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The effect of birth weight on body composition: Evidence from a birth cohort and a Mendelian randomization study.

ABSTRACT: BACKGROUND:Lower birth weight is associated with diabetes although the underlying mechanisms are unclear. Muscle mass could be a modifiable link and hence a target of intervention. We assessed the associations of birth weight with muscle and fat mass observationally in a population with little socio-economic patterning of birth weight and using Mendelian randomization (MR) for validation. METHODS:In the population-representative "Children of 1997" birth cohort (n = 8,327), we used multivariable linear regression to assess the adjusted associations of birth weight (kg) with muscle mass (kg) and body fat (%) at ~17.5 years. Genetically predicted birth weight (effect size) was applied to summary genetic associations with fat-free mass and fat mass (kg) from the UK Biobank (n = ~331,000) to obtain unconfounded estimates using inverse-variance weighting. RESULTS:Observationally, birth weight was positively associated with muscle mass (3.29 kg per kg birth weight, 95% confidence interval (CI) 2.83 to 3.75) and body fat (1.09% per kg birth weight, 95% CI 0.54 to 1.65). Stronger associations with muscle mass were observed in boys than in girls (p for interaction 0.004). Using MR, birth weight was positively associated with fat-free mass (0.77 kg per birth weight z-score, 95% CI 0.22 to 1.33) and fat mass (0.58, 95% CI 0.01 to 1.15). No difference by sex was evident. CONCLUSION:Higher birth weight increasing muscle mass may be relevant to lower birth weight increasing the risk of diabetes and suggests post-natal muscle mass as a potential target of intervention.

SUBMITTER: Liu J

PROVIDER: S-EPMC6736493 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The effect of birth weight on body composition: Evidence from a birth cohort and a Mendelian randomization study.

Liu Junxi J Au Yeung Shiu Lun SL He Baoting B Kwok Man Ki MK Leung Gabriel Matthew GM Schooling C Mary CM

PloS one 20190910 9

<h4>Background</h4>Lower birth weight is associated with diabetes although the underlying mechanisms are unclear. Muscle mass could be a modifiable link and hence a target of intervention. We assessed the associations of birth weight with muscle and fat mass observationally in a population with little socio-economic patterning of birth weight and using Mendelian randomization (MR) for validation.<h4>Methods</h4>In the population-representative "Children of 1997" birth cohort (n = 8,327), we used ...[more]

PMID: 31504067

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Project description:Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW. Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BW were estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome. Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BW was 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10-3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis. Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI.

Project description:Purpose: Birth weight has a profound long-term impact on individual's predisposition to various diseases at adulthood-a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight. Materials and methods: Mendelian randomization using multiple genetic instruments associated with birth weight was performed to explore the causal relationship between birth weight and adult diseases. The causal relationship between birth weight and 21 adult diseases as well as 38 other complex traits was examined based on data collected from 37 large-scale genome-wide association studies with up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses, bias calculation, and simulations. Results: Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight after the Bonferroni correction. The measurement unit of birth weight was defined as its standard deviation (i.e., 488 g), and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D), and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17-1.53], 1.30 (95% CI 1.13-1.51), 1.41 (95% CI 1.15-1.73), and 1.54 (95% CI 1.25-1.89), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as reverse causation. In addition, analysis on 38 additional complex traits did not identify candidate traits that may mediate the causal association between birth weight and CAD/MI/T2D. Conclusions: The results suggest that lower birth weight is causally associated with an increased risk of CAD, MI, and T2D in later life, supporting the fetal origins of adult diseases hypothesis.

