Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study
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{"title"=>"Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study", "type"=>"journal", "authors"=>[{"first_name"=>"Raquel", "last_name"=>"Granell", "scopus_author_id"=>"23469333600"}, {"first_name"=>"A. John", "last_name"=>"Henderson", "scopus_author_id"=>"25949938800"}, {"first_name"=>"David M.", "last_name"=>"Evans", "scopus_author_id"=>"7601570762"}, {"first_name"=>"George Davey", "last_name"=>"Smith", "scopus_author_id"=>"35354080500"}, {"first_name"=>"Andrew R.", "last_name"=>"Ness", "scopus_author_id"=>"7006634151"}, {"first_name"=>"Sarah", "last_name"=>"Lewis", "scopus_author_id"=>"35478819000"}, {"first_name"=>"Tom M.", "last_name"=>"Palmer", "scopus_author_id"=>"16310563500"}, {"first_name"=>"Jonathan A.C.", "last_name"=>"Sterne", "scopus_author_id"=>"56962728000"}], "year"=>2014, "source"=>"PLoS Medicine", "identifiers"=>{"scopus"=>"2-s2.0-84905401194", "sgr"=>"84905401194", "issn"=>"15491676", "doi"=>"10.1371/journal.pmed.1001669", "pmid"=>"24983943", "isbn"=>"1549-1277", "pui"=>"373686447"}, "id"=>"feb181be-a4a0-3ed6-893a-73b1b91b295b", "abstract"=>"BACKGROUND: 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. METHODS AND FINDINGS: We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7(1/2) 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. CONCLUSIONS: 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.", "link"=>"http://www.mendeley.com/research/effects-bmi-fat-mass-lean-mass-asthma-childhood-mendelian-randomization-study", "reader_count"=>75, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>20, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>4, "Other"=>4, "Student > Master"=>11, "Student > Bachelor"=>6, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>20, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>4, "Other"=>4, "Student > Master"=>11, "Student > Bachelor"=>6, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Biochemistry, Genetics and Molecular Biology"=>7, "Nursing and Health Professions"=>5, "Materials Science"=>1, "Mathematics"=>3, "Medicine and Dentistry"=>35, "Agricultural and Biological Sciences"=>8, "Sports and Recreations"=>1, "Psychology"=>3, "Chemistry"=>1, "Social Sciences"=>3, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>35}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>3}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>5}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>7}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "France"=>1, "Australia"=>1}, "group_count"=>3}

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  • {"files"=>["https://ndownloader.figshare.com/files/1575816"], "description"=>"†<p>Adjusted for gender, birth weight, pre- and postnatal maternal exposure to smoking, and maternal education.</p>a<p>Controls were children with no current asthma at 7½ y.</p>b<p>Chi-squared test comparing estimate effects for non-atopic and atopic asthma.</p>‡<p>Test for the null hypothesis that the RR in males is the same as the RR in females (likelihood ratio test).</p><p>*Based on residuals from regression models of mass measure (fat/lean mass) on height, height squared, and gender. Fat mass was divided by two so that its standard deviation was similar to that of BMI and lean mass.</p>c<p>Controls were children with no current asthma at 9 y.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "non-atopic", "atopic", "asthma", "children"], "article_id"=>1089824, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t003", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Associations_of_BMI_fat_mass_and_lean_mass_with_current_asthma_non_atopic_asthma_and_atopic_asthma_in_children_at_7_189_and_9_y_/1089824", "title"=>"Associations of BMI, fat mass, and lean mass with current asthma, non-atopic asthma, and atopic asthma in children at 7½ and 9 y.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575814"], "description"=>"a<p>Chi-squared test comparing estimate effects for non-atopic and atopic asthma.</p>b<p>Controls were children with no current asthma.</p>‡<p>Test for the null hypothesis that the RR in males is the same as the RR in females (likelihood ratio test).</p><p>*Based on residuals from regression models of mass measure (fat/lean mass) on height, height squared, and gender. Fat mass was divided by two so that its standard deviation was similar to that of BMI and lean mass.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "estimates", "causal", "bmi", "non-atopic", "atopic", "asthma", "children", "two-stage", "gmm"], "article_id"=>1089822, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t005", "stats"=>{"downloads"=>5, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Instrumental_variable_estimates_of_the_causal_effect_of_BMI_on_current_asthma_non_atopic_asthma_and_atopic_asthma_in_children_at_age_7_189_and_9_y_using_two_stage_GMM_estimator_/1089822", "title"=>"Instrumental variable estimates of the causal effect of BMI on current asthma, non-atopic asthma, and atopic asthma in children at age 7½ and 9 y using two-stage GMM estimator.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575810"], "description"=>"<p>The left panel shows the mean BMI (with 95% CI) in groups defined by quintiles of genotype-predicted BMI. The right panel shows the same means and confidence intervals superimposed on the overall distribution of BMI plotted against genotype-predicted BMI.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "bmi", "32", "bmi-related"], "article_id"=>1089818, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_BMI_at_7_189_y_of_32_BMI_related_SNPs_/1089818", "title"=>"Association of BMI at 7½ y of 32 BMI-related SNPs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575818"], "description"=>"a<p>Number of children with data available.</p>†<p>BMI cut points for overweight and obese defined by Cole et al. <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001669#pmed.1001669-Cole2\" target=\"_blank\">[16]</a>.</p>‡<p>Median lean mass and median fat mass were calculated and used separately for females and males.</p><p>*Educated to General Certificate of Education level (school leaving certificate at 16 y) or lower.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "children", "bmi", "risks", "asthma"], "article_id"=>1089826, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_4_835_children_with_data_on_genetic_markers_asthma_and_BMI_and_risks_of_current_asthma_at_7_189_y_/1089826", "title"=>"Characteristics of 4,835 children with data on genetic markers, asthma, and BMI and risks of current asthma at 7½ y.