Genetic Analysis Of Klotho In Diseases Of Aging

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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.