Interaction between diet and genetics in patients with inflammatory bowel disease

In this editorial,we comment on the article by Marangoni et al,published in the recent issue of the World Journal of Gastroenterology 2023;29:5618-5629,about“Diet as an epigenetic factor in inflammatory bowel disease”.The authors emphasized the role of diet,especially the interaction with genetics,in promoting the inflam-matory process in inflammatory bowel disease(IBD)patients,focusing on DNA methylation,histone modifications,and the influence of microRNAs.In this editorial,we explore the interaction between genetics,gut microbiota,and diet,in an only way.Furthermore,we provided dietary recommendations for patients with IBD.The Western diet,characterized by a low fiber content and deficiency the micronutrients,impacts short-chain fatty acids production and may be related to the pathogenesis of IBD.On the other hand,the consumption of the Mediter-ranean diet and dietary fibers are associated with reduced risk of IBD flares,particularly in Crohn’s disease(CD)patients.According to the dietary guidance from the International Organization for the Study of Inflammatory Bowel Diseases(IOIBD),the regular consumption of fruits and vegetables while reducing the consumption of saturated,trans,dairy fat,additives,processed foods rich in maltodextrins,and artificial sweeteners containing sucralose or saccharine is recommended to CD patients.For patients with ulcerative colitis,the IOIBD recommends the increased intake of natural sources of omega-3 fatty acids and follows the same restrictive recommendations aimed at CD patients,with the possible inclusion of red meats.In conclusion,IBD is a complex and hetero-geneous disease,and future studies are needed to elucidate the influence of epigenetics on diet and microbiota in IBD patients.

Genetic risk stratification of inflammatory bowel disease-associated venous thromboembolism:An Asian perspective

The utilisation of polygenic scoring models may enhance the clinician’s ability to risk stratify an inflammatory bowel disease patient’s individual risk for venous thromboembolism(VTE)and guide the appropriate usage of VTE thromboprophylaxis,yet there is a need to validate such models in ethnically diverse populations.

Age-specific heterogeneity of genetic susceptibility to cardiovascular disease might have opposite outcomes depending on the presence of prediabetes

Examining age-specific heterogeneity of susceptibility to cardiovascular disease is also essential in individuals without prediabetes to determine its relative size and direction compared to those with prediabetes.Of particular interest,age-specific heterogeneity in genetic susceptibility may exhibit opposite directions depending on the presence or absence of prediabetes.

Insights into the genetic architecture of congenital heart disease from animal modeling

Congenital heart disease(CHD)is observed in up to 1%of live births and is one of the leading causes of mortality from birth defects.While hundreds of genes have been implicated in the genetic etiology of CHD,their role in CHD pathogenesis is still poorly understood.This is largely a reflection of the sporadic nature of CHD,as well as its variable expressivity and incomplete penetrance.We reviewed the monogenic causes and evidence for oligogenic etiology of CHD,as well as the role of de novo mutations,common variants,and genetic modifiers.For further mechanistic insight,we leveraged single-cell data across species to investigate the cellular expression characteristics of genes implicated in CHD in developing human and mouse embryonic hearts.Understanding the genetic etiology of CHD may enable the application of precision medicine and prenatal diagnosis,thereby facilitating early intervention to improve outcomes for patients with CHD.

Propensity for Progressive Renal Disease in Nephroangiosclerosis: A Refractory Phenotype of Genetic Vasculopathy in Essential Hypertension

Background: Inadequate treatment of essential hypertension (EH), Obesity, smoking, carbohydrate intolerance, hyperlipidemia, and nephrotox-in-exposure are major confounding factors in progression of Nephroangiosclerosis (N). However, neither the prevalence nor the severity of EH is a reliable predictor of individuals at risk for subsequent nephropathy. Patients and Methods: A 10-years retrospective analysis of 165 adequately treated patients with EH. Results: We observed 2 different renal outcomes. Twenty-three (14%) patients manifested progressive renal disease with > doubling serum creatinine and proteinuria with 3 reaching end-stage kidney disease. At start, biopsy of those patients showed features of “benign” nephroangiosclerosis (N) ± secondary form of focal and segmental glomerulosclerosis (without immune deposits). On the other hand;142 with similar demographic characteristics, duration and severity of disease did not show significant renal disease on follow up. Conclusion: Induction of progressive N, in patients with EH, is compatible with phenotypic susceptibilities of genetic disorders.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Epidemiological Surveillance: Genetic Diversity of Rotavirus Group A in the Pearl River Delta, Guangdong, China in 2019