Project description:BackgroundNon-communicable diseases are the leading cause of death, worldwide. Obesity is one of the factors that is associated with the development of such diseases. The role of reproductive factors on women body composition has been evaluated, but the findings are controversial. This study was aimed at assessing the association of parity with body composition among women.MethodsIn 1982, the maternity hospital of Pelotas, a southern Brazilian city, were visited daily and all deliveries were identified. Those livebirths whose family lived in the urban area of the city have been prospectively followed (n = 5914). In 2012-13, we tried to follow the whole cohort, the subjects were interviewed and examined. We evaluated the association of parity with the following body composition variables: body mass index, waist circumference and fat mass %. Estimates were adjusted for family income, skin color, maternal schooling, occupational status, alcohol, smoking, physical activity, and consumption of processed and ultraprocessed foods. All these analyses were replicated among the cohort men as a comparison. We also assessed whether duration of breastfeeding moderated the association.ResultsIn the 2012-13 visit, 3701 subjects were evaluated (mean age of 30.2 years). In the present analysis, we included 1620 women and 1653 men. 33% of women were nulliparous and 48% of men were without children. Even after controlling for confounding, parous women had a BMI 0.96 kg/m2 (95% CI: 0.30; 1.62) higher than nulliparous and for men the regression coefficient was 0.79 kg/m2 (95% CI: 0.29; 1.29). Waist circumference was also higher among parous women. Among men, the association was not linear and the regression coefficients were lower than that observed among women [3.41 cm (95% CI: -0.91; 7.73) among men and 4.83 cm (95% CI: 2.43; 7.24) among women with more than 3 children when compared with those without children], but this difference was not statistically significant (interaction p value = 0.58). Fat mass % was not associated with parity. Breastfeeding did not modify the association between parity and body composition.ConclusionsParity was positively associated with body mass index and waist circumference among women. However, similar results among men suggest that there is no causal effect of parity.

Project description:Background: Adenosine triphosphate-citrate lyase (ACLY) inhibition has proven clinically efficacious for low-density lipoprotein cholesterol (LDL-c) lowering and cardiovascular disease (CVD) risk reduction. Clinical and genetic evidence suggests that some LDL-c lowering strategies, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition with statin therapy increase body weight and the risk of developing type 2 diabetes mellitus (T2DM). However, whether ACLY inhibition affects metabolic risk factors is currently unknown. We aimed to investigate the effects of ACLY inhibition on glycaemic and anthropometric traits using Mendelian randomization (MR). Methods: As genetic instruments for ACLY inhibition, we selected weakly correlated single-nucleotide polymorphisms at the ACLY gene associated with lower ACLY gene expression in the eQTLGen study (N = 31,684) and lower LDL-c levels in the Global Lipid Genetic Consortium study (N = 1.65 million). Two-sample Mendelian randomization was employed to investigate the effects of ACLY inhibition on T2DM risk, and glycaemic and anthropometric traits using summary data from large consortia, with sample sizes ranging from 151,013 to 806,834 individuals. Findings for genetically predicted ACLY inhibition were compared to those obtained for genetically predicted HMGCR inhibition using the same instrument selection strategy and outcome data. Results: Primary MR analyses showed that genetically predicted ACLY inhibition was associated with lower waist-to-hip ratio (β per 1 standard deviation lower LDL-c: -1.17; 95% confidence interval (CI): -1.61 to -0.73; p < 0.001) but not with risk of T2DM (odds ratio (OR) per standard deviation lower LDL-c: 0.74, 95% CI = 0.25 to 2.19, p = 0.59). In contrast, genetically predicted HMGCR inhibition was associated with higher waist-to-hip ratio (β = 0.15; 95%CI = 0.04 to 0.26; p = 0.008) and T2DM risk (OR = 1.73, 95% CI = 1.27 to 2.36, p < 0.001). The MR analyses considering secondary outcomes showed that genetically predicted ACLY inhibition was associated with a lower waist-to-hip ratio adjusted for body mass index (BMI) (β = -1.41; 95%CI = -1.81 to -1.02; p < 0.001). In contrast, genetically predicted HMGCR inhibition was associated with higher HbA1c (β = 0.19; 95%CI = 0.23 to 0.49; p < 0.001) and BMI (β = 0.36; 95%CI = 0.23 to 0.49; p < 0.001). Conclusions: Human genetic evidence supports the metabolically favourable effects of ACLY inhibition on body weight distribution, in contrast to HMGCR inhibition. These findings should be used to guide and prioritize ongoing clinical development efforts.

Project description:ImportanceObservational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.ObjectiveTo test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis.Design, setting, and participantsThis mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180?056 participants from 49 studies were included.Main outcomes and measuresType 2 diabetes and glycemic traits.ResultsThis mendelian randomization analysis included 49 studies with 41?155 patients with T2D and 80?008 control participants from study-level data and 34?840 patients with T2D and 114?981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P?=?4.03?×?10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P?=?.04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P?=?.04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (??=?0.189; SE?=?0.060; P?=?.002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration.Conclusions and relevanceIn this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

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The effect of birth weight on body composition: Evidence from a birth cohort and a Mendelian randomization study.

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The effect of birth weight on body composition: Evidence from a birth cohort and a Mendelian randomization study.

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