Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study "Treviso Longeva (TRELONG)".

Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study "Treviso Longeva," including elderly over 70 years of age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders = 0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders = 0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population.

Interleukin-1α, interleukin-1ß and tumor necrosis factor-α genetic variants and risk of dementia in the very old: evidence from the "Monzino 80-plus" prospective study.

The association among single nucleotide polymorphisms in inflammatory genes as interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß) or tumor necrosis factor alpha (TNF-α) and dementia has been explored mostly in Alzheimer's disease, while few data addressing their association with dementia in very old people are available. We performed a prospective, door-to-door population-based study of 80 years or older residents in eight municipalities of Varese province, Italy (the Monzino 80-plus study). No difference was found by a cross-sectional approach comparing IL-1α rs1800587, IL-1ß rs3087258 and TNF-α rs1799724 genotypic and allelic frequencies between those affected and not affected by dementia. After a 5-year follow-up, the elderly carriers of T-allele of TNF-α rs1799724 were at an increased risk of dementia (p = 0.03). This association was no more significant adjusting for the apolipoprotein E epsilon-4 allele (APOE-ε4, p = 0.26), which was an independent predictor of dementia onset (p = 0.0002). In short, in this Italian population of oldest olds, dementia was associated to the APOE-ε4 allele only.

Association of SORL1 alleles with late-onset Alzheimer's disease. findings from the GIGAS_LOAD study and mega-analysis.

The pathophysiology of Alzheimer's disease (AD) is influenced by sorting-protein related receptor (sorLa) that is less expressed in AD patients. The gene encoding sorLa (SORL1) has been investigated as a susceptibility factor for late-onset AD (LOAD) with conflicting results. Our objectives were to confirm the association between SORL1 SNPs and LOAD in two independent South-European centers and to perform a mega-analysis of published samples. We analyzed three SORL1 SNPs (intron 6: rs668387; rs689021; rs641120) from the Greece-Italy Genetic Association Study on lateonset AD (GIGAS_LOAD). Greek sample included 96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a community-based sample is ongoing. 47 LOAD patients and 165 controls were recruited until study endpoint. These samples and previously published ones (Alzgene) were pooled as in a single study. A test for trend was used to analyze genotype association. In the GIGAS_LOAD sample no association was detected between SORL1 genotypes and LOAD. Conversely all SNPs were associated with LOAD in mega-analysis based on ordinal classification of genotypes (Armitage's test: p < 0.001). Although our analysis of pooled samples has positive results for the association between SORL1 and AD, there is substantial heterogeneity across studies. Thus further examination into SORL1 SNPs and the population is necessary to determine the role of SORL1 in LOAD.

A novel study and meta-analysis of the genetic variation of the serotonin transporter promoter in the italian population do not support a large effect on Alzheimer's disease risk.

Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A → G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk.