Gender Differences in Gene Polymorphisms Are Linked to Up-Reguated Leukotriene Pathway in Asthma

Background: Single nucleotide polymorphisms (SNPs) of the leukotriene (LT) pathway might represent a risk factor for many inflammatory diseases associated with LT production. The 5-lipoxygenase protein enzyme (5-LO) and its downstream LT metabolites are important modulators of inflammation in asthma, but whether gender differences underlie the different phenotypes observed in males (M) and females (F) is unknown. Aims and objectives: We investigated the gender-associated genetic variations of Arachidonate 5-lipoxygenase (ALOX-5), encoding for 5-LO, and the ALOX-5 activating protein (AP), encoding for the 5-lipoxygenase-activating protein (FLAP), in M and F from a clinical well-characterized patient cohort. Methods: In a prospective cohort of 158 age- and sex-matched subjects with asthma and healthy controls, three SNPs involved in LTs pathway were genotyped with allele-specific rtPCR from dry buccal swab samples. Also, serum levels of 5-LO were measured by ELISA. Results: Homozygous variant allele of ALOX5 rs2029253 and rs2115819 were more frequent in M compared to F (p< 0.0001) and were associated with lower levels of 5-LO (p< 0.0001) in M. Instead, F with the ALOX-5 homozygous variant allele rs2029253 had higher levels of 5-LO (p<0.0001). Moreover, the ALOX5AP homozygous wildtype allele rs10507391 was more frequent in F compared to M (p < 0.05). Conclusions: Our results point at gender-associated genetic polymorphisms associated with increased levels of asthma inflammatory markers. The characterization of such genetic polymorphisms in M and F may represent a new resource in the prediction of drug responses and clinical outcomes in asthma with a gender-informed approach.