Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico

Liver cirrhosis(LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.

Alcoholism and liver disease in Mexico:Genetic and environmental factors

Alcoholism and cirrhosis,which are two of the most serious health problems worldwide,have a broad spectrum of clinical outcomes.Both diseases are influenced by genetic susceptibility and cultural traits that differ globally but are specific for each population.In contrast to other regions around the world,Mexicans present the highest drinking score and a high mortality rate for alcoholic liver disease with an intermediate category level of per capita alcohol consumption.Mexico has a unique history of alcohol consumption that is linked to profound anthropological and social aspects.The Mexican population has an admixture genome inherited from different races,Caucasian,Amerindian and African,with a heterogeneous distribution within the country.Thus,genes related to alcohol addiction,such as dopamine receptor D2 in the brain,or liver alcoholmetabolizing enzymes,such as alcohol dehydrogenase classⅠpolypeptide B,cytochrome P450 2E1 and aldehyde dehydrogenase class 2,may vary from one individual to another.Furthermore,they may be inherited as risk or non-risk haplogroups that confer susceptibility or resistance either to alcohol addiction or abusive alcohol consumption and possibly liver disease.Thus,in this era of genomics,personalized medicine will benefit patients if it is directed according to individual or population-based data.Additional association studies will be required to establish novel strategies for the prevention,care and treatment of liver disease in Mexico and worldwide.

HBV endemicity in Mexico is associated with HBV genotypes H and G

Hepatitis B virus(HBV)genotypes have distinct genetic and geographic diversity and may be associated with specific clinical characteristics,progression,severity of disease and antiviral response.Herein,we provide an updated overview of the endemicity of HBV genotypes H and G in Mexico.HBV genotype H is predominant among the Mexican population,but not in Central America.Its geographic distribution is related to a typical endemicity among the Mexicans which is characterized by a low hepatitis B surface antigen seroprevalence,apparently due to a rapid resolution of the infection,low viral loads and a high prevalence of occult B infection.During chronic infections,genotype H is detected in mixtures with other HBV genotypes and associated with other co-morbidities,such as obesity,alcoholism and co-infection with hepatitis C virus or human immunodeficiency virus.Hepatocellular carcinoma prevalence is low.Thus,antiviral therapy may differ significantly from the standard guidelines established worldwide.The high prevalence of HBV genotype G in the Americas,especially among the Mexican population,raises new questions regarding its geographic origin that will require further investigation.

Hepatitis B virus infection in Latin America:A genomic medicine approach

Hepatitis B virus(HBV)infection is the leading cause of severe chronic liver disease.This article provides a critical view of the importance of genomic medicine for the study of HBV infection and its clinical outcomes in Latin America.Three levels of evolutionary adaptation may correlate with the clinical outcomes of HBV infection.Infections in Latin America are predominantly of genotype H in Mexico and genotype F in Central and South America;these strains have historically circulated among the indigenous population.Both genotypes appear to be linked to a benign course of disease among the native and mestizo Mexicans and native South Americans.In contrast,genotypes F,A and D are common in acute and chronic infections among mestizos with Caucasian ancestry.Hepatocellular carcinoma is rare in Mexicans,but it has been associated with genotype F1b among Argentineans.This observation illustrates the significance of ascertaining the genetic and environmental factors involved in the development of HBV-related liver disease in Latin America,which contrast with those reported in other regions of the world.

Genomic medicine in gastroenterology:A new approach or a new specialty?

Throughout history, many medical milestones have been achieved to prevent and treat human diseases.Man's early conception of illness was naturally holistic or integrative. However, scientific knowledge was atomized into quantitative and qualitative research. In the field of medicine, the main trade-off was the creation of many medical specialties that commonly treat patients in advanced stages of disease. However, now that we are immersed in the post-genomic era, how should we reevaluate medicine? Genomic medicine has evoked a medical paradigm shift based on the plausibility to predict the genetic susceptibility to disease. Additionally, the development of chronic diseases should be viewed as a continuum of interactions between the individual's genetic make-up and environmental factors such as diet, physical activity, and emotions. Thus, personalized medicine is aimed at preventing or reversing clinical symptoms, and providing a better quality of life by integrating the genetic, environmental and cultural factors of diseases. Whether using genomic medicine in the field of gastroenterology is a new approach or a new medical specialty remains an open question. To address this issue, it will require the mutual work of educational and governmental authorities with public health professionals, with the goal of translating genomic medicine into better health policies.

