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Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 April 2026) | Viewed by 9794

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Prof. Dr. Anna Cieslinska

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Department of Biology and Biotechnology, University of Warmia and Mazury, 10-719 Olsztyn, Poland
Interests: proteins; opioids; nutrigenomics; polymorphism; SNPs; mutations; vitamins; markers
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Special Issue Information

Dear Colleagues,

This is a continuation of the series on the hot topic of the “Role of Mutations and Polymorphisms in Various Diseases”; our first Special Issue on this topic received interesting contributions and discussions (https://www.mdpi.com/journal/ijms/special_issues/13BKNJIRQ4).

Genetic polymorphisms and mutations can affect the gene expression, modify the quantity and quality of the encoded product (protein), and significantly alter the metabolic pathway and its control, and thus cause changes in the functioning of metabolic pathways. In this way, some changes in the genome are involved in not only the initiation but also the progression/regression of diseases.

In this Special Issue of the International Journal of Molecular Sciences, we focus our attention on the latest discoveries and developments in correlations between genetic mutations and their relation to diseases in animals and human studies and possible underlying mechanisms. We also indicate metabolic pathways considered to have an impact on the development of the disease, as well as genes and polymorphisms involved in the process.

We provide a comprehensive update on the literature accessible to scientists from the field. Thus, we wish to invite investigators from basic, genetic, pathophysiological, nutritional, and metabolism research or closely related disciplines to contribute original articles, reviews, communications, and conceptual papers.

Prof. Dr. Anna Cieslinska
Guest Editor

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Keywords

nutrigenomics
polymorphism
SNPs
mutations
predisposition
correlation
diversity
deletion
insertion

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Published Papers (9 papers)

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Research

18 pages, 1228 KB

Open AccessArticle

Associations Between OPN-CD44 Axis Genetic Variability, Plasma Osteopontin, and Treatment Outcomes in Head and Neck Squamous Cell Carcinoma

by Agnieszka Gdowicz-Kłosok, Regina Deja, Tomasz Rutkowski, Magdalena Bugowska, Jolanta Mrochem-Kwarciak, Krzysztof Składowski and Dorota Butkiewicz

Int. J. Mol. Sci. 2026, 27(9), 3724; https://doi.org/10.3390/ijms27093724 - 22 Apr 2026

Abstract

Inter-individual variability in outcomes following radiotherapy-based treatment remains a major challenge in head and neck squamous cell carcinoma (HNSCC). Osteopontin (OPN) and its receptor CD44 are key mediators of tumor progression, hypoxia-related treatment resistance, and metastatic dissemination. In this exploratory, hypothesis-generating study, we investigated selected functional polymorphisms in OPN (SPP1) and CD44 genes, together with pretreatment plasma OPN levels, in relation to overall survival (OS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MFS) in 242 HNSCC patients treated with curative-intent radiotherapy alone (RT) or combined with chemotherapy (RT + CT). In individual multivariable models, the OPN rs11730582 C and CD44 rs13347 T variants were associated with improved survival outcomes, while elevated OPN levels correlated with shorter OS. In full multivariable models, rs11730582 C and high OPN levels remained independent predictors of OS in the entire cohort. In the RT + CT subgroup, high OPN independently predicted worse OS, whereas rs13347 T was associated with better MFS. In the RT subset, rs11730582 CC independently predicted longer OS. These findings suggest that both germline variability within the OPN-CD44 signaling axis and circulating OPN levels are associated with treatment outcomes in HNSCC patients receiving radiotherapy-based regimens. Given the exploratory design, further validation in independent cohorts is warranted. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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14 pages, 466 KB

Open AccessArticle

Association Between Polymorphisms in Genes Encoding PD-1/PD-L1 Molecules and Clinicopathological Features in Clear Cell Renal Cell Carcinoma

by Magdalena Onyszczuk, Nikola Szweda-Gandor, Magdalena Rynkiewicz and Bogna Drozdzowska

