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A recent genome-wide study on late-onset Alzheimer's disease identified a SNP (rs5984894) on Xq21.3 in the PCDH11X gene strongly associated with LOAD individuals of European descent from the United States. We genotyped the same polymorphism in 1222 cases and 938 controls from central-northern Italy and could not confirm the association on the Italian population: multivariate logistic regression adjusted for gender and APOE ℇ4 allele resulted in a global p value of 0.56. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD. Methodology/Principal Findings: We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR = 1.85, 95% CI:1.04-3.23) in particular for females (OR = 2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls. Conclusions: Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study investigated DNA methylation differences in easily accessible white blood cells (WBCs) between malignant pleural mesothelioma (MPM) cases and asbestos-exposed cancer-free controls. A multiple regression model highlighted that the methylation level of two single CpGs (cg03546163 in FKBP5 and cg06633438 in MLLT1) are independent MPM markers. The epigenetic changes at the FKBP5 and MLLT1 genes were robustly associated with MPM in asbestos-exposed subjects. Interaction analyses showed that MPM cases and cancer-free controls showed DNAm differences which may be linked to asbestos exposure. Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study is the first one to investigate DNA methylation changes in white blood cells (WBCs) from easily accessible peripheral blood as malignant pleural mesothelioma (MPM) survival biomarker. The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases. The identification of simple and valuable prognostic markers for MPM will enable clinicians to select patients who are most likely to benefit from aggressive therapies and avoid subjecting non-responder patients to ineffective treatment. Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM. [ABSTRACT FROM AUTHOR]

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events. [ABSTRACT FROM AUTHOR]

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes., Results: We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition., Conclusions: We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes.

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.

The study of the genetics of longevity has been mainly addressed by GWASs that considered subjects from different populations to reach higher statistical power. The "price to pay" is that population-specific evolutionary histories and trade-offs were neglected in the investigation of gene-environment interactions. We propose a new "diachronic" approach that considers processes occurred at both evolutionary and lifespan timescales. We focused on a well-characterized population in terms of evolutionary history ( i.e. Italians) and we generated genome-wide data for 333 centenarians from the peninsula and 773 geographically-matched healthy individuals. Obtained results showed that: (i) centenarian genomes are enriched for an ancestral component likely shaped by pre-Neolithic migrations; (ii) centenarians born in Northern Italy unexpectedly clustered with controls from Central/Southern Italy suggesting that Neolithic and Bronze Age gene flow did not favor longevity in this population; (iii) local past adaptive events in response to pathogens and targeting arachidonic acid metabolism became favorable for longevity; (iv) lifelong changes in the frequency of several alleles revealed pleiotropy and trade-off mechanisms crucial for longevity. Therefore, we propose that demographic history and ancient/recent population dynamics need to be properly considered to identify genes involved in longevity, which can differ in different temporal/spatial settings.

Little is known about the impact of space (geography/ancestry) and time (age of the individuals) on DNA methylation variability in humans. We investigated DNA methylation of the imprinted IGF2/H19 locus in: i) a cohort of individuals homogeneous for age and gender (males with restricted age range: 30-50 years) belonging to four Italian districts representative of the major genetic clines, informative for the geographical dimension; ii) a cohort of monozygotic (MZ) and dizygotic (DZ) twins of different ages (age-range: 22-97 years), informative for the temporal dimension. DNA methylation of the analyzed regions displayed high levels of inter-individual variability that could not be ascribed to any geographical cline. In MZ twins we identified two IGF2/H19 regions where the intra-couple variations significantly increased after the age of 60 years. The analysis of twins' individual life histories suggests that the within twin pairs difference is likely the result of the aging process itself, as sharing a common environment for long periods had no effect on DNA methylation divergence. On the whole, the data here reported suggest that: i) aging more than population genetics is responsible for the inter-individual variability in DNA methylation patterns in humans; ii) DNA methylation variability appears to be highly region-specific.

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and ε rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and ε4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/ε4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified.