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.

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.

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.

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.

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.

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.

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.

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.

Role of genetics in prediction of disease course and response to therapy

The clinical course of Crohn's disease and ulcerative colitis is highly variable between patients,and this has therapeutic implications.A number of clinical features have been identified,which predict a mild or more severe outcome.However,several of these are subjective and/or not persistent over time.With the progress in genetics research in inflammatory bowel disease(IBD),genetic markers are increasingly being proposed to improve stratification of patients.Genetics have the major advantage of being stable over time and not prone to subjective interpretation.Nevertheless,none of the genetic variants associated with particular outcomes have shown sufficient sensitivity or specificity to have been implemented in daily management.Along the same line of thinking,pharmacogenetics or the study of association between variability in drug response and genetic variation has also received more attention as part of the endeavor for personalized medicine.The ultimate goal in this area of medicine is to adapt medication to a patient's specific genetic background and therefore improve on efficacy and safety rates.Although pharmacogenetic studies have been performed for all classes of drugs applied in IBD,few have generated consistent findings or have been replicated.The only genetic test approved for clinical practice is thiopurine S-methyltransferase testing prior to starting treatment with thiopurine analogues.The other reported associations have suffered from lack of confirmation or still need replication efforts.Nevertheless,the importance and necessity of pharmacogenetic studies will increase further as more therapeutic classes are being developed.

Role of genetics in the diagnosis and prognosis of Crohn's disease

Considering the epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have so far been related to the diagnosis of Crohn's disease. These genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the strongest and most replicated associations with Crohn's disease have been demonstrated with NOD2 , IL23R and ATG16L1 genes. Many genes have so far been implicated in the prognosis of Crohn's disease and many attempts have been made for classification of genetic profiles in Crohn's disease.CARD15 seems to be not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding of Crohn's disease genetics is of value, but when combining genetic data with functional data the outcome could be of major importance to clinicians.

Genetics of inflammatory bowel disease: The role of the HLA complex

染色体 6p21.3 上的人的白细胞抗原(HLA ) 建筑群是在煽动性的肠疾病(IBD ) 的最广泛地学习的基因区域。到 IBD3 (6p21.1-23 ) 的连接的一致证据，包含 HLA 建筑群的一个区域，为两 Crohn 的疾病被表明了， ulcerative，和有疾病危险性和显型的很多个复制协会最近出现了。然而，尽管有这些努力为 IBD 遗体的 HLA 危险性基因(s) 逃犯，越过这个区域的强壮的连接不平衡，广泛的多型性和高基因密度的后果。这篇文章在 IBD 危险性和显型考察 HLA 复杂基因的角色的当前的知识，并且讨论当前限制这知识的翻译到临床的实践的因素。

Pharmacogenetics in inflammatory bowel disease

遗传药理学是在在药反应的可变性之间的协会的学习并且(或) 在基因的药毒性和多型性。科学的这个领域的目标是使药适应一个病人的特定的基因背景因此使他们更有效、安全。在这篇文章，我们在影响的基因描述变体在煽动性的肠疾病( IBD )的治疗使用的普通的药的功效或毒性， ulcerative ( UC )，和 Crohn 包括 sulfasalazine 和 mesalazine 是疾病( CD )， azathioprine ( AZA )和 6-mercaptopurine ( 6-MP )， methotrexate ( MTX )， glucocorticosteroids ( CS )和 infliximab 。而且， pharmacogenetic 研究的困难一般来说并且更明确地在 IBD 被描述。尽管遗传药理学是已经贡献了一些药的行动的内在的机制的更好的理解的一个有希望的领域，在 IBD 使用，翻译直到现在成每日的实践的唯一的发现是在 thiopurine S-methyltransferase (TPMT ) 基因多型性和 thiopurine 治疗的 hematological 毒性之间的关系。在未来，在很好描绘的耐心的队组织研究是必要的谁一致地被对待并且系统地评估了以便测定药反应更客观地。一个努力应该被作从为 pharmacogenetic 研究在适当知情同意以后在临床的药试用注册的所有病人收集 genomic DNA。

Contribution of genetics to a new vision in the understanding of inflammatory bowel disease

煽动性的肠疾病(IBD ) 例如 Crohn 的疾病(CD ) 和 ulcerative (UC ) ，是胃肠道的长期的煽动性的自体免疫的条件。另外的机关例如眼睛，皮肤和连接，经常被影响， IBD 可以被自体免疫的起源的另外的疾病伴随。没有为 IBD 的发作负责的单个病因学的因素。在遗传并且在这些基因编码的蛋白质的分子的机制的最近的进展在理解这些复杂疾病产生了新视觉。影响抗原表示并且由先天免疫处理房间的特定的基因的激活可以与主要组织适合性建筑群(MHC ) 的作为结果的激活导致汽车免疫，多重 cytokines 在后天免疫的规定包含。在这评论， IBD 被描述为能最好作为障碍疾病被分类的疾病的一个星座。这视觉，在德国由 Kiel 发展了，包括在我们的环境的变化没由于文明的 westernization 受到天生的免疫系统的改编，并且这产生了自体免疫的疾病的想法。这些疾病影响 1000 个个人的 1-5 并且在不同大陆上在许多国家的国家健康系统上代表主要负担。在世界规模上，主要挑战是产生干预在亚洲，拉丁美洲和非洲阻止这些疾病的发展。

Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.

Challenges in pediatric inherited/metabolic liver disease: Focus on the disease spectrum, diagnosis and management of relatively common disorders

The clinical scenario of pediatric liver disease is becoming more intricate due to changes in the disease spectrum,in which an increasing number of inherited/metabolic liver diseases are reported,while infectious diseases show a decreasing trend.The similar clinical manifestations caused by inherited/metabolic diseases might be under-recognized or misdiagnosed due to nonspecific characteristics.A delayed visit to a doctor due to a lack of symptoms or mild symptoms at an early stage will result in late diagnosis and treatment.Moreover,limited diagnostic approaches,especially liver biopsy,are not easily accepted by pediatric patients,leading to challenges in etiological diagnosis.Liver dysfunction due to inherited/metabolic diseases is often caused by a variety of metabolites,so precision treatment is difficult;symptomatic treatment is a compelling option for inherited disorders.

Crohn’s disease: Why the ileum?

Crohn’s disease(CD)is an inflammatory bowel disease characterized by immunemediated flares affecting any region of the intestine alternating with remission periods.In CD,the ileum is frequently affected and about one third of patients presents with a pure ileal type.Moreover,the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes.Most of these genes are associated with Paneth cell dysfunction,a cell type found in the intestinal crypts of the ileum.Besides,a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota,which in turn modulates the susceptibility of the ileum to inflammation.Thus,the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis.Indeed,both immune response and cellular healing processes harbour differences between ileal and non-ileal CD.Taken together,these findings advocate for a dedicated therapeutic approach to managing ileal CD.Currently,interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site.However,the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.

Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease,with insights into Pink1 knockout models

Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor network.Genetic studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy activation.Pharmacological intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation model.As such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug pharmacology.These rats retain clinical features encompassing basal mitophagic flux changes with PD progression.We demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.