Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Abstract

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.

Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

“…However, the common Cys273 allele of rs2230624 is associated with increased risk, suggesting that loss of CD30 function may be protective for asthma. This hypothesis would be consistent with data showing that the Tyr273 leads to reduced cellular and soluble CD30 levels 13 and that CD30 increases pro-inflammatory cytokine production by CD4 + T cells in the context of Th1, Th2, and Th17 immune responses 44 . Furthermore, soluble CD30 levels are elevated in patients with asthma or atopic dermatitis and correlate with disease severity 45,46 .…”

“…Altogether, the 66 loci explained an additional 1.5% of the heritability for asthma and bring the total number of susceptibility loci to 212 at the time of this analysis. However, we note that while this manuscript was under consideration, 13 of the 66 loci identified herein were reported in two other independent studies 12,13 (Table 1).…”

“…Of these regions, 41 loci were not previously known to be associated with asthma or the combined phenotype of asthma and allergic diseases. The remaining 104 overlapped with the 146 loci previously identified for either asthma alone in adults, children, or subjects from multiple ancestries, or the combined phenotype of asthma, eczema, and hay fever [5][6][7][8][9][10][11][12][13] (Supplementary Data 2).…”

“…This concept is also supported by the nature of specific candidate causal genes located at some of the susceptibility loci. One such example is the chromosome 1p36.22 locus, which was identified independently in two other recent studies while this manuscript was under consideration 12,13 . In our analysis, the lead SNP (rs2230624; G>A) yielded the strongest effect size for asthma (OR = 1.…”

“…Consistent with this notion, estimates for the heritability of asthma have ranged between 35% and 95% 3 , although those based on twin studies have been lower 4 . Genome-wide association studies (GWAS) have confirmed the contribution of genetic factors to risk of asthma, with over 140 susceptibility loci having been identified thus far [5][6][7][8][9][10][11][12][13] . However, the risk alleles, most of which are common in the population, still only explain a small fraction of the overall heritability for asthma [5][6][7] .…”