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 × 10−41) and MASLD/MASH (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 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.

中文翻译：

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脂肪质量比（脂肪营养不良的生物标志物）与心脏代谢特征的关系

家族性部分脂肪代谢障碍（FPLD）是一组与心脏代谢疾病高患病率相关的异质性综合征。先前的工作提出了 DEXA 衍生的脂肪质量比 (FMR)——定义为躯干脂肪百分比（躯干脂肪 %）除以腿部脂肪百分比（腿部脂肪 %）——作为 FPLD 的生物标志物，但该指标之前尚未在大型队列研究。我们着手 (1) 了解英国生物银行多达 40,796 名参与者和 Fenland 研究中 9,408 名参与者的高 FMR 个体的心脏代谢负担，(2) 描述 FMR 的常见变异遗传基础，(3) 构建并测试 FMR 的多基因预测因子。英国生物银行中，FMR 高的参与者患 2 型糖尿病（OR = 2.30，p = 3.5 × 10−41）和 MASLD/MASH（OR = 2.55，p = 4.9 × 10−7）的风险较高，并且禁食率较高Fenland 研究中的胰岛素（差异 = +19.8 pmol/L，p = 5.7 × 10−36）和空腹甘油三酯（差异 = +36.1 mg/dL，p = 2.5 × 10−28）。在 FMR 及其组成特征中，发现了 61 个条件独立的变异特征对，其中包括 13 个新识别的对。 FMR 的多基因评分与心脏代谢疾病风险增加相关。这项工作在两项大型队列研究中确定了高 FMR（FPLD 的生物标志物）对心脏代谢的重要性，并且可能有助于提高代谢不健康脂肪分布患者的诊断率，从而实现治疗或预防性治疗。