Paroni Giulia, Seripa Davide, Panza Francesco, Addante Filomena, Copetti Massimiliano, D'Onofrio Grazia, Pellegrini Fabio, Fontana Luigi, Pilotto Alberto
Geriatric Unit and Gerontology-Geriatric Research Laboratory, Department of Medical Sciences, I.R.C.C.S. Casa Sollievo della Sofferenza, Viale Cappuccini 1, San Giovanni Rotondo, Foggia, Italy.
Age (Dordr). 2012 Aug;34(4):949-68. doi: 10.1007/s11357-011-9273-x. Epub 2011 Jun 22.
Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.
klotho（KL）基因与生理生化参数的严重改变有关，这些改变会导致早衰样表型并显著缩短寿命。KL参与多种细胞内生化途径的调节，包括脂质谱和葡萄糖代谢。本研究的目的是调查KL基因座与通常被视为住院老年患者临床状态指标的生物学参数之间的可能关联。我们对594名连续入住老年病房的住院老年患者（65 - 99岁）的KL基因座上的单核苷酸多态性（SNP）rs9536314、rs1207568和rs564481进行了基因分型，并使用协方差分析和遗传风险评分模型测试了这些KL变体与生物学定量性状的关联。观察到rs9536314与血红蛋白、白蛋白和高密度脂蛋白胆固醇（HDL-C）血清水平之间存在显著关联，以及rs564481与血红蛋白、空腹胰岛素和空腹血糖血清水平之间存在显著关联。按性别分层分析证实了这些关联，并表明KL基因型与HDL-C、空腹血糖和空腹胰岛素水平的关联可能由女性驱动，而与血红蛋白血清水平的关联可能由男性驱动。仅在女性中发现KL基因型与肌酐水平的关联，而仅在男性中发现与胰岛素样生长因子-1（IGF-1）和淋巴细胞计数（LC）的关联。遗传风险评分（GRS）模型进一步证实了KL SNP与血红蛋白、总胆固醇和HDL-C之间的显著关联。使用GRS标记方法进行的按性别分层分析证实了女性中与HDL-C、空腹血糖和空腹胰岛素水平的关联，以及男性中与血红蛋白和LC的关联。我们的研究结果表明，KL基因座可能影响住院老年患者的定量性状，如脂质血清水平、空腹血糖、白蛋白和血红蛋白，对于肌酐、IGF-1水平和LC存在一些性别差异，因此是可能导致与年龄相关疾病和长寿的遗传因素之一。