Int. J. Mol. Sci. 2026, 27(8), 3435; https://doi.org/10.3390/ijms27083435 - 11 Apr 2026

Viewed by 388

Abstract

The PD-1/PD-L1 axis is crucial for immune regulation and homeostasis, but cancer cells can exploit this pathway to evade immune surveillance. PD-1, a key immune checkpoint receptor, interacts with its ligands PD-L1 and PD-L2 to modulate immune responses within the tumor microenvironment. We hypothesized that single nucleotide polymorphisms (SNPs) in the PDCD1 and CD274 genes, encoding PD-1 and PD-L1, are associated with clinicopathological features, PD-L1 immunohistochemical expression, and clinical outcomes in clear cell renal cell carcinoma (ccRCC). We analyzed four SNPs using TaqMan allelic discrimination assays in 238 ccRCC cases: rs11568821 and rs7603052 (PDCD1), and rs4143815 and rs17718883 (CD274). The rs7603052 polymorphism in PDCD1 and rs17718883 in CD274 were significantly associated (p = 0.033 and p = 0.043 respectively) with PD-L1 expression in tumor-infiltrating immune cells (TIICs). Specifically, the C allele of rs7603052 and the CC genotype of rs17718883 correlated with PD-L1 positivity in TIICs. Additionally, the C allele of rs4143815 in CD274 was associated with PD-L1 positivity in tumor cells (p = 0.039). Notably, rs17718883 in CD274 was associated with ccRCC patient prognosis: carriers of the T allele, particularly those with the CT genotype, demonstrated improved overall survival compared to CC genotype carriers (p < 0.001). These findings suggest that PDCD1 and CD274 polymorphisms may serve as potential predictive and prognostic biomarkers in ccRCC. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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18 pages, 1000 KB

Open AccessArticle

A Pilot Study on Multigenic Thrombophilic Risk in Recurrent Pregnancy Loss: Interactions Between MTHFR Polymorphisms and Classical Thrombophilia-Associated SNPs

by Oana-Viola Badulescu, Monica Hancianu, Cornelia Mircea, Andrei Bojan, Dragos-Florin Tesoi, Maria Cristina Vladeanu, Manuela Ciocoiu, Otilia-Elena Frasinariu, Carmen Elena Plesoianu, Dan Iliescu-Halitchi and Iris Bararu Bojan

Int. J. Mol. Sci. 2026, 27(7), 3112; https://doi.org/10.3390/ijms27073112 - 29 Mar 2026

Viewed by 484

Abstract

Recurrent spontaneous miscarriages represent a significant reproductive challenge, often associated with inherited thrombophilia. Among the genetic factors involved, methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been increasingly studied. The two main variants, MTHFR C677T and MTHFR A1298C, have been suggested to contribute to thrombotic events and adverse pregnancy outcomes. This study aims to evaluate the higher prevalence and potential role of MTHFR gene polymorphisms (C677T and A1298C) in the etiology of recurrent spontaneous miscarriages in pregnant women with inherited thrombophilia, in comparison with the classical thrombophilia-associated SNPs—F5 Leiden and the F2 G20210A gene mutation. In this single-center retrospective observational study, 64 women with recurrent pregnancy loss and confirmed inherited thrombophilia were evaluated. Genomic DNA extracted from peripheral blood samples was analyzed for thrombophilia-associated polymorphisms, including F5 Leiden (G1691A), F2 G20210A, MTHFR C677T, MTHFR A1298C, SERPINE1 4G/5G, and F13A1 V34L, using a real-time PCR-based Bosphore^® Thrombophilia Panel. The presence of MTHFR C677T and A1298C polymorphisms was investigated and compared to the incidence of F5 Leiden and F2 G20210A gene SNPs. Associations between genotypes and clinical characteristics, including the number of pregnancy losses, were assessed using chi-square tests, Kruskal–Wallis analysis, and logistic regression models. The most frequently detected polymorphisms were heterozygous variants of the MTHFR gene, with prevalences of 57.8% for C677T and 53.1% for A1298C. Homozygous MTHFR C677T was significantly associated with a higher number of pregnancy losses (Kruskal–Wallis test, p = 0.001). Similarly, the homozygous MTHFR A1298C genotype showed a significant association with increased miscarriage frequency (p = 0.012). Classical thrombophilic mutations were less frequent, with F2 G20210A identified in only two patients, although its presence was associated with a higher number of pregnancy losses (p = 0.030). These findings suggest that combined thrombophilic polymorphisms may contribute to recurrent pregnancy loss, although larger studies are required to confirm these observations. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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17 pages, 463 KB

