背景:适应寒冷对于欧亚大陆的人类迁徙至关重要。通过棕色脂肪组织(BAT)的非发抖产热参与冷适应,因为一些参与BAT分化和功能的基因在高纬度人群中表现出积极的自然选择特征。这些基因是否与BAT产热的个体间变异性相关尚不清楚。在这项研究中,我们评估了东亚人群中候选基因区域的BAT活性与单核苷酸多态性(SNPs)之间的潜在关联.
方法:使用氟脱氧葡萄糖-正电子发射断层扫描和计算机断层扫描(FDG-PET/CT)在399名健康的日本男性和女性中测量了轻度冷暴露引起的BAT活性。在56名男性中测量了冷诱导的产热和脂肪氧化的能力。对六个基因座的11个SNP进行了与生理性状的关联分析(LEPR,ANGPTL8,PLA2G2A,PLIN1,TBX15-WARS2和FADS1)报告处于正自然选择状态。在FDG-PET/CT人群中发现的关联在84名健康的东亚男性和女性中得到了进一步验证,使用红外热成像法测定BAT活性。使用多个逻辑和线性回归模型测试了SNP基因型与BAT活性或其他相关性状之间的关联。
结果:在6个基因的11个推定的适应性等位基因中,LEPR中的两个内含子SNP(rs1022981和rs12405556)倾向于与较高的BAT活性相关。然而,这些试验未能在多重试验比较中幸存.与较低的身体脂肪百分比的关联,血浆甘油三酯,胰岛素,在FDG-PET/CT人群中观察到HOMA-IR水平(P<0.05)。其他基因座,包括TBX15-WARS2,它被推测为调节格陵兰因纽特人的冷适应,在BAT产热方面没有显着差异。
结论:我们的结果表明LEPRSNP之间存在边缘但显著的关联。然而,对于积极自然选择下的其他基因座通过BAT产热参与东亚成年人的冷适应,没有建立有力的支持证据。鉴于这些基因的多效性功能,除了通过BAT产热进行冷适应之外的其他因素,比如饮食适应,可能有助于这些基因座的积极自然选择。
BACKGROUND: Adaptation to cold was essential for human migration across Eurasia. Non-shivering thermogenesis through brown adipose tissue (BAT) participates in cold adaptation because some genes involved in the differentiation and function of BAT exhibit signatures of positive natural selection in populations at high latitudes. Whether these genes are associated with the inter-individual variability in BAT thermogenesis remains unclear. In this study, we evaluated the potential associations between BAT activity and single nucleotide polymorphisms (SNPs) in candidate gene regions in East Asian populations.
METHODS: BAT activity induced by mild cold exposure was measured in 399 healthy Japanese men and women using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). The capacity for cold-induced thermogenesis and fat oxidation was measured in 56 men. Association analyses with physiological traits were performed for 11 SNPs at six loci (LEPR, ANGPTL8, PLA2G2A, PLIN1, TBX15-WARS2, and FADS1) reported to be under positive natural selection. Associations found in the FDG-PET/CT population were further validated in 84 healthy East Asian men and women, in whom BAT activity was measured using infrared thermography. Associations between the SNP genotypes and BAT activity or other related traits were tested using multiple logistic and linear regression models.
RESULTS: Of the 11 putative adaptive alleles of the six genes, two intronic SNPs in LEPR (rs1022981 and rs12405556) tended to be associated with higher BAT activity. However, these did not survive multiple test comparisons. Associations with lower body fat percentage, plasma triglyceride, insulin, and HOMA-IR levels were observed in the FDG-PET/CT population (P < 0.05). Other loci, including TBX15-WARS2, which is speculated to mediate cold adaptation in Greenland Inuits, did not show significant differences in BAT thermogenesis.
CONCLUSIONS: Our results suggest a marginal but significant association between LEPR SNPs. However, robust supporting evidence was not established for the involvement of other loci under positive natural selection in cold adaptation through BAT thermogenesis in East Asian adults. Given the pleiotropic function of these genes, factors other than cold adaptation through BAT thermogenesis, such as diet adaptation, may contribute to positive natural selection at these loci.