Genetic Analysis Of Klotho In Diseases Of Aging

根据对klotho突变小鼠的研究，klotho基因在抑制几种不同的衰老表型方面发挥了作用。Klotho基因缺陷纯合的小鼠表现出一种与人类衰老非常相似的症状，包括动脉粥样硬化、骨质疏松症、肺气肿、不孕不育和皮肤萎缩。我们假设，在老鼠身上发现的与寿命延长相关的特定klotho变体可能在人类身上起作用。 我们已经对整个BLSA和Inchianti人群的KL-VS等位基因进行了基因分型。数据分析正在进行中，以寻找BLSA和INCHIANTI研究中检查的特定等位基因变异和表型之间的相关性。在上一次报告期间，我们扩大了分析范围，包括BLSA和INCHIANTI人群中LMNA基因的多态。 我们完成了BLSA中Klotho与多态的关系分析，发现它与男性的胰岛素抵抗(异常的2小时葡萄糖耐量试验)有关，但与女性无关。有趣的是，在男性和女性中，VS+基因多态与空腹胰岛素无关。Inchianti研究中关于Klotho多态的数据尚未分析。 我们已经提交了一份手稿，我们正在进行进一步的分析，旨在证明尽管Klotho在OGTT测试中影响葡萄糖代谢，可能是通过调节胰岛素抵抗，但它不会影响静止时的葡萄糖代谢，这可能解释了其他研究报告的否定结果。

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.