Biomedical subjects

Giovanni Malerba

Publications and source records attributed to Giovanni Malerba.

9 recordsLinked to original sources

PubMed2026

Integrating machine learning and GWAS for variant prioritization in the INCIPE cohort highlights ABC transporter genes in chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health challenge, affecting approximately 674 million people worldwide and representing one of the fastest-growing causes of mortality. Since CKD is frequently asymptomatic in its early stages, the identification of novel genetic biomarkers may improve early detection and risk stratification. Genome-Wide Association Studies (GWAS) have identified numerous genetic loci associated with CKD and related traits; however, their performance is often limited in small and imbalanced cohorts, where reduced statistical power increases both false-positive and false-negative findings. Machine learning (ML) approaches can complement conventional GWAS by prioritizing biologically relevant genetic signals from high-dimensional genomic data. METHODS: In this study, we implemented a nested ensemble (NCBC) model composed of an undersampler and a CatBoostClassifier (CBC) to prioritize candidate genetic variants associated with CKD in the INCIPE cohort. Prioritized variants were functionally annotated and evaluated through enrichment analyses, GTEx gene expression profiling, and protein-protein interaction network analyses. Genes identified by the CKDGen Consortium were analysed as an external reference set and used to validate the biological relevance of the prioritized results. RESULTS: The NCBC model outperformed conventional ML classifiers, achieving a ROC AUC score of 87.77%, compared to 50%-53% for the other evaluated models. Among the prioritized genes, 56.25% showed protein-protein interactions with genes previously reported by the CKDGen Consortium, whereas only 1.9% of randomly generated gene sets showed interactions. DISCUSSION: Our study demonstrates that the NCBC model improves the prioritization of biologically plausible candidate variants in a small and imbalanced CKD cohort. Functional analyses suggested ABC transporter-related genes, including ABCA13, ABCA4, and ABCC4 genes, as promising candidate for future validation, with ABCA4 showing substantial expression in kidney tissues. Overall, these findings support the integration of ML with GWAS to prioritize candidate genes and investigate the genetic architecture of complex diseases.

SNP prioritization↗

PubMed2006

Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.

The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of the disorder(s) are elusive. We performed a mutational analysis of NEFL in a series of 177 index cases with CMT and without mutations in the genes for peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five new pedigrees with four mutations in the head and rod domains of NF-L, including a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several examined affected members exhibited marked variability in the severity of disease and age at onset. Nerve conduction alterations were consistent with an axonal neuropathy often associated with demyelinating features, such as prolonged distal latencies (DL). Pathological examination of sural nerve biopsies in the probands detected in four cases a chronic axonal neuropathy dominated by focal accumulations of NF with axonal swellings (giant axons) and significant secondary demyelination; in the fifth case no NFs accumulations were evident but many myelinated fibres consisted exclusively of microtubules with few or absent NF. The pathological phenotype correlated with the pattern of nerve conduction alterations and indicated that NEFL mutations cause a profound alteration of the cytoskeleton possibly related to defective targeting of NF.

Adolescent↗

PubMed2006

The genetic background of osteoporosis in cystic fibrosis: association analysis with polymorphic markers in four candidate genes.

BACKGROUND: Reduced Bone Mass Density (BMD) is frequent in Cystic Fibrosis (CF). Potentially, other genes than the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may contribute to the bone phenotype variability in CF patients. METHODS: Four candidate genes likely associated with BMD variability were studied: the vitamin D receptor (VDR) gene, the estrogen receptor alpha (ESR1), the calcitonin receptor (CALCR) and the type I alpha 1 collagen (COL1A1) gene. A complete bone and CF evaluation was obtained for 82 subjects (39 m, 43 f): 15 had normal BMD (group 1), 46 were osteopenic (group 2), and 21 were osteoporotic (group 3). RESULTS: No statistical difference was found among the three groups for age, sex, pancreatic status, and vertebral fractures, nor for any of the biochemical markers. Weight, Body Mass Index (BMI), and FEV1, scored significantly worse in the two groups with the lowest T score. The CFTR mutations R1162X and F508del were more frequent in patients with lower BMD (p=0.044 and p=0.071). There was no significant difference in the distribution of the five marker genotypes among the 3 groups defined according to the unadjusted or adjusted (BMI and FEV1) BMD T score. No significant correlation was found between the VDR, CALCR, or COL1A1 gene polymorphisms and reduced BMD values. The individual ESR1 PvuII-XbaI haplotype C-A is associated to elevated u-calcium levels whereas the haplotype T-A is associated to lower values (p=0.00251). CONCLUSIONS: There was no evidence that the genes under study, with the possible exception of ESR1 gene variants, may modulate bone phenotype in CF.

Adult↗

PubMed2006

The -1131 T>C and S19W APOA5 gene polymorphisms are associated with high levels of triglycerides and apolipoprotein C-III, but not with coronary artery disease: an angiographic study.

