An IL6 variant -174 G-C alters cardiac hypertrophy but not cardiometabolic responses to HFD in mice

Chronic elevations in interleukin-6 (IL6) signaling have been shown to exacerbate features of cardiometabolic disease. A common variant in the IL6 promoter (location -174 G/C, identifier rs1800795) is associated with increased circulating IL6, and increased cardiometabolic disease incidence in some populations. This study's objective was to isolate the impact of this gene variant on cardiometabolic responses to metabolic stress, using knock-in mice with a GG wildtype or variant CC genotype for the murine homolog of rs1800795. Male and female IL6 variant CC mice on a high fat diet exhibited enhanced systemic IL6 levels but similar weight gain, energy expenditure, adipose tissue inflammation, glucose homeostasis, and cardiac function relative to control GG mice. Sex differences in the effect of the IL6 variant on cardiomyocyte dimensions were observed, with male variant mice exhibiting smaller cardiomyocyte volume, and female variant mice exhibiting larger cardiomyocyte volume with smaller raw heart mass relative to control GG mice. These findings suggest that, in a controlled experimental setting, the IL6 promoter variant (-174 G/C) does not increase susceptibility to cardiometabolic disease. Further work is required to understand the mechanistic link between this IL6 variant and associated increased cardiometabolic risk observed in population studies.