Phenotype data for the 300FG and 500FG cohorts

Differences of 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.