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Abstract：
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.
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摘要：
家族性部分脂肪营养不良（FPLD）是一组与心脏代谢疾病的高患病率相关的异质性综合征。先前的工作已提出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，但这一指标以前还没有在大型队列研究中得到表征.我们着手（1）了解英国生物银行多达40,796名参与者和Fenland研究中的9,408名参与者的高FMR个体的心脏代谢负担，(2)表征FMR的常见变异遗传基础，（3）建立并测试FMR的多基因预测因子。在英国生物银行中，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）的风险更高，并有较高的空腹胰岛素（差异=19.8pmol/L，p=5.7×10-36）和空腹甘油三酯（差异=36.1mg/dL，p=2.5×10-28)在芬兰研究中。在FMR及其组成特征中，发现了61对条件独立的变异性状对，包括13个新确定的对。FMR的多基因评分与心脏代谢疾病的风险增加相关。这项工作在两项大型队列研究中确立了高FMR（FPLD的生物标志物）的心脏代谢意义，并可能证明可用于提高代谢不健康脂肪分布患者的诊断率，以实现治疗或预防性治疗。
