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Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 July 2022) | Viewed by 32445

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Special Issue Editor

Dr. Cinzia Ciccacci

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Guest Editor

UniCamillus, Saint Camillus International University of Health Sciences, 8, 00131 Roma, Italy
Interests: genetics of multifactorial disorders; pharmacogenetics; miRNA variability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multifactorial disorders, with their heterogeneity in clinical phenotypes and their inter-individual variability in prognosis and treatment response, still represent a great challenge for medicine. The etiology of these disorders is triggered by the interaction among predisposing genetic factors, epigenetic factors and environmental factors. In recent decades, the improvement of technology has permitted one to investigate the genetic component of multifactorial disorders. Many genome-wide association studies (GWAS) have been extremely successful in identifying genes that contribute to multifactorial disorders susceptibility. In recent years, epigenetics have also attracted the interest of researchers, and we have today evidence of epigenetic alterations in different diseases, including cancers, cardiovascular diseases, and autoimmune diseases. Although epigenetic factors are now considered as important risk factors for the onset of multifactorial disorders, their investigation is still at an early stage and the knowledge about the functional relevance of epigenetics needs to be implemented. Looking ahead, the understanding of the role of epigenetic modifications in the pathogenesis of these diseases and their interaction with genetic factors could suggest novel targets for disease therapy and promote a more personalized medicine.

Therefore, the aim of this Special Issue will be to welcome original articles and reviews covering all aspects of genetics and epigenetics, and their potential interactions, involved both in the susceptibility to multifactorial disorders and in the modulation of their clinical phenotypes and complications.

Dr. Cinzia Ciccacci
Guest Editor

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Keywords

multifactorial disorders
genetic factors
epigenetic factors
polymorphisms
gene–gene interactions
gene–miRNA interactions
miRNA
methylation state

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Research

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16 pages, 2475 KiB

Open AccessArticle

RNA Sequencing in Hypoxia-Adapted T98G Glioblastoma Cells Provides Supportive Evidence for IRE1 as a Potential Therapeutic Target

by Brian E. White, Yichuan Liu, Hakon Hakonarson and Russell J. Buono

Genes 2023, 14(4), 841; https://doi.org/10.3390/genes14040841 - 31 Mar 2023

Cited by 3 | Viewed by 2178

Abstract

Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resistant GBM stem-like cells are thought to drive this high recurrence rate. We used human T98G GBM cells as a model to identify differential gene expression induced by hypoxia and to search for potential therapeutic targets of hypoxia adapted GBM cells. RNA sequencing (RNAseq) and bioinformatics were used to identify differentially expressed genes (DEGs) and cellular pathways affected by hypoxia. We also examined expression of lactate dehydrogenase (LDH) genes using qRT-PCR and zymography as LDH dysregulation is a feature of many cancers. We found 2630 DEGs significantly altered by hypoxia (p < 0.05), 1241 upregulated in hypoxia and 1389 upregulated in normoxia. Hypoxia DEGs were highest in pathways related to glycolysis, hypoxia response, cell adhesion and notably the endoplasmic reticulum, including the inositol-requiring enzyme 1 (IRE1)-mediated unfolded protein response (UPR). These results, paired with numerous published preclinical data, provide additional evidence that inhibition of the IRE1-mediated UPR may have therapeutic potential in treating GBM. We propose a possible drug repurposing strategy to simultaneously target IRE1 and the spleen tyrosine kinase (SYK) in patients with GBM. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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19 pages, 1409 KiB

Open AccessArticle

SNP-by-CpG Site Interactions in ABCA7 Are Associated with Cognition in Older African Americans

by Dima L. Chaar, Kim Nguyen, Yi-Zhe Wang, Scott M. Ratliff, Thomas H. Mosley, Sharon L. R. Kardia, Jennifer A. Smith and Wei Zhao

Genes 2022, 13(11), 2150; https://doi.org/10.3390/genes13112150 - 18 Nov 2022

Cited by 1 | Viewed by 2076

Abstract

SNPs in ABCA7 confer the largest genetic risk for Alzheimer’s Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined. We investigated the effects of five known AD risk SNPs and 72 CpGs in ABCA7, as well as their interactions, on general cognitive function (cognition) in 634 older AA without dementia from Genetic Epidemiology Network of Arteriopathy (GENOA). Using linear mixed models, no SNP or CpG was associated with cognition after multiple testing correction, but five CpGs were nominally associated (p < 0.05). Four SNP-by-CpG interactions were associated with cognition (FDR q < 0.1). Contrast tests show that methylation is associated with cognition in some genotype groups (p < 0.05): a 1% increase at cg00135882 and cg22271697 is associated with a 0.68 SD decrease and 0.14 SD increase in cognition for those with the rs3764647 GG/AG (p = 0.004) and AA (p = 2 × 10⁻⁴) genotypes, respectively. In addition, a 1% increase at cg06169110 and cg17316918 is associated with a 0.37 SD decrease (p = 2 × 10⁻⁴) and 0.33 SD increase (p = 0.004), respectively, in cognition for those with the rs115550680 GG/AG genotype. While AD risk SNPs in ABCA7 were not associated with cognition in this sample, some have interactions with proximal methylation on cognition. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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20 pages, 1232 KiB