Open AccessArticle

Vitamin D Receptor (VDR) Polymorphisms and Cardiometabolic Profiles in Orthopedic Patients: A Cluster-Based Analysis

by Dariusz Larysz, Remigiusz Recław, Aleksandra Suchanecka, Wojciech Dziurawiec, Rafał Tkacz, Aleksandra Strońska-Pluta, Krzysztof Chmielowiec, Anna Grzywacz and Jolanta Chmielowiec

Int. J. Mol. Sci. 2026, 27(4), 1958; https://doi.org/10.3390/ijms27041958 - 18 Feb 2026

Viewed by 349

Abstract

Genetic polymorphisms contribute to inter-individual variability in cardiometabolic risk and quality-of-life outcomes, yet their clinical relevance often remains unclear due to population heterogeneity and reliance on single-variant analyses. Integrative approaches combining genetic and phenotypic data may improve the characterization of complex disease profiles, particularly in orthopedic populations burdened by cardiometabolic comorbidities. This study included 289 patients scheduled for orthopedic surgery. Polymorphisms in the vitamin D receptor (VDR; ApaI, FokI, BsmI), catechol-O-methyltransferase (COMT rs4680), and opioid receptor mu 1 (OPRM1 rs510769) genes were genotyped. Clinical, anthropometric, hematological, biochemical, and quality-of-life (SF-36) data were collected. Unsupervised k-means clustering was applied to standardized phenotypic variables to identify homogeneous patient subgroups. Inter-cluster differences were assessed using analysis of variance and chi-squared tests. Three distinct patient clusters were identified, characterized by specific combinations of cardiometabolic, inflammatory, and quality-of-life features. VDR polymorphisms were differentially distributed across clusters associated with differences in body mass index, hypertension prevalence, and inflammatory status. COMT and OPRM1 variants were primarily associated with variability in physical and mental quality-of-life dimensions. The cluster-based approach revealed multidimensional clinical heterogeneity not captured by conventional univariate analyses. Integrating genetic polymorphisms with clinical and quality-of-life data may support the identification and interpretation of distinct cardiometabolic profiles among orthopedic patients. Cluster-based stratification represents a valuable framework for capturing complex patient heterogeneity and supports future precision-oriented research in orthopedic and cardiometabolic populations. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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15 pages, 792 KB

Open AccessArticle

The Interplay of Genetics and Lifestyle in MASLD: Focus on LPIN1 rs13412852 and Sedentary Behaviour

by Isabella Franco, Rossella Donghia, Antonella Bianco, Claudia Beatrice Bagnato, Nicola Verrelli, Caterina Bonfiglio, Elisabetta Di Nicola, Giovanna Forte, Martina Lepore Signorile, Marialaura Latrofa, Marika D’Addabbo, Katia De Marco, Vittoria Disciglio, Paola Sanese, Gianluigi Giannelli, Candida Fasano, Cristiano Simone and Valentina Grossi

Int. J. Mol. Sci. 2026, 27(4), 1644; https://doi.org/10.3390/ijms27041644 - 8 Feb 2026

