Sex-biased genetic regulation of inflammatory proteins in the Dutch population

Differences in inflammation between males and females can explain sex-biased susceptibility and severity of various common diseases such as atherosclerosis, cancer, autoimmune diseases and many more [1]. While females are less prone to infectious diseases than males, they account for more than 80% of individuals presented with autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatic arthritis (RA) and autoimmune thyroid disease [2]. Sex differences in immunological responses and disease susceptibility may be influenced by the complex interaction of sex hormones [3], host microbiome [4], immune-regulatory genes located on the X-chromosome [5] and environmental exposures [6,7,8]. It is also possible that genetic polymorphisms associated with immune phenotypes partially account for sex-based differences in immune response. In this regard and given the recent recognition of sex-stratified analysis, studies in the context of epigenetics [9, 10] and transcriptomics [11, 12] have been conducted. The disproportionate sex influence on all these phenotypes, including treatment efficacy [13], makes it imperative to understand the role of sex on modulation of inflammation in complex traits and diseases which will ultimately help our quest of developing personalized treatments.

Many of the key inflammatory markers which are released into the bloodstream during inflammation and are associated with chronic diseases are proteins, the functional molecules encoded by the genome [14]. A plethora of protein quantitative trait loci (pQTL) studies have been conducted to characterize genetic variants associated with circulating protein levels in both healthy and disease individuals [15,16,17,18,19,20,21]. Despite the burgeoning number of studies reporting sex-based differences in the immune response, most of the research on pQTLs analysis mainly adjust for sex differences in the model without seeking to identify sex-specific pQTLs. A recent study clearly demonstrated sex-dependent effect on the circulating concentrations of inflammatory proteins [22]. Therefore, identifying the precise factors driving the inter-individual variability in inflammatory protein levels especially in sex-dependent fashion will help to comprehensively understand sex differences in inflammatory-driven diseases and to make meaningful prediction of individual risk for diseases.

In the present study, using two population-based cohorts, we aimed to identify which genetic variants affect inflammatory protein levels in sex-specific manner. We identified and compared genetic variants associated with protein concentrations profiled with the Olink Inflammation panel using meta-analytic approach in males and females separately. We demonstrate that while the regulation of numerous pQTL variants is independent of sex, some key loci act discordantly between sexes and are correlated with sex-dependent traits.