High plasma concentrations of triglycerides (TG) and apolipoprotein C-III (ApoC-III) are well-known risk factors for cardiovascular disease. Two variants of the recently discovered APOA5, 1131 C>T and S19W, have been associated with hypertriglyceridemia, whereas their relation with coronary artery disease (CAD) remains controversial. Nine hundred and thirteen angiografically defined patients (669 CAD and 244 CAD-free) were genotyped for APOA5 -1131 C>T and S19W polymorphisms. Carriership of the APOA5 -1131 C allele was identified, by multiple linear regression models, as a significant independent predictor for both TG (standardized beta-coefficient=0.112; p=0.010) and ApoC-III variability (standardized beta-coefficient=0.113; p=0.013). Similarly, APOA5 19W allele carriership was a significant independent predictor for both TG (standardized beta-coefficient=0.113; p=0.007) and ApoC-III variability (standardized beta-coefficient=0.088; p=0.045). Despite the association with at-risk lipid profile, no significant difference was detected in the distribution of both APOA5 gene polymorphisms between subjects with or without CAD. Moreover, homozygous carriers of the APOC3 -455 C, another TG- and ApoC-III raising variant, showed a significant increased risk for CAD (OR 1.90 with 95% CI 1.002-3.62; p=0.049; by multiple logistic regression). Different genotypes, i.e., APOA5 and APOC3 variants, may lead to similar biochemical phenotypes, namely hypertriglyceridemia, but to contrasting clinical phenotypes such as the presence of angiographically proven CAD.

Adult↗

PubMed2006

On the association of the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction or coronary artery disease.

The human oxidised low-density lipoprotein receptor 1 (OLR1) gene is a functional candidate for atherosclerosis. An association of the OLR1 gene with acute myocardial infarction (AMI) or coronary artery disease (CAD) has recently been reported. In the present study a total of 677 Italian subjects, 327 CAD-free, 350 CAD, of which 190 with AMI and 160 AMI-free, was genotyped for the following four OLR1 single nucleotide polymorphisms: exon 4 K167N, IVS4 -73C>T, IVS4 -14A>G, and 3'UTR 188 C>T. No statistically significant difference was observed in allele or genotype distribution of the exon 4, intron 4, or 3'UTR SNPs in CAD patients compared to CAD-free subjects, or within CAD, in AMI patients compared to AMI-free patients. A correlation was found between the K167N G/G genotype and the increased number of obstructed vessels. Even if the OLR1 genotype frequency distribution data in CAD or AMI subjects here reported do not fully confirm the positive results of some other association studies, an association with a marker of CAD severity was observed.

3' Untranslated Regions↗

PubMed2006

Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients.

Solid organ transplant recipients are at higher risk of non-melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S-transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1-2.5); P = 0.017]. Homozygosity for allele GSTP1 Val(105) was lower in cases [OR 0.3 (0.1-0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0-0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4-6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val(462) genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val(462), show a higher risk of developing NMSC [OR 4.5 (1.1-21.4); P = 0.03], especially SCC [OR 6.5 (1.4-34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val(462) are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.

Adult↗

PubMed2005

A review of asthma genetics: gene expression studies and recent candidates.

Recent evidence indicates an important role of inflammation pathways, airways remodeling and epithelium activation in asthma genetics. In particular, transcriptome studies have detected differentially expressed genes involved in eosinophil apoptosis, the arginase pathway, response to allergens or interleukins, and to inhaled corticosteroids. Candidate gene and genome wide studies have localized genetic regions involved in the disease, such as the A1AR and CLCA1 genes (chromosome 1), IL-1RN and DPP10 (2q14), HLA-G and TNF-a (6p21), GPRA (7p14), FceRI and GSTP1 (11q13), NOS1, IFNG, STAT6, VDR, and other genes (12q13-26), PHF11 and flanking genes (13q14), AACT and PTGDR (14q), and ADAM33 (20p13). The role of these and other genetic determinants has to be confirmed in future, preferably longitudinal, studies.

Allergens↗

PubMed2004

Association of the interleukin-1 receptor antagonist gene with asthma.

The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05-0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.

Asthma↗

PubMed2002

Complement receptor 1 gene polymorphisms in sarcoidosis.

Sarcoidosis is likely to result from exposure of genetically susceptible hosts to environmental agents. Erythrocyte (E) complement receptor 1 (CR1) is a membrane protein mediating the transport of immune complexes (ICs) to phagocytes, and at least three polymorphisms on the CR1 gene are related to erythrocyte surface density of CR1 molecules, in turn related to the rate of IC clearance from circulation. We hypothesized that sarcoidosis could be associated with increased frequency of the CR1 gene alleles coding for reduced CR1/E ratio. We studied 91 sarcoid patients and two control groups: 94 healthy volunteers and 71 patients with chronic obstructive pulmonary disease (COPD). Three polymorphic sites of CR1 gene, His1208Arg, intron 27 HindIII/RFLP, and Pro1827Arg, were analyzed. The three polymorphisms were in linkage disequilibrium. The GG genotype for the Pro1827Arg (C(5507)G) polymorphism was significantly associated with sarcoidosis in comparison to both control groups (odds ratio [OR] = 3.13; 95% confidence interval [CI] 1.49-6.69 versus healthy control subjects, and OR= 2.82, 95% CI 1.27-6.39 versus COPD control subjects). The same genotype was particularly associated to disease in females (OR = 7.05; 95% CI 3.10-16.61 versus healthy control subjects). These findings agree with speculations on the role of CR1 gene as a possible susceptibility factor.

Adult↗