.jhepr.2020.100150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495103PMC
December 2020

Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults.

Environ Health Perspect 2020 09 15;128(9):97003. Epub 2020 Sep 15.

Telethon Kids Institute, University of Western Australia, Nedlands, Perth, Western Australia, Australia.

Background: Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for cigarette smoke exposure.

Methods: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina's Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression.

Results: Sensitivity and specificity values for the best performing previously developed classifier ("Reese Score") were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966.

Conclusion: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076.
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http://dx.doi.org/10.1289/EHP6076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491641PMC
September 2020

Methylome-wide association study of central adiposity implicates genes involved in immune and endocrine systems.

Epigenomics 2020 09 9;12(17):1483-1499. Epub 2020 Sep 9.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near , ,  and that had not previously been associated with obesity-related traits.
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http://dx.doi.org/10.2217/epi-2019-0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923253PMC
September 2020

Dietary fibre intake and its associations with depressive symptoms in a prospective adolescent cohort.

Br J Nutr 2021 05 3;125(10):1166-1176. Epub 2020 Sep 3.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS7000, Australia.

Depression is a major cause of disability in adolescents. Higher dietary fibre intake has been associated with lower depressive symptoms in adults, but there is a lack of research in adolescents. We examined the association between dietary fibre intake (Commonwealth Scientific and Industrial Research Organisation (CSIRO) FFQ) and depressive symptoms (Beck Depression Inventory for Youth) in adolescents with prospective data from the Raine Study Gen2 14- and 17-year follow-ups (n 1260 and 653). Odds of moderate/extreme (clinically relevant) depressive symptoms by quartile of fibre intake were calculated using mixed-effects logistic regression for all participants, in a paired sample without moderate/extreme depressive symptoms at 14 years and in a sub-sample of participants with available inflammatory data at the ages of 14 and 17 years (n 718 and 547). Odds of moderate/extreme depressive symptoms were lower in the fourth (highest) quartile of overall fibre intake (OR 0·273, 95 % CI 0·09, 0·81) compared with the first (lowest) quartile, adjusting for sex, age, energy intake, adiposity, and family and lifestyle factors. However, further adjustment for dietary patterns attenuated the results. Associations of depressive symptoms with cereal or fruit and vegetable fibre intake were not significant in the final model. Adjustment for inflammation had no effect on OR. The association between a higher dietary fibre intake and lower odds of clinically relevant depressive symptoms may be more reflective of a high-fibre diet with all its accompanying nutrients than of an independent effect of fibre.
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http://dx.doi.org/10.1017/S0007114520003426DOI Listing
May 2021

ApoB48-Lipoproteins Are Associated with Cardiometabolic Risk in Adolescents with and without Polycystic Ovary Syndrome.

J Endocr Soc 2020 Aug 26;4(8):bvaa061. Epub 2020 May 26.

Medical School, University of Western Australia, Royal Perth Hospital Unit, Perth, Australia.

Context: Adolescents with polycystic ovary syndrome (PCOS) have increased incidence of cardiometabolic risk factors including dyslipidemia. Atherogenic apolipoprotein (apo) B-lipoprotein remnants are associated with increased cardiovascular disease (CVD) risk.

Objective: The aim of this study was to determine the concentrations of fasting plasma apoB-lipoprotein remnants, apoB48 and apoB100, and their association with cardiometabolic risk factors and androgen indices in adolescent girls with and without PCOS.

Design Setting And Participants: Participants (n = 184) aged 17 years were recruited in the Menstruation in Teenagers Study from the Western Australian Pregnancy Cohort (Raine) Study.

The Main Outcome Measures: Fasting plasma apo-B48 and -B100 lipoprotein remnant concentrations in adolescent girls with and without PCOS.

Results: Fasting plasma apoB48-lipoprotein remnants but not apoB100-lipoprotein remnants were elevated in adolescent girls with increased cardiometabolic risk compared with those with lower cardiometabolic risk (13.91 ± 5.06 vs 12.09 ± 4.47 µg/mL, < .01). ApoB48-lipoprotein remnants were positively correlated with fasting plasma triglycerides (b = .43, < .0001). The prevalence of increased cardiometabolic risk factors was 2-fold higher in those diagnosed with PCOS (35.3%) than in those without PCOS (16.3%). Adolescents with PCOS have a 2-fold higher incidence of cardiometabolic risk factors than those without PCOS. Fasting apoB48-lipoprotein remnants are elevated in adolescent girls with a high prevalence of cardiometabolic risk factors.
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http://dx.doi.org/10.1210/jendso/bvaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417872PMC
August 2020

Evaluating Engagement in a Digital and Dietetic Intervention Promoting Healthy Weight Gain in Pregnancy: Mixed Methods Study.