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575813"], "description"=>"†<p>Adjusted for gender, birth weight, pre- and postnatal maternal exposure to smoking, and maternal education.</p><p>*Derived using ever doctor-diagnosed asthma (available at 7½, 11, 14, and 15 y) and parent-reported current asthma or wheezing or treatment in last 12 mo.</p><p>DDA, doctor-diagnosed asthma; NA, not available.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "instrumental", "estimates", "bmi", "asthma", "ages", "11", "14-diagnosed", "15", "boys", "girls", "stratified", "atopy"], "article_id"=>1089821, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t006", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Observational_and_instrumental_variable_estimates_of_the_effect_of_BMI_on_current_asthma_at_ages_11_to_14_diagnosed_asthma_at_ages_7_189_to_15_y_in_boys_and_girls_and_stratified_by_atopy_at_7_189_y_/1089821", "title"=>"Observational and instrumental variable estimates of the effect of BMI on current asthma at ages 11 to 14-diagnosed asthma at ages 7½ to 15 y in boys and girls and stratified by atopy at 7½ y.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575812"], "description"=>"<p>The SNPs are those previously reported in a meta-analysis <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001669#pmed.1001669-Speliotes1\" target=\"_blank\">[9]</a> that excluded ALSPAC data. rs2287019 and rs4771122 were omitted from the forest plot because IV RRs were not estimable. Also rs10150332, rs10767664, rs10938397, rs1555543, rs206936, rs2112347, rs2287019, rs2890652, rs381029, rs4771122, rs4836133, rs9816226, and rs987237 were excluded because the corresponding SE (of the log RR) was >2.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "causal", "asthma", "32", "bmi-related"], "article_id"=>1089820, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.g003", "stats"=>{"downloads"=>3, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Forest_plot_of_the_individual_causal_effects_on_current_asthma_at_7_189_y_of_32_BMI_related_SNPs_/1089820", "title"=>"Forest plot of the individual causal effects on current asthma at 7½ y of 32 BMI-related SNPs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575808"], "description"=>"<p>(A) depicts the IV assumptions, and (B) shows the two unconfounded associations used to estimate causal effects of BMI on asthma: the association of the allele score with BMI and the association of the allele score with asthma.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "mendelian", "randomization"], "article_id"=>1089816, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Main_Mendelian_randomization_features_and_results_of_the_study_/1089816", "title"=>"Main Mendelian randomization features and results of the study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575820", "https://ndownloader.figshare.com/files/1575821", "https://ndownloader.figshare.com/files/1575822", "https://ndownloader.figshare.com/files/1575823"], "description"=>"<div><p>Background</p><p>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.</p><p>Methods and Findings</p><p>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 <i>p</i>-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, <i>p</i> = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m<sup>2</sup>, <i>p</i> = 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 (<i>p</i> = 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 <i>FTO</i> 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.</p><p>Conclusions</p><p>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.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "asthma", "mendelian", "randomization"], "article_id"=>1089828, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001669.s001", "https://dx.doi.org/10.1371/journal.pmed.1001669.s002", "https://dx.doi.org/10.1371/journal.pmed.1001669.s003", "https://dx.doi.org/10.1371/journal.pmed.1001669.s004"], "stats"=>{"downloads"=>10, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_BMI_Fat_Mass_and_Lean_Mass_on_Asthma_in_Childhood_A_Mendelian_Randomization_Study_/1089828", "title"=>"Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575817"], "description"=>"<p>Of the 14,062 participants, 8,365 had genetic data (after genetic quality control filters excluding individuals with incorrect sex assignments, minimal or excessive heterozygosity, disproportionate levels of missingness, cryptic relatedness, and non-European ancestry). 4,835 individuals had both genetic data and data on BMI and current asthma at 7–7½ y, and these individuals form the core sample for these analyses.</p><p>*Chi-squared tests and <i>t</i>-test were used as appropriate.</p><p>**General Certificate of Education level (school leaving certificate at 16 y) or lower, compared with A-level (qualification at 18 y) or degree level.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "included", "excluded"], "article_id"=>1089825, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparing_participants_included_and_excluded_in_these_analyses_/1089825", "title"=>"Comparing participants included and excluded in these analyses.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1575815"], "description"=>"†<p>Linear regression coefficient, adjusted for gender. RR for number non-asthma/asthma and number non-atopic/atopic.</p><p>*Based on residuals from regression models of mass measure (fat/lean mass) on height, height squared, and gender. Fat mass was divided by two so that its standard deviation was similar to that of BMI and lean mass.</p>a<p>Controls were children with no current asthma at 7½ y.</p>b<p>Chi-squared test comparing estimate effects for non-atopic and atopic asthma.</p>c<p>Controls were children with no current asthma at 9 y.</p>", "links"=>[], "tags"=>["epidemiology", "Genetic epidemiology", "pediatrics", "Child health", "Pediatric pulmonology", "Public and occupational health", "preventive medicine", "weighted", "allele", "bmi"], "article_id"=>1089823, "categories"=>["Biological Sciences"], "users"=>["Raquel Granell", "A. John Henderson", "David M. Evans", "George Davey Smith", "Andrew R. Ness", "Sarah Lewis", "Tom M. Palmer", "Jonathan A. C. Sterne"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001669.t004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Associations_of_the_weighted_allele_score_with_BMI_at_age_7_189_and_9_y_/1089823", "title"=>"Associations of the weighted allele score with BMI at age 7½ and 9 y.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-07-01 02:48:06"}

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