Abstract

<p dir="ltr">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 (trunk fat %) divided by leg fat percentage (leg fat %) – 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 (OR = 2.30, p = 3.5 x 10<sup>-41</sup>) and MASLD/MASH (OR = 2.55, p = 4.9 x 10<sup>-7</sup>) in UK Biobank, and had higher fasting insulin (difference = +19.8 pmol/L, p = 5.7 x 10<sup>-36</sup>) and fasting triglycerides (difference = +36.1 mg/dL, p = 2.5 x 10<sup>-28</sup>) 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 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.</p>

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