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Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

ABSTRACT: Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p?=?0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p?=?0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p?=?0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

SUBMITTER: Granell R

PROVIDER: S-EPMC4077660 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

Granell Raquel R Henderson A John AJ Evans David M DM Smith George Davey GD Ness Andrew R AR Lewis Sarah S Palmer Tom M TM Sterne Jonathan A C JA

PLoS medicine 20140701 7

<h4>Background</h4>Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.<h4>Methods and findings</h4>We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALS ...[more]

PMID: 24983943

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Project description:Fat mass may be a causal determinant of bone mass, but the evidence is conflicting, possibly reflecting the influence of confounding factors. The recent identification of common genetic variants related to obesity in children provides an opportunity to implement a Mendelian randomization study of obesity and bone outcomes, which is less subject to confounding and several biases than conventional approaches. Genotyping was retrieved for variants of two loci reliably associated with adiposity (the fat mass and obesity-related gene FTO and that upstream of the MC4R locus) within 7470 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had undergone total body DXA scans at a mean of 9.9 yr. Relationships between both fat mass/genotypes and bone measures were assessed in efforts to determine evidence of causality between adiposity and bone mass. In conventional tests of association, both with and without height adjustment, total fat mass was strongly related to total body, spinal, and upper and lower limb BMC (ratio of geometric means [RGM]: 1.118 [95% CI: 1.112, 1.123], 1.110 [95% CI: 1.102, 1.119], 1.101 [95% CI: 1.093, 1.108], 1.146 [95% CI: 1.143, 1.155]; p < 10(-10) [adjusted for sex, height, and sitting height]). Equivalent or larger effects were obtained from instrumental variable (IV) regression including the same covariates (1.139 [95% CI: 1.064, 1.220], 1.090 [95% CI: 1.010, 1.177], 1.142 [95% CI: 1.049, 1.243], 1.176 [95% CI: 1.099, 1.257]; p = 0.0002, 0.03, 0.002, and 2.3(-6) respectively). Similar results were obtained after adjusting for puberty, when truncal fat mass was used in place of total fat, and when bone area was used instead of bone mass. In analyses where total body BMC adjusted for bone area (BA) was the outcome (reflecting volumetric BMD), linear regression with fat mass showed evidence for association (1.004 [95% CI: 1.002, 1.007], p = 0.0001). IV regression also showed a positive effect (1.031 [95% CI: 1.000, 1.062], p = 0.05). When MC4R and FTO markers were used as instruments for fat mass, similar associations with BMC were seen to those with fat mass as measured by DXA. This suggests that fat mass is on the causal pathway for bone mass in children. In addition, both directly assessed and IV-assessed relationships between fat mass and volumetric density showed evidence for positive effects, supporting a hypothesis that fat effects on bone mass are not entirely accounted for by association with overall bone size.

Project description:BackgroundChildhood obesity is reported to be associated with the risk of many diseases in adulthood. However, observational studies cannot fully account for confounding factors. We aimed to systematically assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR).MethodsAfter data filtering, 263 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. Inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods were used to estimate the causal effects. Multivariable MR analysis was performed to test whether the effects of childhood BMI on adult traits are independent from adult BMI.ResultsWe identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = - 0.10, 95% CI - 0.13 to - 0.07, P = 6.26 × 10-11). Specifically, higher childhood BMI was associated with increased odds of coronary artery disease (OR = 1.09, 95% CI 1.06 to 1.11, P = 4.28 × 10-11), essential hypertension (OR = 1.12, 95% CI 1.08 to 1.16, P = 1.27 × 10-11), type 2 diabetes (OR = 1.36, 95% CI 1.30 to 1.43, P = 1.57 × 10-34), and arthrosis (OR = 1.09, 95% CI 1.06 to 1.12, P = 8.80 × 10-9). However, after accounting for adult BMI, the detrimental effects of childhood BMI on disease-related traits were no longer present (P > 0.05). For dietary habits, different from conventional understanding, we found that higher childhood BMI was associated with low calorie density food intake. However, this association might be specific to the UK Biobank population.ConclusionsIn summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Multivariable MR analysis suggested that the associations between childhood BMI and increased risks of diseases in adulthood are likely attributed to individuals remaining obese in later life. Therefore, ensuring that childhood obesity does not persist into later life might be useful for reducing the detrimental effects of childhood obesity on adult diseases.

Dataset Information

Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

Publications

Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

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