J Med Internet Res 2020 06 26;22(6):e17845. Epub 2020 Jun 26.

Telethon Kids Institute, Perth, Australia.

Background: Early excess and inadequate gestational weight gain (GWG) have been associated with negative outcomes for mother and child. The use of digital media to deliver pregnancy lifestyle interventions is increasing, but there is little data on participant engagement. The Pregnancy Lifestyle Activity and Nutrition (PLAN) intervention pilot study was an electronic health and dietetic-delivered intervention program promoting healthy GWG in early pregnancy.

Objective: This study aims to explore the interactions of participants with the program and to assess its acceptability.

Methods: This study uses both quantitative and qualitative methods using data from parent randomized controlled trial (ACTRN12617000725369). Quantitative data from 22 participants in the intervention arm who completed the study provided measures of the interactions participants had with the digital components of the program and with dietetic consultations. A descriptive qualitative analysis employed semistructured interviews with 9 participants to elicit views on the acceptability of the intervention and its components.

Results: The electronic delivery of information and recording of weight from 8 to 20 weeks of gestation were universally accepted. Component (face-to-face dietitian, weight tracker, website information delivery, and SMS goal prompting) acceptability and engagement differed between individuals. A total of 4 key themes emerged from the qualitative analysis: supporting lifestyle change, component acceptability and value, delivery platforms, and engagement barriers.

Conclusions: The PLAN intervention and its delivery via a blend of personal dietetic consultations and digital program delivery was found to be acceptable and valuable to pregnant women. Individuals responded differently to various components, emphasizing the importance of including women in the development of lifestyle interventions and allowing participants to choose and tailor programs. Larger randomized controlled trials using these insights in a broader section of the community are needed to inform the iterative development of practical, time-efficient, and cost-effective ways of supporting optimal GWG with the potential to optimize outcomes for pregnant women and their child.
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http://dx.doi.org/10.2196/17845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380982PMC
June 2020

ApoB48-remnant lipoproteins are associated with increased cardiometabolic risk in adolescents.

Atherosclerosis 2020 06 4;302:20-26. Epub 2020 May 4.

Metabolic and Cardiovascular Disease Laboratory, Molecular Cell Biology of Lipids Group, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background And Aims: Cardiovascular disease (CVD) begins in youth, and is exacerbated by obesity and metabolic syndrome. Apolipoprotein (Apo)B-remnant cholesterol is considered a primary contributor to CVD risk. Fasting plasma apoB48 can be used as a biomarker of intestinal remnant cholesterol as well as postprandial dyslipidemia. In adults, elevated fasting plasma apoB48 strongly associates with cardiometabolic risk factors and obesity, whereas in adolescents there is limited data. The aim of this study was to measure fasting plasma apoB48 and determine the relationship with cardiometabolic risk factors in adolescents.

Methods: This is a cross-sectional study of fasting plasma apoB48 from the Western Australian Pregnancy Cohort (Raine) Study. Subjects were adolescent males and females aged 17 years with complete fasting plasma apoB48, biochemical, and anthropometry data (n = 1045). The relationship between fasting plasma apoB48 and other cardiometabolic risk factors was determined. The high-risk metabolic cluster variable was defined using elevated BMI, HOMA-IR, fasting plasma triglycerides, and systolic blood pressure.

Results: Fasting plasma apoB48 was significantly higher in male (15.28 ± 2.95 μg/mL) compared to female (12.45 ± 2.43 μg/mL) adolescents (p = 0.0003), and was increased by 21% (3.60 μg/mL; p = 0.0000) in the high-risk metabolic cluster group and more pronounced in males (31%, 6.15 μg/mL; p = 0.0000). Fasting plasma apoB48 was positively associated with fasting plasma triglycerides, total-cholesterol (but not LDL-C), insulin, leptin, HOMA-IR, and the anthropometric parameters, waist-circumference and skinfold-thickness. Fasting plasma apoB48 was inversely associated with fasting plasma HDL-C, and adiponectin.

