Genetic Analysis Of Klotho In Diseases Of Aging

该方案的主要目标是对来自巴尔的摩老龄化纵向研究（BLSA）参与者的预衍生DNA样品进行LMNA和KLOTHO中的两种多态性的基因分型，这两种基因与过早衰老相关（分别为Hutchinson-Guilford早衰症和Klotho小鼠）。 虽然目前还没有已知的人类疾病是由KLOTHO突变引起的，但我们相信这两个基因的特定多态性可能与年龄相关疾病有关。 为此，使用焦磷酸测序技术，我们对来自BLSA的1329名参与者的KL-VS等位基因的三个单核苷酸多态性（SNP）的KLOTHO基因的外显子2进行了基因分型。 此外，我们对LMNA基因外显子10的3408 C/T SNP进行了基因分型，该SNP先前已被证明与胰岛素抵抗相关因素相关。 我们已经完成了KLOTHO基因型与糖尿病和胰岛素抵抗相关性的分析，并在横断面分析中发现了几个非常显著的（p<0.00001）关联，表明女性风险增加（OR>8）。 我们在一个更大的纵向分析中重复了这些相关性，风险比增加，并使用考克斯比例风险回归显示，在25年的随访中，糖尿病和胰岛素抵抗的风险增加。 共有2642份DNA样本可用于我们的分析;其中1329份来自BLSA，1313份来自InCHIANTI研究。 我们在InChianti样本中没有任何显著发现，这些样本的参数与BLSA中使用的参数不同。 我们已经修改了一份手稿，包括BLSA中KL-VS发现的新纵向分析，并将分析LMNA SNP基因型数据的相似关系。

The major goal of this protocol is to genotype pre-derived DNA samples from Baltimore Longitudinal Study of Aging (BLSA) participants for two polymorphisms in LMNA and KLOTHO, two genes related to premature aging (Hutchinson-Guilford progeria and the Klotho mouse, respectively). While no human disease is currently known to be caused by KLOTHO mutations, it is our belief that specific polymorphisms in these two genes may be associated with age-related illness. To that end, using the Pyrosequencing technique, we have genotyped exon two of the KLOTHO gene for the three single nucleotide polymorphisms (SNPs) of the KL-VS allele from 1329 participants in the BLSA. In addition, we have genotyped exon 10 of the LMNA gene for the 3408 C/T SNP that previously has been shown to be associated with factors related to insulin resistance. We have completed analysis of the KLOTHO genotype in relation to both diabetes and insulin resistance and have found in cross-sectional analysis several extremely significant (p<0.00001) associations indicating women at increased risk (OR>8). We have replicated these associations in a larger longitudinal analysis with increased hazard ratios and have shown using Cox proportional-hazards regression increased risk of diabetes and insulin resistance extending through 25 years of follow-up. A total of 2642 DNA samples were made available for our analysis; 1329 of these were from the BLSA and 1313 were from the InCHIANTI study. We did not have any significant findings with the InCHIANTI samples which had different parameters than those used in the BLSA. We have revised a manuscript to include the new longitudinal analysis of the KL-VS findings in the BLSA and will be analyzing the LMNA SNP genotype data for similar relationships.