Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

Abstract

RATIONALE: Pulmonary mast cells (MC) have been associated with asthma pathogenesis. We have previously shown differences in MC phenotype by location in the lung (submucosa and epithelium) [Balzar, AJRCCM, 2011]. Little is known regarding the relative importance of luminal MCs to asthma. We hypothesized that distal/luminal MCs would better predict more severe clinical outcomes than proximal/epithelial MCs. METHODS: In 102 University of Pittsburgh asthmatics enrolled in NHLBI trials, bronchial epithelial brushings, bronchoalveolar (BAL) cells and fluid were obtained at bronchoscopy. Expression of the MC protease, tryptase mRNA was determined by qRT-PCR. Using the median tryptase mRNA values for epithelial brushings and BAL cells, subjects were classified as proximal and distal MC ''Hi'' or ''Lo.'' Regression analysis was performed to assess the effect of MC ''Hi'' on the outcomes of history of recent exacerbation, baseline FEV1% predicted and FEV1/FVC. RESULTS: Distal MCHi asthma significantly predicted exacerbation [OR53.6, p50.004], while proximal MCHi asthma did not [OR51.7, p50.2]. Distal MCHi asthma negatively associated with baseline FEV1% predicted [Beta5 -12.5, p50.006, R250.07] and baseline FEV1/FVC [Beta5 -0.06, p50.019, R250.05]. This relationship was not seen with proximal MCHi asthma [p for FEV1% predicted50.6, p for FEV1/ FVC50.8]. CONCLUSIONS: In matched samples from asthmatic subjects, the distal/ BAL cell MC signature better predicted asthma exacerbation, lower FEV1%predicted and decreased FEV1/FVC than the proximal/epithelial MC signature. In asthma, this suggests an important difference in MC function based on the location in the lung. Use of distal MC biomarkers should better identify more clinically severe asthma. 900 Association study in African-admixed J ALLERGY CLIN IMMUNOL FEBRUARY 2019 AB296 Abstracts MONDAY

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

“…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).…”

“…Second, recent studies have shown that both common and distinct loci underlie susceptibility to asthma in adulthood and in children 10,11 , but we did not take age of onset into account for our analyses in order to increase power for detecting associations and due to the unavailability of this information in publicly available summary data from the TAGC. Third, since most subjects in the UK Biobank and TAGC were of European ancestry, some, but not all, of the genetic associations we identified may be relevant in non-European populations 9 . This notion has previously been observed with both common and rare variants even among closely related Latino populations and in comparison, to subjects of African ancestry 14,58 .…”

“…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] .…”

The Advantages and Challenges of Diversity in Pharmacogenomics: Can Minority Populations Bring Us Closer to Implementation?

“…In this study, the investigators found rs28450894 (located within NFKB1 and quantitative trait locus for SLC39A8 ), which is significantly associated with drug response, was predominantly found in African ancestry populations (8.8–28.7%), vs. European populations (3.7–7.6%) and Puerto Ricans (6.2%), and Mexicans (1.5%) . An admixture mapping meta‐analysis of genetic ancestry identified a new locus at 18q21 that contributed to asthma susceptibility and therapies in Latinos and a recent paper identified two novel loci in 8p23 and 8q24 specific to asthma risk in African populations . These novel loci found through admixture mapping and population‐specific cohorts may yield novel drug targets and biomarkers that may be useful, if replicated, for patient stratification.…”

“…80 An admixture mapping meta-analysis of genetic ancestry identified a new locus at 18q21 that contributed to asthma susceptibility and therapies in Latinos 84 and a recent paper identified two novel loci in 8p23 and 8q24 specific to asthma risk in African populations. 85 These novel loci found through admixture mapping and population-specific cohorts may yield novel drug targets and biomarkers that may be useful, if replicated, for patient stratification.…”