Open AccessArticle

Exploration of the Moderating Effects of Physical Activity and Early Life Stress on the Relation between Brain-Derived Neurotrophic Factor (BDNF) rs6265 Variants and Depressive Symptoms among Adolescents

by Catalina Torres Soler, Sofia H. Kanders, Susanne Olofsdotter, Sofia Vadlin, Cecilia Åslund and Kent W. Nilsson

Genes 2022, 13(7), 1236; https://doi.org/10.3390/genes13071236 - 13 Jul 2022

Cited by 10 | Viewed by 2344

Abstract

Depression affects one in five persons at 18 years of age. Allele A of the brain-derived neurotrophic factor (BDNF) rs6265 is considered to be a risk factor for depression. Previous studies of the interaction between BDNF rs6265, early adversity, and/or physical activity have shown mixed results. In this study, we explored the relation between BDNF rs6265 polymorphism and childhood stress, as well as the moderating effect of physical activity in relation to depressive symptoms using binary logistic regressions and process models 1, 2 and 3 applied to data obtained at three times (waves 1, 2 and 3) from the Survey of Adolescent Life in Västmanland cohort study (SALVe). Results revealed that both childhood stress and physical activity had a moderation effect; physical activity in wave 1 with an R² change = 0.006, p = 0.013, and the Johnson–Neyman regions of significance (RoS) below 1.259, p = 0.05 for 11.97%; childhood stress in wave 2 with the R² change = 0.008, p = 0 002, and RoS below 1.561 with 26.71% and >4.515 with 18.20%; and a three-way interaction in wave 1 in genotype AA carriers. These results suggest that allele A is susceptible to physical activity (positive environment) and childhood stress (negative environment). Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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9 pages, 248 KiB

Open AccessEditor’s ChoiceArticle

The Role of Functional Polymorphisms in the Extracellular Matrix Modulation-Related Genes on Dupuytren’s Contracture

by Gediminas Samulenas, Ruta Insodaite, Edita Kunceviciene, Roberta Poceviciute, Lorena Masionyte, Urte Zitkeviciute, Loreta Pilipaityte and Alina Smalinskiene

Genes 2022, 13(5), 743; https://doi.org/10.3390/genes13050743 - 23 Apr 2022

Cited by 5 | Viewed by 2276

Abstract

(1) Background: genetic variations, localized in the functional regions of the extracellular matrix (ECM) modulation-related genes, may alter the transcription process and impact the Dupuytren’s contracture (DC). The present study investigated the association of single nucleotide polymorphisms (SNPs), localized in the functional regions of the MMP8, MMP14, and CHST6 genes, with DC risk. (2) Methods: we enrolled 219 genomic DNA samples, which were extracted from 116 patients with DC and 103 healthy controls. Genotyping of selected SNPs was performed using TaqMan single nucleotide polymorphisms genotyping assay. Three polymorphisms (MMP8 rs11225395, MMP14 rs1042704, and CHST6 rs977987) were analyzed. All studied SNPs were in Hardy–Weinberg equilibrium. (3) Results: significant associations of the studied SNPs with the previous onset of the disease were observed between the CHST6 rs977987 minor T allele (p = 0.036) and the MMP14 rs1042704 mutant AA genotype (p = 0.024). Significant associations with the previous onset of the disease were also observed with a positive family history of the DC (p = 0.035). Moreover, risk factor analysis revealed that a combination of major disease risk factors (smoking and manual labor) and the MMP14 minor A allele increases the risk of DC development by fourteen times (p = 0.010). (4) Conclusions: our findings suggest that CHST6 rs977987, MMP14 rs1042704, and positive family history are associated with the previous onset of Dupuytren’s contracture. In addition, the combination of the MMP14 minor A allele and additional risk factors increase the likelihood of the manifestation of the DC. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

9 pages, 272 KiB

Open AccessArticle

APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population

by Stephanie Lozano, Victoria Padilla, Manuel Lee Avila, Mario Gil, Gladys Maestre, Kesheng Wang and Chun Xu

