(CSEMP009) INVESTIGATING SEX SPECIFIC EFFECTS BETWEEN WAIST-HIP RATIO, ERYTHROCYTOSIS AND CARDIORESPIRATORY FITNESS THROUGH MENDELIAN RANDOMIZATION

Background: Our prior Mendelian randomization (MR) analyses suggest insulin resistance/hyperinsulinemia (IR/HI) increases erythrocytosis. Increased waist-hip ratio (WHR) is causally implicated in IR/HI and cardiometabolic traits with sex-differential effects. Aerobic fitness can independently impact cardiometabolic health and can be modulated by hemoglobin and diastolic function. Whether WHR increases hemoglobin is unknown, nor is it known if it impacts aerobic fitness. Further, whether these effects of WHR differ by sex is unknown.

METHODS AND RESULTS: For our primary analyses, we undertook bidirectional MR in combined and sex-stratified European ancestry cohorts to investigate potential causal associations between WHR and erythrocytosis. For our secondary analyses, we investigated the sex-stratified effect of WHR on cardiorespiratory fitness with adjustments for hemoglobin, diastolic function (longitudinal peak diastolic strain rate, LPDSR) and testosterone.

Results: Inverse variance weighted MR (IVWMR) primary analyses suggest increased WHR increases haemoglobin in combined sex analyses (Hb, b=0.11, p=7.47x10-6). This effect was confirmed in females (b=0.28, p=2.37x10-27) but not in males (b=0.054, p=0.197). In males, increased WHR associates with low testosterone, a regulator of erythrocytosis. Multivariable MR (MVMR) indicates increased WHR increases Hb after adjustment for testosterone (b=0.12, p=0.035).

Univariable MR did not find consistent evidence that increased WHR decreases VO2 max in sex-combined analyses. In males, increased WHR decreases VO2Max (b=-0.20, p=2.83x10-5) even after adjustment for Hb (b=-0.25, p=1.54x10-7), LPDSR (b=-0.21, p=3.43x10-5) or testosterone (b=-0.24, p=2.24x10-6). In females, increased WHR does not affect VO2Max (b=0.034, p=0.14).

Conclusion: MR suggests increased WHR increases erythrocytosis in females but this does not impact aerobic fitness. WHR does not increase erythrocytosis in males potentially due to the effects of reduced testosterone. Increased WHR likely decreases cardiorespiratory fitness in males independent of erythrocytosis, diastolic function and testosterone.