Sex-stratified genetic regulators of cytokine production in the Dutch and Tanzanian populations

Differences in immune responses are observed between males and females, influenced by genetic, hormonal, and environmental factors. The sex-specific genetic effects on cytokine production however remain underexplored. This study aimed to identify sex-specific quantitative trait loci (QTLs) affecting cytokine production in response to diverse infectious antigens. We performed sex-stratified cytokine QTL (cQTLs) mapping in two population-based cohorts from Tanzania and the Netherlands. In the Tanzanian cohort, twelve genome-wide significant cytokine QTLs were identified, with seven observed in males and five in females. In the Dutch cohort, twelve genome-wide significant cQTLs were identified, with six cQTLs each in males and females. Colocalization analysis confirmed that all twelve genome-wide cQTLs from the Tanzanian cohort are sex-specific, while in the Dutch cohort ten genome-wide cQTL variants are modulated in a sex-specific manner. Furthermore, pathway and phenotype enrichment analyses linked the identified cQTL variants to relevant immune functions and sex-biased traits. Our study highlights the importance of sex-stratified genetic analyses when investigating the genetic basis of cytokine production in humans. We show that sex-specific cQTLs may underlie observed phenotypic differences between males and females and that accounting for such effects can inform the development of personalized medical treatments for sex-biased diseases.