Objective This study aimed to understand the epidemic status and phylogenetic relationships of rotavirus group A(RVA)in the Pearl River Delta region of Guangdong Province,China.Methods This study included individuals aged 28 days–85 years.A total of 706 stool samples from patients with acute gastroenteritis collected between January 2019 and January 2020 were analyzed for 17 causative pathogens,including RVA,using a Gastrointestinal Pathogen Panel,followed by genotyping,virus isolation,and complete sequencing to assess the genetic diversity of RVA.Results The overall RVA infection rate was 14.59%(103/706),with an irregular epidemiological pattern.The proportion of co-infection with RVA and other pathogens was 39.81%(41/103).Acute gastroenteritis is highly prevalent in young children aged 0–1 year,and RVA is the key pathogen circulating in patients 6–10 months of age with diarrhea.G9P[8](58.25%,60/103)was found to be the predominant genotype in the RVA strains,and the 41 RVA-positive strains that were successfully sequenced belonged to three different RVA genotypes in the phylogenetic analysis.Recombination analysis showed that gene reassortment events,selection pressure,codon usage bias,gene polymorphism,and post-translational modifications(PTMs)occurred in the G9P[8]and G3P[8]strains.Conclusion This study provides molecular evidence of RVA prevalence in the Pearl River Delta region of China,further enriching the existing information on its genetics and evolutionary characteristics and suggesting the emergence of genetic diversity.Strengthening the surveillance of genotypic changes and gene reassortment in RVA strains is essential for further research and a better understanding of strain variations for further vaccine development.

Pathogenic genes associated with Parkinson’s disease:molecular mechanism overview

Parkinson’s disease(PD)is a common neurodegenerative disease in the elderly,accounting for more than 1%of the population aged 65 years.Monogenic inheritance is relatively rare in PD,accounting for approximately 5%to 10%of PD patients,and there is a growing body of evidence suggesting that multiple genetic risk factors play a significant role in the pathogenesis of PD.Several groups have identified and reported a number of genes carrying mutations associated with affected family members.Mutated genes associated with PD are also candidates for idiopathic PD,and these genes may also carry other mutation sites that increase risk.When multiple genetic risk factors are combined,the risk of PD is increased to a greater extent,and to unravel the pathogenic pathways that lead to different forms of PD.This review focuses on the association of PD genes,such as Parkinson Disease 1-24(PARK1-24),glucosylceramidase(GBA),GTP cyclohydrolase 1(GCH1),fibroblast growth factor 20(FGF20),nuclear receptor-related factor 1(NURR1),NUS1 dehydrodolichyl diphosphate synthase subunit(NUS1),diacylglycerol Lipase Beta(DAGLB),transmembrane protein(TMEM),ubiquinol-cytochrome c reductase core protein 1(UQCRC1),glycoprotein non-metastatic melanoma protein B protein(GPNMB),dynactin 1(DCTN1),LDL receptor related protein 10(LRP10),monoamine oxidase(MAO),ataxin 2(ATXN2),microtubule associated protein tau(MAPT),pantothenate kinase 2(PANK2),spastic parapplegia type 11(SPG11),polymer gamma(POLG),TATA-box binding protein associated factor 1(TAF1),dual specificity tyrosine phosphorylation regulated kinase 1A(Dyrk1a),and crystallin alpha A(CRYAA),with the pathogenesis of PD.We introduce what is currently known about the molecular genetics of PD to help explain the molecular mechanisms leading to the neurodegenerative disease.

Computational and bioinformatics tools for understanding disease mechanisms

Computational methods have significantly transformed biomedical research,offering a comprehensive exploration of disease mechanisms and molecular protein functions.This article reviews a spectrum of computational tools and network analysis databases that play a crucial role in identifying potential interactions and signaling networks contributing to the onset of disease states.The utilization of protein/gene interaction and genetic variation databases,coupled with pathway analysis can facilitate the identification of potential drug targets.By bridging the gap between molecular-level information and disease understanding,this review contributes insights into the impactful utilization of computational methods,paving the way for targeted interventions and therapeutic advancements in biomedical research.

