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Davide Seripa

Publications and source records attributed to Davide Seripa.

17 recordsLinked to original sources
PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗
PubMed2006

Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease.

The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.

Aged↗
PubMed2006

Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy.

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.

Aged↗
PubMed2006

Simple and effective determination of apolipoprotein E genotypes by positive/negative polymerase chain reaction products.

Several protein and DNA-based methods have been previously described for the identification of apolipoprotein E isoforms or genotypes. However, all of them generate frequently false-positive results. The purpose of this study was to set up a new, simple, and effective method for the analysis of the apoE polymorphism. A total of 1,253 subjects previously examined for the apolipoprotein E polymorphism by restriction fragment length polymorphism were reanalyzed by our new method based on Taq DNA polymerase's inability to correctly initiate the replication in the presence of a mismatch at the 3' end of the primer. We conceived a combination of 4 specific primers in 3 different pairs sharing the same stringent polymerase chain reaction conditions to directly detect the presence/absence of polymerase chain reaction products, and thus reveal the 6 apolipoprotein E genotypes. We confirm our previous results in 1,171 subjects, whereas in 82 subjects out of 1,253 (about 6%), the results have been reinterpreted. The final analysis revealed a total of 12 homozygotic subjects for the e2 allele (1.0%), 874 homozygotes for the e3 allele (69.8 %), and 8 homozygotes for the e4 allele (0.6 %). The frequence of heterozygotes was 8.7% for the e2/e3 genotype (n=109), 1.4% for the e2/e4 genotype (n=17), and 0.6% for the e3/e4 genotype (n=8). Relative allele frequencies were e2=0.060, e3=0.834, and e4=0.106. We describe a new, simple, unequivocal, and nonexpensive method for the identification of the 6 apoE genotypes.

Adult↗
PubMed2006

Clinical features of reflux esophagitis in older people: a study of 840 consecutive patients.

OBJECTIVES: To compare symptoms and other clinical characteristics of reflux esophagitis in patients of different ages. DESIGN: Observational cross-sectional study of consecutive patients. SETTING: Geriatric Unit, Casa Sollievo della Sofferenza Hospital, Istituto di Ricovero e Cura a Carattere Scientifico. PARTICIPANTS: Eight hundred forty patients with endoscopically diagnosed erosive esophagitis divided into four groups according to age (young (<50, mean 36.7, n=114), adult (50-69, mean 59.1, n=126), elderly (70-84, mean 77.3, n=425), and very elderly (>or=85, mean 88.4, n=175)). MEASUREMENTS: Gastrointestinal symptoms were evaluated using the Gastrointestinal Symptom Rating Scale questionnaire. Other symptoms were recorded when present as an indication for endoscopy. Severity of esophagitis, presence of Helicobacter pylori infection, presence and size of hiatus hernia, Barrett's esophagus, antrum or corpus gastric atrophy, and nonsteroidal antiinflammatory drug (NSAID) use were also evaluated. RESULTS: Elderly and very elderly patients had a significantly lower prevalence of typical gastroesophageal reflux disease symptoms (heartburn or acid regurgitation (P<.001) and epigastric pain (P<.001)) than young and adult patients. Conversely, the prevalence of other symptoms (anorexia (P<.001), weight loss (P<.007), anemia (P<.001), vomiting (P<.001), and dysphagia (P<.001)) significantly increased with age. The prevalence of severe esophagitis (P<.001), hiatus hernia (P<.005), the size of hiatus hernia (P<.001), antrum and corpus gastric atrophy (P<.05) and NSAID use (P<.005) also significantly increased with age. Multivariate analysis demonstrated that older age (65-84, odds ratio (OR)=2.66, 95% confidence interval (CI)=1.38-5.12; >or=85, OR=4.57, 95% CI=2.15-9.71), hiatus hernia larger than 3 cm in diameter (OR=2.38, 95% CI=1.41-4.01), and male sex (OR=2.83, 95% CI=1.72-4.64) are independent risk factors for severe esophagitis, whereas H. pylori infection, gastric atrophy, NSAID use, and the presence of hiatus hernia were not. CONCLUSION: Elderly patients with reflux esophagitis had less-typical and more-nonspecific symptoms than young or adult patients. Old age, male sex, and hiatus hernia size greater than 3 cm are significantly associated with severe esophagitis. Clinicians caring for older patients should be aware of the nonspecific presentation and potential severity of reflux esophagitis in this population.

Adolescent↗
PubMed2005

DNA end binding activity and Ku70/80 heterodimer expression in human colorectal tumor.

AIM: To determine the DNA binding activity and protein levels of the Ku70/80 heterodimer, the functional mediator of the NHEJ activity, in human colorectal carcinogenesis. METHODS: The Ku70/80 DNA-binding activity was determined by electrophoretic mobility shift assays in 20 colon adenoma and 15 colorectal cancer samples as well as matched normal colonic tissues. Nuclear and cytoplasmic protein expression was determined by immunohistochemistry and Western blot analysis. RESULTS: A statistically significant difference was found in both adenomas and carcinomas as compared to matched normal colonic mucosa (P<0.00). However, changes in binding activity were not homogenous with approximately 50% of the tumors showing a clear increase in the binding activity, 30% displaying a modest increase and 15% showing a decrease of the activity. Tumors, with increased DNA-binding activity, also showed a statistically significant increase in Ku70 and Ku86 nuclear expression, as determined by Western blot and immunohistochemical analyses (P<0.001). Cytoplasmic protein expression was found in pathological samples, but not in normal tissues either from tumor patients or from healthy subjects. CONCLUSION: Overall, our DNA-binding activity and protein level are consistent with a substantial activation of the NHEJ pathway in colorectal tumors. Since the NHEJ is an error prone mechanism, its abnormal activation can result in chromosomal instability and ultimately lead to tumorigenesis.

Adenoma↗
PubMed2005

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.

Aged↗
PubMed2004

Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors.

PURPOSE: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions. EXPERIMENTAL DESIGN: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTP1, TRbeta1, RARbeta2, HIC1, APC, CCND2, and CDH1 genes. RESULTS: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRbeta1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RARbeta2 locus (P < 0.03). CONCLUSIONS: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.

Analysis of Variance↗
PubMed2003

Mutations of the D310 mitochondrial mononucleotide repeat in primary tumors and cytological specimens.

A mononucleotide repeat (D310) in mitochondrial DNA has been recently identified as a mutational hot spot in primary tumors. We analyzed 56 tumors for insertion/deletion mutations in the D310 repeat. A total of 13 mutations were detected. The highest frequency of mutations was found for cervical cancer, followed by bladder tumors, breast cancer and endometrial neoplasia. No alterations were observed in four patients suspected of malignancy but without evidence of malignant tumor. We detected identical changes in four of four urine sediments from patients with bladder cancer and in three of three fine needle aspirates of patients with breast cancer. Our results indicate that D310 abnormalities are detectable in cytology specimens from patients with cancer and support the notion that D310 analysis may represent a new molecular tool for cancer detection.

Breast Neoplasms↗
PubMed2003

Methylenetetrahydrofolate reductase and angiotensin converting enzyme gene polymorphisms in two genetically and diagnostically distinct cohort of Alzheimer patients.

The role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) gene polymorphisms as risk factors for the occurrence of Alzheimer's disease (AD) is still controversial. In this study, we investigated the common MTHFR C677-->T and ACE insertion/deletion (I/D) gene polymorphisms as risk factors for AD in two genetically and diagnostically distinct cohort of Alzheimer's patients. We analyzed a neuropathologically confirmed American cohort of 124 AD patients and 97 elderly controls, and a clinically diagnosed Italian cohort of 126 probable AD cases, 106 elderly controls, and a community-based sample of 1232 subjects aged under 65 years. No difference was found in polymorphism distribution between cases and controls in both study cohorts. We also tested a possible association between the polymorphisms investigated. No interaction was found between the MTHFR and ACE alleles. Moreover, no association was found for the ACE and MTHFR polymorphisms with age at onset, disease duration and MMSE score at observation. Thus, in our study, MTHFR C677-->T and ACE I/D polymorphisms do not appear to confer an added risk for AD.

Age of Onset↗
PubMed2003

Differential modulation of Ku70/80 DNA-binding activity in a patient with multiple basal cell carcinomas.

Ku70/80 nonhomologous end-joining activity is essential for resolving random DNA double-strand breaks, and the Ku70/80 protein complex has been proposed as "caretaker" of genomic stability. We studied the Ku70/80 heterodimer activity in a patient affected by multiple basal cell carcinomas with a personal history of moderate exposure to ionizing radiation. The Ku70/80 DNA-binding activity was analyzed, by electrophoretic mobility shift assay, in five tumor biopsies from different sites and at distinct clinical stages, and in three matched normal skin samples from the same patient. As control normal tissues from healthy individuals were also tested. The five basal cell carcinomas were classified as "non aggressive" and "aggressive" on the basis of morphologic parameters and expression of the molecular markers bcl-2, Ki67/MIB1, and p53. A 62% increase in the Ku70/80 DNA-binding activity was found in normal skin from the patient, compared to unexposed individuals (p<0.0001). The nuclear activity of the heterodimer was further increased in nonaggressive basal cell carcinomas compared to both matched normal skin from the patient (31%, p=0.0001) and tissues from healthy controls (73%, p=0.0001). Strikingly, the two aggressive basal cell carcinomas tested showed very low Ku70/80 DNA-binding activity with a reduction of 87% compared to normal skin from the patient (p<0.0001) and 64% compared to controls (p=0.001). Although these results are limited to only one patient, together with other recent studies they support the hypothesis that downregulation of the nonhomologous end-joining pathway may be associated with tumor progression.

