Genetic Analysis Of Klotho In Diseases Of Aging

根据对klotho突变小鼠的研究，klotho基因已知在抑制几种不同的衰老表型中发挥作用。klotho基因缺陷的纯合子小鼠表现出一种与人类衰老非常相似的综合征，包括动脉粥样硬化、骨质疏松症、肺气肿、不孕症和皮肤萎缩。我们假设在小鼠中发现的与长寿相关的特定klotho变体可能在人类中起作用。 我们对整个BLSA和InChianti人群进行了KL-VS等位基因的基因分型。正在进行数据分析，以寻找BLSA和InChianti研究中检查的特定等位基因变体和表型之间的相关性。 在最后一个验证阶段，我们扩大了分析范围，包括BLSA和InChianti人群中LMNA基因的多态性。 我们完成了BLSA中Klotho VS多态性之间关系的分析，发现它与男性胰岛素抵抗（2小时葡萄糖耐量试验异常）有关，但与女性无关。有趣的是，在男性和女性中，VS+多态性与空腹胰岛素无关。 尚未分析InCHIANTI研究中Klotho多态性的数据。 已经提交了一份手稿，我们正在进行进一步的分析，旨在证明Klotho可能通过调节胰岛素抵抗影响OGTT试验期间的葡萄糖代谢，但它不会影响静息时的葡萄糖代谢，这可能解释了其他研究报告的阴性结果。

The klotho gene is known to play a role in suppressing several different aging phenotypes, based on studies in the klotho mutant mouse. Mice homozygous for defects in the klotho gene exhibit a syndrome that closely resembles human aging, including atherosclerosis, osteoporosis, emphysema, infertility and skin atrophy. We hypothesize that specific klotho variants found in mice associated with increased longevity may operate in humans. We have genotyped the entire BLSA and InChianti populations for the KL-VS allele. Data analysis is underway to search for correlations between specific allelic variants and phenotypes examined in the BLSA and InChianti studies. In the last reporteing period, we expanded the analysis to include polymorphisms in the LMNA gene in both the BLSA and InCHIANTI populations. We completed analysis of the relationship between the Klotho VS polymorphism in the BLSA and found it to be associated with insulin resistance (abnormal 2h glucose tollerance test) in men but not in women. Interestingly, both in men and in women, the VS+ polymorphism was not associated with fasting insulin. The data on the Klotho polymorphism in the InCHIANTI study have not been analyzed. A manuscript has been submitted and we are conducting further analyses aimed at demonstrating that while Klotho affect glucose metabolism during an OGTT test, perhaps by modulating insulin resistance, it does not affect glucose metabolism at rest which may explain the negative results reported by other studies.