Conclusions: Plasma apoB48 remnant lipoproteins associate with cardiometabolic risk factors in adolescents and provide support for the screening of remnant cholesterol in youth.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.04.021DOI Listing
June 2020

Dietary fibre intake and its association with inflammatory markers in adolescents.

Br J Nutr 2021 02 7;125(3):329-336. Epub 2020 May 7.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania7000, Australia.

A high dietary fibre intake has been associated with improvements in inflammatory conditions in adults. However, little is known on whether associations between dietary fibre and inflammation are evident during adolescence. We examined the relationship between dietary fibre intake measured by FFQ and the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and the adipokines leptin and adiponectin cross-sectionally in 17-year-olds participating in the Raine Study (n 621). In weighted analysis using tobit and linear regression, and after excluding participants with hs-CRP > 10 mg/l, higher total dietary fibre intake (per 5 g/d) was significantly associated with lower leptin (β = -0·13, 95 % CI -0·17, -0·09) and adiponectin (β = -0·28, 95 % CI -0·49, -0·07), but not hs-CRP, in unadjusted analyses. These associations were no longer significant after adjustment for sex, anthropometry and a number of lifestyle factors. However, higher cereal and grain fibre intake was significantly associated with lower leptin (β = -0·06, 95 % CI -0·10, -0·01) in fully adjusted analysis. Our findings suggest that a higher intake of cereal and grain fibre may contribute to lower leptin in adolescents. This may contribute to reductions in low-grade chronic inflammation and improved health outcomes.
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http://dx.doi.org/10.1017/S0007114520001609DOI Listing
February 2021

The effect of regular consumption of lupin-containing foods on glycaemic control and blood pressure in people with type 2 diabetes mellitus.

Food Funct 2020 Jan;11(1):741-747

School of Public Health, Curtin University, Perth, Australia.

Background: Type 2 diabetes mellitus is a metabolic disorder characterized by high glucose and insulin resistance. It is strongly linked to lifestyle, including poor diet and physical inactivity. Lupin is a novel food ingredient, rich in protein and fibre with negligible sugar and starch, which can be incorporated into various foods to reduce glycaemic load. Regular consumption of lupin-enriched foods may be a novel and easily achievable means of reducing overall glycaemic load and improving glycaemic control in diabetes.

Objective: To determine whether regular consumption of lupin-enriched foods can improve glycaemic control and lower blood pressure in people with type 2 diabetes mellitus.

Design: Fourteen men and 8 women (mean age 58.0 ± 6.6 years and BMI 29.0 ± 3.5 kg m-2) with type 2 diabetes mellitus were recruited from the general population to take part in a double-blind, randomised, controlled cross-over study. Participants consumed lupin or control foods for breakfast and lunch every day, and for dinner at least 3 days per week during the 8-week treatment periods. Lupin-enriched foods consisted of bread, pasta, Weetbix™ cereal and crumbs, with energy-matched control products. Treatments were completed in random order with an 8-week washout period. All participants monitored their blood glucose levels pre- and post-breakfast and lunch, and their blood pressure in the morning and evening, 3 days per week for the duration of each treatment period.

Results: Seventeen participants completed both treatment arms, with all 22 participants (14 males, 8 females) analysed on an intention-to-treat basis. Eight weeks consumption of lupin-enriched food had no significant effect on mean blood glucose levels (mean difference: -0.08 ± 0.06 mmol L-1, p = 0.214) or post-prandial blood glucose levels (-0.13 ± 0.10 mmol L-1, p = 0.196). There was no effect on home systolic (-0.4 ± 0.4 mmHg, p = 0.33) or diastolic (0.3 ± 0.3 mmHg, p = 0.321) blood pressure and heart rate (0.5 ± 0.3 bpm, p = 0.152), and no effect on body weight throughout the treatment periods.

Conclusion: Regular consumption of lupin-enriched foods had no significant effect on glycaemic control or blood pressure in people with type 2 diabetes mellitus.
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http://dx.doi.org/10.1039/c9fo01778jDOI Listing
January 2020

Association of Extreme Nocturnal Dipping With Cardiovascular Events Strongly Depends on Age.

