IL-10 is both an immunoinhibitory (monocytes and T cells) and an immunostimulatory (B cells) cytokine that may confer susceptibility and modulate disease expression in rheumatoid arthritis (RA). The capacity to produce IL-10 (as measured by production of IL-10 in a lipopolysaccharide-stimulated whole blood culture) differs about fourfold between individuals. By comparing variance between monozygotic and dizygotic twins it was estimated that 60% of these differences are caused by genetic factors.

To determine relevance for susceptibility to diseases, we determined production levels of IL-10 in lipopolysaccharide-induced whole blood cultures from 76 new incident, non-treated RA patients and 63 healthy controls. RA patients had a 50% lower IL-10 production than controls (P < 0.001). In a cohort of women (≥ 85 years) with high risk of cardiovascular death 1, we observed that low innate IL-10 production yielded a threefold increase in risk of dying, which, interestingly, correlates with the presence of the A allele of the IL-10 -2849 promoter polymorphism (P = 0.021).

To elucidate this genetic basis of IL-10 secretion and the functionality of IL-10 promoter polymorphisms, we used the technique of allele-specific transcript quantification to characterise the ratio between two alleles of the IL-10 gene in 15 healthy heterozygous individuals. We identified two groups whereby five healthy donors exhibited a 1:1 ratio whereas seven exhibited a ratio >1 (P < 0.0017) 2. Donors heterozygous for haplotype IL-10.2 were only prevalent in the group with higher allelic expression ratios. The G allele of the IL-10 promoter single nucleotide polymorphism -2849 tags this haplotype, providing functional evidence that differential allelic transcription partly explains the constant associations found with IL-10 production levels.

In conclusion, this study provides evidence that IL-10 haplotypes dictating production of IL-10 are involved not only in conferring susceptibility to RA, but also in risk for cardiovascular death in old age.