Genes 2021, 12(11), 1768; https://doi.org/10.3390/genes12111768 - 8 Nov 2021

Cited by 7 | Viewed by 3133

Abstract

Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene’s associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer’s Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10⁻⁴) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

13 pages, 2881 KiB

Open AccessArticle

Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy

by Russell J. Buono, Jonathan P. Bradfield, Zhi Wei, Michael R. Sperling, Dennis J. Dlugos, Michael D. Privitera, Jacqueline A. French, Warren Lo, Patrick Cossette, Steven C. Schachter, Heather Basehore, Falk W. Lohoff, Struan F. A. Grant, Thomas N. Ferraro and Hakon Hakonarson

Genes 2021, 12(9), 1441; https://doi.org/10.3390/genes12091441 - 18 Sep 2021

Cited by 6 | Viewed by 2431

Abstract

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10⁻⁸) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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12 pages, 1963 KiB

Open AccessArticle

T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes

by John P. Mordes, Laura Cort, Zhijun Liu, Ryan Eberwine, Elizabeth P. Blankenhorn and Brian G. Pierce

Genes 2021, 12(6), 852; https://doi.org/10.3390/genes12060852 - 1 Jun 2021

Cited by 3 | Viewed by 2920

Abstract

Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/D^u) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/D^u and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the Vβ13a T cell receptor β chain, completely prevents diabetes. Using the RT1B/D^u-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 β chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vβ13a TCR and its class II RT1^u ligand suggests a mechanism by which a germline TCR β chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vβ13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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17 pages, 602 KiB

Open AccessReview

The Genetic Side of the Mood: A Scientometric Review of the Genetic Basis of Mood Disorders

by Giovanni Bonacina, Alessandro Carollo and Gianluca Esposito

Genes 2023, 14(2), 352; https://doi.org/10.3390/genes14020352 - 30 Jan 2023

Cited by 8 | Viewed by 3467

Abstract

Mood disorders are highly heritable psychiatric disorders. Over the years, many genetic polymorphisms have been identified to pose a higher risk for the development of mood disorders. To overview the literature on the genetics of mood disorders, a scientometric analysis was performed on a sample of 5342 documents downloaded from Scopus. The most active countries and the most impactful documents in the field were identified. Furthermore, a total of 13 main thematic clusters emerged in the literature. From the qualitative inspection of clusters, it emerged that the research interest moved from a monogenic to a polygenic risk framework. Researchers have moved from the study of single genes in the early 1990s to conducting genome-wide association studies around 2015. In this way, genetic overlaps between mood disorders and other psychiatric conditions emerged too. Furthermore, around the 2010s, the interaction between genes and environmental factors emerged as pivotal in understanding the risk for mood disorders. The inspection of thematic clusters provides a valuable insight into the past and recent trends of research in the genetics of mood disorders and sheds light onto future lines of research. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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22 pages, 798 KiB

Open AccessReview

Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022

by Mengyu Lim, Alessandro Carollo, Dagmara Dimitriou and Gianluca Esposito

Genes 2022, 13(9), 1646; https://doi.org/10.3390/genes13091646 - 14 Sep 2022

Cited by 15 | Viewed by 6321

Abstract

Genetic research in Autism Spectrum Disorder (ASD) has progressed tremendously in recent decades. Dozens of genetic loci and hundreds of alterations in the genetic sequence, expression, epigenetic transformation, and interactions with other physiological and environmental systems have been found to increase the likelihood of developing ASD. There is therefore a need to represent this wide-ranging yet voluminous body of literature in a systematic manner so that this information can be synthesised and understood at a macro level. Therefore, this study made use of scientometric methods, particularly document co-citation analysis (DCA), to systematically review literature on ASD genetic research from 2018 to 2022. A total of 14,818 articles were extracted from Scopus and analyzed with CiteSpace. An optimized DCA analysis revealed that recent literature on ASD genetic research can be broadly organised into 12 major clusters representing various sub-topics. These clusters are briefly described in the manuscript and potential applications of this study are discussed. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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11 pages, 709 KiB

Open AccessReview

Emerging Role of microRNAs and Long Non-Coding RNAs in Sjögren’s Syndrome

by Giada De Benedittis, Cinzia Ciccacci, Andrea Latini, Lucia Novelli, Giuseppe Novelli and Paola Borgiani

Genes 2021, 12(6), 903; https://doi.org/10.3390/genes12060903 - 11 Jun 2021

Cited by 13 | Viewed by 3317

Abstract

Sjögren’s Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors and Their Interactions in the Susceptibility to Multifactorial Diseases)

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