Genome-based nutrition:An intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis

Obesity and nonalcoholic steatohepatitis are increasing in westernized countries, regardless of their geographiclocation. In Latin America, most countries, including Mexico, have a heterogeneous admixture genome with Amerindian, European and African ancestries. However, certain high allelic frequencies of several nutrientrelated polymorphisms may have been achieved by past gene-nutrient interactions. Such interactions may have promoted the positive selection of variants adapted to regional food sources. At present, the unbalanced diet composition of the Mexicans has led the country to a 70% prevalence rate of overweightness and obesity due to substantial changes in food habits, among other factors. International guidelines and intervention strategies may not be adequate for all populations worldwide because they do not consider disparities in genetic and environmental factors, and thus there is a need for differential prevention and management strategies. Here, we provide the rationale for an intervention strategy for the prevention and management of obesity-related diseases such as nonalcoholic steatohepatitis based on a regionalized genome-based diet. The components required to design such a diet should focus on the specific ancestry of each population around the world and the convenience of consuming traditional ethnic food.

Genes, emotions and gut microbiota:The next frontier for the gastroenterologist

Most medical specialties including the field of gastroenterology are mainly aimed at treating diseases rather than preventing them. Genomic medicine studies the health/disease process based on the interaction of the human genes with the environment. The gastrointestinal(GI) system is an ideal model to analyze the interaction between our genes, emotions and the gut microbiota. Based on the current knowledge, this mini-review aims to provide an integrated synopsis of this interaction to achieve a better understanding of the GI disorders related to bad eating habits and stress-related disease. Since human beings are the result of an evolutionary process, many biological processes such as instincts, emotions and behavior are interconnected to guarantee survival. Nourishment is a physiological need triggered by the instinct of survival to satisfy the body's energy demands. The brain-gut axis comprises a tightly connected neuralneuroendocrine circuitry between the hunger-satiety center, the dopaminergic reward system involved in the pleasure of eating and the gut microbiota that regulates which food we eat and emotions. However, genetic variations and the consumption of high-sugar and high-fat diets have overridden this energy/pleasure neurocircuitry to the point of addiction of several foodstuffs. Consequently, a gut dysbiosis generates inflammation and a negative emotional state may lead to chronic diseases. Balancing this altered processes to regain health may involve personalized-medicine and genome-based strategies. Thus, an integrated approach based on the understanding of the gene-emotions-gut microbiota interaction is the next frontier that awaits the gastroenterologist to prevent and treat GI disorders associated with obesity and negative emotions.

Hepatitis B Virus Genotype H and Environmental Factors Associated to the Low Prevalence of Hepatocellular Carcinoma in Mexico

Purpose: Hepatocellular carcinoma (HCC) is a leading health problem worldwide. Any agent causing chronic liver damage and cirrhosis is a risk factor for HCC. Genetic and environmental factors may be responsible for regional variations in the occurrence of HCC worldwide. The aim of this review was to describe the risk factors that may be contributing to low prevalence of HCC in the Mexican population. Methods: An electronic systematic search was conducted in four databases to retrieve studies on hepatocellular carcinoma inMexico. Results: Eighteen publications gave a total of 1042 HCC cases with a percentage that ranged from 0.25% to 1.87%. Cirrhosis was registered in 7 studies while the main etiologies were: HCV (66%), HBV (11%) and alcoholism (6.6%). Conclusions: In the last 50 years, the studies performed inMexicohave shown a very low incidence and/or mortality rate of HCC. These findings contrast from those reported in high endemic regions, such asAsia, where viral hepatitis and HCC are prevalent. One significant difference is the predominance of HBV genotype H in Mexico and HBV/B and C in Asia. InMexico, high endemic areas of HBV infection have been detected, mainly among the native population;however, infection seems to resolve very quickly, due to a prominent immunological response among the population. Other factors are that patients with liver cirrhosis die prematurely before that HCC can be detected. Furthermore, an environmental factor that may exert a protective effect against HCC, in spite of the high consumption of potentially aflatoxin-contaminated food products, is the neutralization of these substances by alkaline treatment. This study shows that genetic and environmental factors associated to HCC among the Mexican population are different from others reported worldwide.