Viewed by 652

Abstract

The LPIN1 rs13412852 variant has been linked to lipid levels and liver disease in children. This genotype may modulate the liver’s response to sedentary behaviour, potentially increasing the vulnerability of certain individuals to liver dysfunction. These findings underscore the need to consider both genetic predisposition and environmental exposures when evaluating disease risk. This study aims to investigate the association between the LPIN rs13412852 T-allele and sedentary behaviour and to explore how the interplay between genetic and environmental factors may contribute to individual susceptibility to liver-related conditions. rs13412852 was genotyped in a cohort from Southern Italy (n = 394), and all participants were administered an International Physical Activity Questionnaire (IPAQ), collected a blood sample, and underwent an abdominal ultrasound analysis. The association between metabolic dysfunction-associated steatotic liver disease (MASLD), rs13412852, and sedentary behaviour, alone and together with interaction, was studied. The results indicated a statistical association on MASLD, of rs13412852, and sedentary levels (OR = 1.80, 1.06 to 3.05 95% C.I., p = 0.03, and OR = 1.72, 1.13 to 2.64 95% C.I.), respectively, and also with interaction between moderate or sever sedentary level and T-carrier (OR = 2.99, 1.39 to 6.45 95% C.I., p = 0.005) adjusted for some covariates. The risk of MASLD was highest among individuals with both moderate/severe sedentary behaviour and the CT/TT genotype, suggesting a potential synergistic effect. These findings establish LPIN1 as both a physiological gatekeeper and a genetic susceptibility locus, with its influence subject to modification via behavioural treatments. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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11 pages, 287 KB

Open AccessArticle

Is PTEN rs397510595 an Unexpected Guardian in Canine Mammary Neoplasia?

by Ana Canadas-Sousa, Marta Santos and Patrícia Dias-Pereira

Int. J. Mol. Sci. 2025, 26(21), 10654; https://doi.org/10.3390/ijms262110654 - 1 Nov 2025

Viewed by 542

Abstract

Despite steps having been taken to study the influence of genetic polymorphisms in canine mammary neoplasia, the knowledge of their relevance is still incipient compared to the knowledge of human breast cancer. Among tumor suppressor genes, PTEN plays a pivotal role in carcinogenesis; however, the contribution of its constitutional variants to the biology of canine mammary neoplasia remains poorly understood. This observational study assessed the association between PTEN SNPs rs397510595 and rs397513087, genotyped from peripheral blood, and the clinicopathological features, including survival, in a cohort of 206 female dogs with mammary neoplasia. The minor A allele of rs397510595 was present in 17.5% of the population. Carriers of the variant allele were more frequently diagnosed at a late age ≥ 11 years, displayed a complete absence of vascular invasion, and exhibited significantly longer overall survival (mean 22.2 vs. 19.5 months). The SNP rs397513087 did not show a significant association with clinicopathological features or survival. Our data suggests that SNP rs397510595 of the PTEN gene is a putative protective factor for developing canine mammary neoplasia at an early age and might be used as a biomarker for prognostic assessment in dogs with malignant mammary neoplasia. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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15 pages, 2310 KB

Open AccessCommunication

β-Casein A1 and A2 Genetic Variants and β-Casomorphin-7 in Raw Milk and Processed Milk Products

by Stanisław Kamiński and Anna Cieślińska

Int. J. Mol. Sci. 2025, 26(17), 8612; https://doi.org/10.3390/ijms26178612 - 4 Sep 2025

Cited by 2 | Viewed by 3586

Abstract

The A1 and A2 variants of bovine β-casein (CSN2) have gained attention in the dairy industry due to potential health effects. The A1 variant, prevalent in Holstein-Friesian cattle, is a major source of β-casomorphin-7 (BCM-7)—an opioid-like peptide released during digestion and associated with lower digestive comfort. In this study, β-casein A1 and A2 variants and BCM-7 levels were quantified in raw milk and three commonly consumed dairy products (pasteurized milk, UHT milk, and milk powder) using ELISA. The samples came from dairy plants within a single operating zone. The A1 variant was significantly more frequent (13.69–22.41 ng/mL) than the A2 variant (8.10–12.60 ng/mL), although the local Holstein cattle population had a higher frequency of the A2 allele (63%) than A1 (37%). This discrepancy could be due to a more efficient expression of the A1 allele in cows with heterozygous or A1A1 genotypes. BCM-7 levels were low and did not vary significantly with CSN2 genotype or processing method. These results provide new insights into the composition of dairy products and contribute to the ongoing debate on the health implications and consumer acceptance of milk with the A1 β-casein variant. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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11 pages, 932 KB

