Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy

Peer reviewe

Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 1.

Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases-related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response

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

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12–q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations

Author Correction: Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations (Nature Communications, (2019), 10, 1, (880), 10.1038/s41467-019-08469-7)

The original version of this Article contained an error in the spelling of a member of the CAAPA Consortium, Hrafnhildur Bjarnadóttir which was incorrectly given as Hilda Bjarnadóttir. This has now been corrected in both the PDF and HTML versions of the Article.

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

Rationale: Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its high burden, representation of African ancestry individuals in asthma genome-wide association studies (GWAS) has been inadequate to date, and true associations in these underrepresented minority groups may have been missed. Here, we report the largest asthma GWAS to date from the Consortium on Asthma among African Ancestry Populations (CAAPA). Methods: CAAPA participants (7009 asthmatics, 7645 controls) were genotyped using the African Diaspora Power Chip (ADPC), an array designed to complement existing genome-wide array data, as well as Illumina’s Multi-Ethnic Genotyping array. Genotypes were imputed using the CAAPA whole genome-sequence reference panel. Logistic mixed effects models were used to test for association between allelic dosage and asthma, separately for each study. Results were meta-analyzed using a meta-regression approach that accounts for heterogeneity in allelic effects among ethnic groups. Results: We identified two novel loci that may be specific to asthma risk in African ancestry populations (lead SNP rs13277810, intronic to LOC101927815, p=3E-8; lead SNP rs114647118, intronic to TATDN1, p=3E-7). We found strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations (p\u3c0.05/810 candidate SNPs investigated), including the chr12q13 region, a novel locus identified by the Trans-National Asthma Genetic Consortium (TAGC) that has previously not been replicated. Conclusions: We report two associations that may bespecific to asthma risk in African ancestry populations. Our results also suggest some asthma risk loci discovered in non-African populations are relevant in African ancestry populations