Assessing the Validity of Asthma Associations for Eight Candidate Genes and Age at Diagnosis Effects

Abstract

BackgroundBefore the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis.Methodology/Principal FindingsWe systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R.Conclusions/SignificanceOur results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

Association between β2-Adrenoceptor Gene Polymorphisms and Asthma Risk: An Updated Meta-Analysis

“…Nevertheless, neither an individual GWAS study nor meta-analysis of GWAS has implicated ADRB2 the susceptibility gene for asthma. In our meta-analysis, we found that neither ADRB2 Arg/Gly16 nor ADRB2 Gln/Glu27 has significant association with asthma in Caucasian population, which further confirmed the results of previous published single GWAS and meta-analysis [51], [59], [60]. However, significant associations were found between ADRB2 Arg/Gly16 and asthma in Asian population, and this result contrasts with the results of studies recently conducted in Japan and Singapore [61]–[63], in which no single nucleotide polymorphisms in ADRB2 gene was found statistically significant.…”

“…Genome-wide association study (GWAS) has been productive genotyping method to test a vast number of single nucleotide polymorphisms and assess their relations with complex diseases and phenotypes [57] . Since the first GWAS investigating susceptibility gene for asthma published in 2007 [58] , more than ten GWAS of asthma have been performed in Caucasian, Mexican, and African-ancestry populations [51] , [59] , [60] and more recently in Japan and Singapore of Asian populations [61] – [63] . Nevertheless, neither an individual GWAS study nor meta-analysis of GWAS has implicated ADRB2 the susceptibility gene for asthma.…”

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

“…Another possible explanation may be due in part to the differing LD patterns displayed by genetic variants between racial/ethnic groups (Shifman et al 2003; Xu et al 2007). It is also possible that a portion of the previous associations identified in adult studies of asthma susceptibility were age-dependent and may not have the same impact in a pediatric cohort (Castro-Giner et al 2010; Pino-Yanes et al 2013). We must also consider the possibility that the original findings reported in published GWAs studies were false positives or spurious associations.…”

Genetic Aspects of Respiratory Allergy

“…Unlike other diseases, allergy and asthma appear to be arguably multifactorial and multigenic disorders, and therefore it has not been possible identify till now one or a set of specific genes that may be genetic markers [57,81], although recent paper identifies the involvement of GSTO2 loci in asthma, and GSTA1 as risk factor for asthma and allergies in Italian patients [56], while Genome-wide association studies (GWAS) represent the most powerful approach for asthma, have identified several distinct others genotypes from IL-18R1, IL-33, SMAD3, ORMDL3, HLA-DQ and IL-2RB loci [31].…”