Role of Sex on the Genetic Susceptibility to Childhood Asthma in Latinos and African Americans

Abstract

Asthma is a respiratory disease whose prevalence changes throughout the lifespan and differs by sex, being more prevalent in males during childhood and in females after puberty. In this study, we assessed the influence of sex on the genetic susceptibility to childhood asthma in admixed populations. Sex-interaction and sex-stratified genome-wide association studies (GWAS) were performed in 4291 Latinos and 1730 African Americans separately, and results were meta-analyzed. Genome-wide (p ≤ 9.35 × 10−8) and suggestive (p ≤ 1.87 × 10−6) population-specific significance thresholds were calculated based on 1000 Genomes Project data. Additionally, protein quantitative trait locus (pQTL) information was gathered for the suggestively associated variants, and enrichment analyses of the proteins identified were carried out. Four independent loci showed interaction with sex at a suggestive level. The stratified GWAS highlighted the 17q12-21 asthma locus as a contributor to asthma susceptibility in both sexes but reached genome-wide significance only in females (p-females < 9.2 × 10−8; p-males < 1.25 × 10−2). Conversely, genetic variants upstream of ligand-dependent nuclear receptor corepressor-like gene (LCORL), previously involved in height determination and spermatogenesis, were associated with asthma only in males (minimum p = 5.31 × 10−8 for rs4593128). Enrichment analyses revealed an overrepresentation of processes related to the immune system and highlighted differences between sexes. In conclusion, we identified sex-specific polymorphisms that could contribute to the differences in the prevalence of childhood asthma between males and females.

Identification of Sex-Specific Genetic Polymorphisms Associated with Asthma in Middle-Aged and Older Canadian Adults: An Analysis of CLSA Data

“…In previous studies, male and female-specific genetic markers have been associated with asthma. 22 , 25 However, these studies did not consider the influence of socio-demographic, socio-economic, and lifestyle factors.…”

“…20,21 Studies have shown that several gene polymorphisms and gene expressions associated with asthma are sex-specific. [22][23][24][25] For instance, a large genome-wide association study (GWAS) using EVE Asthma Genetics Consortium discovered six sex-specific asthma risk loci, with two male-specific SNPs in/near IRF and RAB11FIP2 gene and four female-specific SNPs in/near RAP1GAP2, C6orf118, ERBB4, and AK057517. 25 Other sex-specific polymorphisms in many genes have been identified, eg, a male-specific SNP in the LCORL gene was significantly associated with childhood asthma, 22 and a female-specific polymorphism in the COX-2 −765 gene was significantly associated with bronchial asthma.…”

Sex Differences in Airway Remodeling and Inflammation: Clinical and Biological Factors

“…Many studies focused on sex differences in asthma after adolescence identified that changes in DNA methylation in blood and lung tissue could play a role in the observed disparities ( 171 – 178 ). Furthermore, the interaction between sex-specific and sex-stratified genomes has also been found associated with childhood asthma ( 179 ). In this regard, the 17q12-21 -asthma locus was highlighted to be associated with asthma in both males and females but was widely significant in females ( 179 ).…”

“…Furthermore, the interaction between sex-specific and sex-stratified genomes has also been found associated with childhood asthma ( 179 ). In this regard, the 17q12-21 -asthma locus was highlighted to be associated with asthma in both males and females but was widely significant in females ( 179 ). Similarly, the ligand-dependent nuclear receptor co-repressor-like gene, located within the regulatory region was highlighted in males only ( 179 ).…”

“…In this regard, the 17q12-21 -asthma locus was highlighted to be associated with asthma in both males and females but was widely significant in females ( 179 ). Similarly, the ligand-dependent nuclear receptor co-repressor-like gene, located within the regulatory region was highlighted in males only ( 179 ). This gene peculiar to the males only is known to play a vital role in the determination of height and sperm production.…”