Hypertension 2020 02 23;75(2):324-330. Epub 2019 Dec 23.

University of Perugia, Italy (S.S., G.R.).

Whether extreme dipping is associated with cardiovascular events (CVE) is unclear. The present study was conducted to test the hypothesis that the prognostic role of extreme dipping varies as a function of age. The analysis was performed in 10 868 participants (53% men) aged 53±15 (mean±SD) years enrolled in 8 prospective studies. Using the ambulatory systolic blood pressure nocturnal decline, we identified 4 groups: dippers (>10%-20%), nondippers (>0%-10%), reverse dippers (≤0%), and extreme dippers (>20%). The association between dipping category and CVE was estimated as a function of age using Cox models adjusted for sex, average 24-hour systolic blood pressure, and traditional risk factors. During a median follow-up of 5.7 years, there were a total of 829 CVE (168 fatal). For extreme dippers, no increase in risk of CVE was observed among the participants <70 years (hazard ratio, 0.99 [95% CI, 0.73-1.34]; =0.93) compared with dippers. In contrast, among the participants ≥70 years, there was a significant increase in risk (hazard ratio, 1.88 [95% CI, 1.14-3.11]; =0.013). Among the octogenarians, the hazard ratio (95% CI) for CVE were 2.34 (1.12-4.93) for nondippers (=0.024), 3.91 (1.75-8.73) for reverse dippers (=0.001), and 4.12 (1.64-10.37) for extreme dippers (=0.003) compared with dippers. These data show that extreme dipping is not associated with poorer outcome in people younger than 70 years. A U-shaped relationship between nocturnal blood pressure dipping and adverse outcome is present in subjects older than 70 years. In the octogenarian extreme dippers, the risk of CVEs was 4× higher than in the dippers and similar to that in the reverse dippers.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14085DOI Listing
February 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Factors Associated With Treatment and Control of Hypertension in a Healthy Elderly Population Free of Cardiovascular Disease: A Cross-sectional Study.

Am J Hypertens 2020 04;33(4):350-361

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Background: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP.

Methods: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control.

Results: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US).

Conclusions: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population.

Clinical Trials Registration: NCT01038583.
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http://dx.doi.org/10.1093/ajh/hpz192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109352PMC
April 2020

Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality.

J Am Heart Assoc 2019 11 4;8(21):e012630. Epub 2019 Nov 4.

School of Public Health Curtin University Perth Western Australia Australia.

Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long-term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24-hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow-up). Weighted day-night systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as and based on the baseline median BPV value and then classified BPV changes into , , , and . We observed an annual decline (mean±SD: -0.37±1.95; 95% CI, -0.54 to -0.19; <0.001) in weighted day-night systolic BPV between baseline and follow-up. Having constant stable: high BPV was associated with an increase in all-cause mortality (hazard ratio: 3.03; 95% CI, 1.67-5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62-8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow-up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow-up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long-term mortality.
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http://dx.doi.org/10.1161/JAHA.119.012630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898807PMC
November 2019

Maternal Smoking During Pregnancy Induces Persistent Epigenetic Changes Into Adolescence, Independent of Postnatal Smoke Exposure and Is Associated With Cardiometabolic Risk.

Front Genet 2019 5;10:770. Epub 2019 Sep 5.

Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.