Investigating the causal associations between five anthropometric indicators and nonalcoholic fatty liver disease:Mendelian randomization study

BACKGROUND Although the etiology of nonalcoholic fatty liver disease(NAFLD)has not been thoroughly understood,the emerging roles of anthropometric indicators in assessing and predicting the risk of NAFLD have been highlighted by accumulating evidence.AIM To evaluate the causal relationships between five anthropometric indicators and NAFLD employing Mendelian randomization(MR)design.METHODS The Anthropometric Consortium provided genetic exposure data for five anthropometric indicators,including hip circumference(HC),waist circumference(WC),waist-to-hip ratio(WHR),body mass index(BMI),and body fat percentage(BF).Genetic outcome data for NAFLD were obtained from the United Kingdom Biobank and FinnGen Consortium.Genome-wide significant single nucleotide polymorphisms were chosen as instrumental variables.Univariable MR(UVMR)and multivariable MR(MVMR)designs with analytical approaches,including inverse variance weighted(IVW),MR-Egger,weighted median(WM),and weighted mode methods,were used to assess the causal relationships between anthropometric indicators and NAFLD.RESULTS Causal relationships were revealed by UVMR,indicating that a higher risk of NAFLD was associated with a perunit increase in WC[IVW:odds ratio(OR)=2.67,95%CI:1.42-5.02,P=2.25×10^(−3)],and BF was causally associated with an increased risk of NAFLD(WM:OR=2.23,95%CI:1.07-4.66,P=0.033).The presence of causal effects of WC on the decreased risk of NAFLD was supported by MVMR after adjusting for BMI and smoking.However,no causal association between BF and NAFLD was observed.In addition,other causal relationships of HC,WHR(BMI adjusted),and BMI with the risk of NAFLD were not retained after FDR correction.CONCLUSION This study establishes a causal relationship,indicating that an increase in WC is associated with a higher risk of NAFLD.This demonstrates that a suitable decrease in WC is advantageous for preventing NAFLD.

Prevalence and outcomes of polycystic kidney disease in African populations:A systematic review

BACKGROUND Polycystic kidney disease(PKD)is the most common genetic cause of kidney disease.It is a progressive and irreversible condition that can lead to end-stage renal disease and many other visceral complications.Current comprehensive data on PKD patterns in Africa is lacking.AIM To describe the prevalence and outcomes of PKD in the African population.METHODS A literature search of PubMed,African journal online,and Google Scholar databases between 2000 and 2023 was performed.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed to design the study.Clinical presentations and outcomes of patients were extracted from the included studies.RESULTS Out of 106 articles,we included 13 studies from 7 African countries.Ten of them were retrospective descriptive studies concerning 943 PKD patients with a mean age of 47.9 years.The accurate prevalence and incidence of PKD were not known but it represented the third causal nephropathy among dialysis patients.In majority of patients,the diagnosis of the disease was often delayed.Kidney function impairment,abdominal mass,and hypertension were the leading symptoms at presentation with a pooled prevalence of 72.1%(69.1-75.1),65.8%(62.2-69.4),and 57.4%(54.2-60.6)respectively.Hematuria and infections were the most frequent complications.Genotyping was performed in few studies that revealed a high proportion of new mutations mainly in the PKD1 gene.CONCLUSION The prevalence of PKD in African populations is not clearly defined.Clinical symptoms were almost present with most patients who had kidney function impairment and abdominal mass at the diagnostic.Larger studies including genetic testing are needed to determine the burden of PKD in African populations.

Metabolic dysfunction-associated steatotic liver disease heterogeneity: Need of subtyping

Metabolic dysfunction-associated steatotic liver disease(MASLD)is a widespread global disease with significant health burden.Unhealthy lifestyle,obesity,diabetes mellitus(DM),insulin resistance,and genetics have been implicated in the pathogenesis of MASLD.A significant degree of heterogeneity exists among each of above-mentioned risk factors.Heterogeneity of these risk factors translates into the heterogeneity of MASLD.On the other hand,MASLD can itself lead to insulin resistance and DM.Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice.At present MASLD is considered as one disease despite the variability of etiopathogenic processes,and we lack the consensus definitions of unique subtypes of MASLD.In this review,pathogenic processes of MASLD are discussed and a need of subtyping is recommended.

