[Evaluating the causal relationship between hip circumference and coronary heart disease: a Mendelian randomization study]

Area of Science:

• Genetics
• Cardiovascular Disease Epidemiology
• Metabolic Health

Background:

• Obesity and body fat distribution are associated with cardiovascular disease risk.
• Hip circumference adjusted for body mass index (HCadjBMI) is a measure of central adiposity.
• Mendelian randomization (MR) can infer causal relationships using genetic variants as instrumental variables.

Purpose of the Study:

• To investigate the causal effect of HCadjBMI on coronary heart disease (CHD) using a two-sample Mendelian randomization analysis.
• To assess whether genetic predisposition to higher HCadjBMI influences CHD risk.

Main Methods:

• Utilized genome-wide association study (GWAS) data from the GIANT consortium for HCadjBMI (n=211,114) and the CARDIoGRAM consortium for CHD (n=86,995).
• Employed 70 independent, genome-wide significant genetic variants as instrumental variables.
• Applied the inverse-variance weighted (IVW) method for pooled effect estimation and MR-Egger regression to detect pleiotropy.

Main Results:

• A genetically predicted increase in HCadjBMI was associated with a significantly lower risk of CHD (OR=0.831, 95% CI 0.730-0.946).
• MR-Egger regression indicated no significant directional pleiotropy (intercept=-0.0012, P=0.875), supporting the validity of the causal inference.
• Leave-one-out analysis confirmed the robustness of the findings, with no single nucleotide polymorphism (SNP) unduly influencing the overall result.

Conclusions:

• Genetic predisposition towards a higher hip circumference adjusted for body mass index is causally associated with a reduced risk of coronary heart disease.
• These findings suggest that central adiposity, as indicated by HCadjBMI, may have a protective role against CHD, contrary to some traditional observations.
• Further research is warranted to elucidate the biological mechanisms underlying this association.