| Abstrakt: |
Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR), defined as trunk fat percentage divided by leg fat percentage, as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to 1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796 participants in the UK Biobank and 9,408 participants in the Fenland study, 2) characterize the common variant genetic underpinnings of FMR, and 3) build and test a polygenic predictor for FMR. Participants with high FMR were at higher risk for type 2 diabetes (odds ratio [OR] 2.30, P = 3.5 × 10−41) and metabolic dysfunction–associated liver disease or steatohepatitis (OR 2.55, P = 4.9 × 10−7) in UK Biobank and had higher fasting insulin (difference 19.8 pmol/L, P = 5.7 × 10−36) and fasting triglycerides (difference 36.1 mg/dL, P = 2.5 × 10−28) in the Fenland study. Across FMR and its component traits, 61 conditionally independent variant-trait pairs were discovered, including 13 newly identified pairs. A polygenic score for FMR was associated with an increased risk of cardiometabolic diseases. This work establishes the cardiometabolic significance of high FMR, a biomarker for FPLD, in two large cohort studies and may prove useful in increasing diagnosis rates of patients with metabolically unhealthy fat distribution to enable treatment or a preventive therapy. Article Highlights: Across two population-based cohorts, fat mass ratio, a DEXA-based biomarker of fat distribution previously proposed as a means of discriminating partial lipodystrophy, is associated with an increased risk of cardiometabolic diseases, fasting insulin, and fasting triglycerides. Fat mass ratio and its component traits are highly heritable, with a genome-wide polygenic score explaining 3.4–3.7% of trait variability and genome-wide association study in the UK Biobank revealing 61 conditionally independent variant-trait pairs. A genome-wide polygenic score for fat mass ratio is associated with an increased risk of metabolic syndrome and cardiometabolic diseases in the UK Biobank and Fenland cohorts. [ABSTRACT FROM AUTHOR] |