Genetic testing in congenital heart disease:A clinical approach

Congenital heart disease(CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient followup. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.

Risk factors for gastroesophageal reflux disease and analysis of genetic contributors

Gastroesophageal reflux disease(GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including:(1) motor abnormalities, such as impaired lower esophageal sphincter(LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and(2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD-related disorders development such Barrett's esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett'sesophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis,specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.

Genetically confirmed Wilson disease in a 9-month old boy with elevations of aminotransferases

Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by alteration of the adenosine triphosphatase 7B gene. It is rare to diagnose WD below the age of three years. Molecular genetic testing is one of the most important diagnostic methods and may confirm the diagnosis in equivocal cases. We report a case of a 9-mo old boy with WD who presented as chronic hepatitis. Genetic analysis showed compound heterozygotes of p.G1186S and c.4006delA.

Genetics of coronary artery disease and myocardial infarction

Atherosclerotic coronary artery disease(CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction(MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MIassociated genetic variants identified using candidate gene approaches and genome-wide association studies(GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI.

Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease(NAFLD) onset, severity, and outcome through systematic literature review. METHODS: The authors conducted both systematic and specific searches of Pub Med through December 2015 with special emphasis on more recent data(from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur. RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148 M variant, TM6SF2, particularly the p. E167 K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine. CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.

Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells

Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells（MSC） to secrete brain-derived neurotrophic factor（BDNF） supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington＇s disease（HD）. There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis（ALS）, spinocerebellar ataxia（SCA）, Alzheimer＇s disease, and some forms of Parkinson＇s disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system.

Genetic polymorphism and mRNA levels of cytochrome P450ⅡE1 and glutathione S-transferase P1 in patients with alcoholic liver disease in different nationalities

BACKGROUND:Alcohol abuse and dependence are major factors in the pathogenesis of alcoholic liver disease(ALD).Alcohol abuse is becoming an increasingly severe problem among the Han,Mongol,and Korean nationalities in northeast China.This study aimed to investigate the relationship between ALD and the genetic polymorphism and expression levels of two enzymes,cytochrome P450ⅡE1(CYPⅡE1)and glutathione S-transferase P1(GSTP1)in patients of three nationalities.METHODS:Peripheral blood was collected from 353 Chinese patients with ALD,300 alcohol dependent patients without liver disease(alcoholic),and 360 healthy controls.Each group included patients from the Han,Mongol and Korean nationalities.Real-time polymerase chain reaction(PCR)and PCR-restriction fragment length polymorphism(PCR-RFLP)were used.RESULTS:Regardless of nationality,patients who carried the rare CYPⅡE1 C2 and GSTP1 Val alleles were at higher risk of ALD.The frequency of C2 and Val in patients with ALD was respectively 50.00%and 26.98%in the Han,31.36%and 22.87%in the Mongol,and 45.87%and 22.02% in the Korean nationality.No significant differences were seen in the frequency of either C2 or Val alleles in ALD patients among the three nationalities.In each nationality,the frequency of both C2 and Val alleles was significantly higher in ALD compared to alcoholic and healthy controls.Except for nationality,the average mRNA levels of CYPⅡ E1 in ALD patients and healthy controls were 10.05%and 2.21%,respectively.The average mRNA levels of GSTP1 in ALD patients and healthy controls were 0.53%and 2.12%,respectively.The mRNA level of CYPⅡE1 was higher,and that of GSTP1 was lower in patients with ALD compared to the controls.CONCLUSIONS:Except for nationality,patients with ALD in this series tended to have a higher mRNA expression of CYPⅡE1 and to carry the C2 allele,and tended to have a lower mRNA expression of GSTP1 and to carry the Val allele.There is a causal relationship between the polymorphic alleles,which leads to different mRNA levels and the development of ALD.