Polymorphisms Falling Within Putative miRNA Target Sites in the 3'UTR Region of SIRT2 and DRD2 Genes Are Correlated With Human Longevity.

Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3'-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case-control analysis. Two SNPs,SIRT2-rs45592833 G/T and DRD2-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p= 1.090 × 10(-6)and 1.964 × 10(-4)forSIRT2 and DRD2, respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for SIRT2 and DRD2, and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes.