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Relationship of fat mass ratio – a biomarker for lipodystrophy – with cardiometabolic traits

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posted on 2024-02-12, 16:59 authored by Saaket Agrawal, Jian’an Luan, Beryl B. Cummings, Ethan Weiss, Nick J. Wareham, Amit V. Khera

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 10-41) and MASLD/MASH (OR = 2.55, p = 4.9 x 10-7) in UK Biobank, and had higher fasting insulin (difference = +19.8 pmol/L, p = 5.7 x 10-36) and fasting triglycerides (difference = +36.1 mg/dL, p = 2.5 x 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 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.

Funding

This work was supported by the Sarnoff Cardiovascular Research Foundation Fellowship (to S.A.), grants 1K08HG010155 and 1U01HG011719 (to A.V.K.) from the National Human Genome Research Institute, a Hassenfeld Scholar Award from Massachusetts General Hospital (to A.V.K.), a Merkin Institute Fellowship from the Broad Institute of MIT and Harvard (to A.V.K.). S.A. and A.V.K. are listed as co-inventors on a patent application for the use of imaging data in assessing body fat distribution and associated cardiometabolic risk.

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