Open AccessArticle

Early Insights from Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Patients: An Observational Study on Polygenic Risk and Liver Biomarkers

by Pietro Torre, Benedetta Maria Motta, Tommaso Sarcina, Mariano Festa, Mario Masarone and Marcello Persico

Int. J. Mol. Sci. 2025, 26(17), 8426; https://doi.org/10.3390/ijms26178426 - 29 Aug 2025

Cited by 3 | Viewed by 1404

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern influenced by both genetic and metabolic factors. Polygenic risk scores (PRSs), which combine the effects of known single-nucleotide polymorphisms (SNPs), may improve early risk stratification. We conducted an observational study on 298 MASLD patients: 148 from a Hepatology Unit and 150 from a Bariatric Surgery Unit. Genotyping was performed for the PNPLA3, TM6SF2, MBOAT7, and GCKR variants. A PRS was calculated and used to stratify patients by genetic risk. Liver fibrosis was assessed using the FIB-4 index, and a subset also underwent transient elastography. Clinical, biochemical, and anthropometric data were analyzed across genetic strata. PRSs showed positive correlations with AST, ALT, and FIB-4, indicating increased liver injury and fibrosis risk with higher genetic burden. Transaminases increased significantly across PRS quartiles (p < 0.05), and individuals with PRS > 0.532 exhibited elevated AST, ALT, and borderline FIB-4. Variant-specific associations included PNPLA3 with increased AST and MBOAT7 with higher hepatic steatosis (CAP). Subgroup analyses revealed distinct genetic and phenotypic patterns between the two clinical cohorts. These findings support the additive role of genetic risk in MASLD progression and underscore the value of polygenic profiling for the early identification and personalized management of high-risk patients. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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14 pages, 809 KB

Open AccessArticle

Double Pathogenic or Likely Pathogenic Variants in Cancer Predisposition Genes in Hungarian Cancer Patients

by Tímea Pócza, János Papp, Anikó Bozsik, Vince Kornél Grolmusz, Petra Nagy, Attila Patócs and Henriett Butz

Int. J. Mol. Sci. 2025, 26(17), 8390; https://doi.org/10.3390/ijms26178390 - 29 Aug 2025

Cited by 1 | Viewed by 1439

Abstract

Identification of two or more pathogenic/likely pathogenic (P/LP) variants in cancer susceptibility genes carried by the same patient have important consequences for patient management. We have limited information about the effect of double heterozygosity (DH) in cancer susceptibility genes. The prevalence of DH among Hungarian cancer patients referred to oncogenetic counselling, and comparison of their phenotypes to single variant carriers were performed. In total, 2050 patients were analysed by multigene panel sequencing. Variants of 48 established cancer predisposition genes by ACMG guidelines were evaluated. In overall, P/LP variants were found in 19.8% of cases. DH was observed in 16 cases, amount to 0.8% of all patients, and to 4.0% of positive cases. Appearance of multiple primary tumours was not associated with DH compared to non-P/LP and single P/LP carriers (p = 0.71 and p = 0.54, respectively). Within a cohort of patients referred with suspected HBOC syndrome, earlier tumour formation was observed when DH cases were compared to non-P/LP carriers (p = 0.01), but difference between single and DH carriers was not statistically significant (p = 0.19; Bonferroni corrected alpha = 0.017). Our observations provide information about the incidence of DH status among Hungarian hereditary cancer patients and suggest that DH did not increase the risk of cancer compared to individuals with single P/LP mutation. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases: 2nd Edition)

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