Aged↗
PubMed2003

Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke.

Evidence of inflammatory phenomena associated with atherosclerotic plaques is extensive. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response, and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number of tandem repeats (VNTR) in intron 2 of the human IL-1Ra shows a common polymorphism that has been related to different production of IL-1Ra and IL-1 proteins. In monocytes, the less common allele 2 has been associated with an increased production of IL-1Ra and a decreased production of IL-1. Moreover, a cooperative effect with a C to T polymorphism in the promoter of IL-1beta gene (C(-511)-->T) has been described. In the present study, we investigated the frequency of these polymorphisms in 110 subjects who survived an ischemic stroke, in 101 healthy age-matched individuals, and in a population-based sample of 1,303 healthy Italians. The frequency of the IL- 1Ra 1/1 genotype was significantly higher in stroke survivors with respect to age-matched controls (77.2 and 45.5%, respectively; p < 0.001), and to the wide group of healthy Italians (77.2 and 51.9%, respectively; p < 0.001). As expected, the estimated frequency of the IL-1Ra allele 1 (Ra*1 allele) in stroke survivors was higher than in age-matched controls (0.851 and 0.664, respectively; p < 0.001) and in healthy Italians (0.851 and 0.717, respectively; p < 0.001). Thus, ischemic stroke survivors that carry the Ra*1 allele showed a strong association with the disease with respect to age-matched controls [odds ratio (OR) = 3.905; 95% confidence interval (CI), 2.110-7.229] and healthy Italians [OR = 3.256 (95% CI, 1.971-5.379)]. No significant association was seen for the IL-1beta (C(-511)-->T) polymorphism. However, in stroke survivors, an association between the Ra*1 allele and the C allele of the IL-1beta (-511) polymorphism was found (p < 0.001). Our results implicate the IL-1Ra gene in the susceptibility to ischemic stroke, and suggest that IL-1Ra genotyping may be useful in the identification of patient subgroups for pharmacological intervention in IL-1 production or actions.

Adult↗
PubMedDate not supplied

Undercoding of Alzheimer's disease and related dementias in hospitalized elderly patients in Italy.

The prevalence of Alzheimer's disease (AD) and AD-related dementias (ADRD) in acute ward-hospitalized elderly patients is not well known, owing principally to misclassification and undercoding of AD and ADRD on hospital discharge abstract forms (DAFs). The aims of this study were to evaluate the prevalence of AD and ADRD, as evaluated by the DAF in elderly patients hospitalized in acute wards, and to compare clinical severity, length of stay, comorbidity, and number of diagnostic procedures in patients with AD versus ADRD to explain the different reimbursement costs of DRG12 (AD) versus DRG429 (ADRD). From the inpatient DAF database of the Casa Sollievo della Sofferenza Hospital, the DAFs of patients aged 65 years or over discharged from January 1, 2001, to March 31, 2003, with principal or secondary diagnoses of AD (ICD9-CM code 331) or ADRD (ICD9-CM codes from 290.0 to 290.43) were extracted and grouped by APR-grouper version 12. Age, gender, length of stay, principal and secondary diagnoses and procedures, and APR-DRG severity index (SI) and mortality risk (MR) were evaluated in these patients. Senile dementia was reported in 294 patients (0.58 percent, N = 50,253). In 123 patients (41.8 percent) dementia was the principal diagnosis, whereas in 171 patients (58.2 percent) dementia was reported on the DAF as a secondary diagnosis. Of the 123 patients with a principal diagnosis of dementia, 35 patients were included in the DRG-12 (AD) and 88 patients were included in the DRG-429 (ADRD). No differences were found in mean age, length of stay, comorbidity, or number of diagnostic procedures, as well as in the APR-DRG SI and APR-DRG MR between AD and ADRD patients. Conversely, reimbursement amounts were established as Euro4,033 for DRG-12 (AD) and Euro2,952 for DRG-429 (ADRD). AD and ADRD are undercoded in elderly hospitalized patients. The limits of the ICD9-CM classification system and the influence of reimbursement amounts may influence the coding reports by physicians.

Aged↗