Several studies have shown effects of current and maternal smoking during pregnancy on DNA methylation of CpG sites in newborns and later in life. Here, we hypothesized that there are long-term and persistent epigenetic effects following maternal smoking during pregnancy on adolescent offspring DNA methylation, independent of paternal and postnatal smoke exposure. Furthermore, we explored the association between DNA methylation and cardiometabolic risk factors at 17 years of age. DNA methylation was measured using the Illumina HumanMethylation450K BeadChip in whole blood from 995 participants attending the 17-year follow-up of the Raine Study. Linear mixed effects models were used to identify differential methylated CpGs, adjusting for parental smoking during pregnancy, and paternal, passive, and adolescent smoke exposure. Additional models examined the association between DNA methylation and paternal, adolescent, and passive smoking over the life course. Offspring CpGs identified were analyzed against cardiometabolic risk factors (blood pressure, triacylglycerols (TG), high-density lipoproteins cholesterol (HDL-C), and body mass index). We identified 23 CpGs (genome-wide level: 1.06 × 10) that were associated with maternal smoking during pregnancy, including associated genes (cancer development), (obesity), (developmental processes), (detoxification), (cell signalling), and (nicotine dependence). A sensitivity analysis showed a dose-dependent relationship between maternal smoking and offspring methylation. These results changed little following adjustment for paternal, passive, or offspring smoking, and there were no CpGs identified that associated with these variables. Two of the 23 identified CpGs [cg00253568 () and cg00213123 ()] were associated with either TG (male and female), diastolic blood pressure (female only), or HDL-C (male only), after Bonferroni correction. This study demonstrates a critical timing of cigarette smoke exposure over the life course for establishing persistent changes in DNA methylation into adolescence in a dose-dependent manner. There were significant associations between offspring CpG methylation and adolescent cardiovascular risk factors, namely, TG, HDL-C, and diastolic blood pressure. Future studies on current smoking habits and DNA methylation should consider the importance of maternal smoking during pregnancy and explore how the persistent DNA methylation effects of smoke exposure increase cardiometabolic risk.
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http://dx.doi.org/10.3389/fgene.2019.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764289PMC
September 2019

Alcohol and Hypertension-New Insights and Lingering Controversies.

Curr Hypertens Rep 2019 09 7;21(10):79. Epub 2019 Sep 7.

Medical School, Faculty of Medical and Health Sciences, University of Western Australia, Royal Perth Hospital Unit, PO Box X2213, Perth, Western Australia, 6847, Australia.

Purpose Of Review: To examine outstanding issues in the relationship of alcohol to hypertension. These include whether the increase in BP with alcohol is causally related, the nature of the relationship in women, the contribution of alcohol-related increases in BP to cardiovascular disease and the aetiology of alcohol-related hypertension.

Recent Findings: Intervention studies and Mendelian randomisation analyses confirm the alcohol-BP relationship is causal. The concept that low-level alcohol intake reduces BP in women is increasingly unsustainable. Alcohol-related hypertension is in the causal pathway between alcohol use and increased risk for several cardiovascular outcomes. The aetiology of alcohol-related hypertension is multifactorial with recent data highlighting the effects of alcohol on the vasoconstrictor 20-HETE and oxidative stress. The high prevalence of both alcohol use and hypertension mandates a careful alcohol history in every patient with elevated BP. Early intervention for excessive alcohol use offers the promise of lower levels of BP and reduced risk of adverse cardiovascular outcomes.
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http://dx.doi.org/10.1007/s11906-019-0984-1DOI Listing
September 2019

Added predictive value of high uric acid for cardiovascular events in the Ambulatory Blood Pressure International Study.

J Clin Hypertens (Greenwich) 2019 07 6;21(7):966-974. Epub 2019 Jun 6.

University of Padova, Padua, Italy.

The prognostic value of uric acid (UA) for cardiovascular events (CVE) is still debated. Our purpose was to investigate the association between UA and CVE in 5243 participants of the ABP-International study with the main aim of identifying optimal sex-specific cut-points. In multivariable Cox analyses, the relationship between CVE and UA as a continuous variable was modeled by including both linear and nonlinear terms. Survival models were also estimated with UA as a categorical variable. Optimal UA cut-points were determined using an outcome-oriented approach. During a median follow-up of 5.9 years, there were 423 CVE (93 fatal). In age- and sex-adjusted Cox models, UA as a continuous variable was a significant predictor of CVE in all individuals and in men and women considered separately. The relationship between UA and CVE was linear (P-value for nonlinearity 0.54 and 0.80 for men and women, respectively). For each 1 mg/dL increase in UA, the relative hazard increase was 16% in men and 19% in women. In fully adjusted models, UA remained a significant predictor of CVE in the whole study cohort. The optimal cut-point best separating patients at low and high risk of CVE was 6.3 mg/dL for men and 4.4 mg/dL for women. Subjects with high UA had a 38% greater risk of CVE. In a sex-specific analysis, the association remained significant only in men (hazard ratio, 1.47; P < 0.01). In conclusion, high UA is an independent predictor for subsequent CVE and significantly improves risk discrimination and reclassification over the baseline multivariable model.
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http://dx.doi.org/10.1111/jch.13584DOI Listing
July 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019
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