Genome‐wide association study of body mass index in 23 000 individuals with and without asthma

Abstract

Background Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. Objective To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. Methods In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics. Results We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. Conclusions and Clinical Relevance DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Novel genetic risk factors for asthma in African American children: Precision Medicine and the SAGE II Study

“…Such findings underscore the importance of studying multiple racial and ethnic groups in genetic association studies. To our knowledge, studies of pleiotropy between asthma and obesity genetics have only been performed in pediatric populations of European descent (Gonzalez et al 2014; Melen et al 2013; Melen et al 2010; Wang et al 2015). This presents a gap in our scientific knowledge that limits the standard of care available for populations, such as African Americans, who are among the most severely affected by the co-occurrence of these conditions.…”

“…Genetic associations with asthma may potentially be mediated by obesity status. Pleiotropic effects between obesity and asthma at the single nucleotide polymorphism (SNP) or gene-level may partly explain the association between these two conditions (Gonzalez et al 2014; Melen et al 2013; Melen et al 2010; Wang et al 2015). The majority of asthma genetic studies have not explored whether obesity mediates the association between identified genetic variants and asthma status (Akhabir and Sandford 2011; Hoffjan et al 2003).…”

What the Genetic Background of Individuals with Asthma and Obesity Can Reveal: Is β2-Adrenergic Receptor Gene Polymorphism Important?

“…However, while genetic analysis did not reveal any association for these genes, together with no association for ADRB2, and with the comorbidity of asthma and obesity, a trend was observed for glucosamine-6-phosphate deaminase-2 (GNPDA2), protein tyrosine phosphatise, receptor type D (PTPRD), and roundabout axon guidance receptor homolog 1 (ROBO1), although further research is likely required. In a recent study by Melén et al, 68 the DENN/MAD domain containing 1B (DENND1B), which is a protein that may play a role in clathrin-mediated endocytosis, was identified as being associated with BMI in asthmatic children, while no such relation was revealed for ADRB2. In another study (Tesse et al), the authors suggested that the TNFA and VDR genes probably could be involved in pleiotropic mechanisms responsible for the comorbidity of asthma and some endocrine disorders.…”

Adiposity, Fractional Exhaled Nitric Oxide, and Asthma in U.S. Children

“…Various pathways have been proposed, including mechanical changes from excessive weight (8); existence of comorbidities, such as obstructive sleep apnea; a proinflammatory milieu that exists in obesity; and shared genetic polymorphisms (9,10). It is becoming progressively clear that the "obese asthmatic" phenotype is likely complex and multifactorial.…”