Fig. 3.

Inflammatory-level cytokine association heatmap SKAT (Bonferroni-adjusted) _adjP values. A heatmap representation of SKAT _adjP values testing for association between variants in pro- or anti-inflammatory sets and IL-1β (a) and IL-6 (b) cytokine production in response to four different stimuli; LPS, PHA, C. albicans, and S. aureus. Common and rare variants were tested separately (based on a cohort allele frequency threshold of 5%), by means of the SKAT for common variants and the SKATO for rare variants, in two inflammatory-level groups that distinguish between pro- and anti-inflammatory roles of the respective gene-encoded proteins. Significance of _adjP values is highlighted in color, and only significant _adjP values are labelled. c Zooms in on the details of the significant association between S. aureus-induced IL-6 cytokine production and anti-inflammatory rare variants. The residual (corrected for age and sex) S. aureus-induced IL-6 cytokine production shown on the y-axis, is higher in anti-inflammatory rare variant carriers as compared to non-carriers (NO = individuals without rare variant in the anti-inflammatory group; YES = individuals carrying a rare variant in the anti-inflammatory group as shown on the x-axis). The Wilcoxon rank-sum P value reveals a significant difference between the two categories (P value = 0.003). Annotation: ** = < 0.01. Abbreviations: SKAT = Sequence Kernel Association Test; LPS = Lipopolysaccharide; PHA = Phytohaemagglutinin; C. albicans = Candida albicans; S. aureus = Staphylococcus aureus