Immunologic, metabolic and genetic factors in hepatitis C virus infection

The mechanisms that regulate disease progression during hepatitis C virus(HCV)infection and the response to treatment are not clearly identified.Numerous studies have demonstrated that a strong host immune response against HCV favors HCV clearance.In addition,genetic factors and metabolic machinery,particularly cholesterol modulation,are involved in HCV infection.It is likely that the interplay between all of these factors contributes to the outcome of HCV infection.In recent years,the world has experienced its largest epidemic of obesity.Mexico and the United States are the leading sufferers from this epidemic at the global level.Obesity is associated with the development ofnumerous pathologies including hypercholesterolemia which is one of the eight most important risk factors for mortality in Mexico.This may be related to the course of HCV infection in this population.Here,we focus on the urgent need to study the progression of HCV infection in relation to ethnic characteristics.Discoveries are discussed that hold promise in identifying immune,metabolic and genetic factors that,in conjunction,could be therapeutic targets or predictors of the progression of HCV infection.

Hepatitis C virus clearance and less liver damage in patients with high cholesterol, low-density lipoprotein cholesterol and APOE ε4 allele

BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.

CD36 genetic variation, fat intake and liver fibrosis in chronic hepatitis C virus infection

AIM To analyze the association of the CD36 polymorphism(rs1761667) with dietary intake and liver fibrosis(LF) in chronic hepatitis C(CHC) patients. METHODS In this study, 73 patients with CHC were recruited. The CD36 genotype(G > A) was determined by a TaqM an real-time PCR system. Dietary assessment was carried out using a three-day food record to register the daily intake of macronutrients. Serum lipids and liver enzymes were measured by a dry chemistry assay. LF evaluated by transient elastography(Fibroscan~)and APRI score was classified as mild LF(F1-F2) and advanced LF(F3-F4).RESULTS Overall, the CD36 genotypic frequencies were AA(30.1%), AG(54.8%), and GG(15.1%), whereas the allelic A and G frequencies were 57.5% and 42.5%, respectively. CHC patients who were carriers of the CD36 AA genotype had a higher intake of calories attributable to total fat and saturated fatty acids than those with the non-AA genotypes. Additionally, aspartate aminotransferase(AST) serum values were higher in AA genotype carriers compared to non-AA carriers(91.7 IU/L vs 69.8 IU/L, P = 0.02). Moreover, the AA genotype was associated with an increase of 30.23 IU/L of AST(β = 30.23, 95%CI: 9.0-51.46, P = 0.006). Likewise, the AA genotype was associated with advanced LF compared to the AG(OR = 3.60, 95%CI: 1.16-11.15, P = 0.02) or AG + GG genotypes(OR = 3.52, 95%CI: 1.18-10.45, P = 0.02).CONCLUSION This study suggests that the CD36(rs1761667) AA genotype is associated with higher fat intake and more instances of advanced LF in CHC patients.

Need of righteous attitudes towards eradication of hepatitis C virus infection in Latin America

Over the last few years, we have expanded our knowledge on numerous facets of the hepatitis C virus(HCV). Beginning with its discovery and viral life cycle, its impact on health, the development of liver disease and currently, effective antiviral treatments. The latter point has become of great interest throughout the developed world, where the possible eradication of HCV through specific strategies to reach all HCV-infected people has been announced. However, this scenario is very different in the countries of Latin America(LA), in which < 2% of infected patients requiring treatment have access to HCV medications. It has been estimated that at least ten million Latin Americans may be infected with HCV. Despite the numbers, viral hepatitis does not seem to be considered a health problem in this region of the world. This reality poses a challenge for politicians and governments of these countries, as well as to the pharmaceutical industry, the medical practitioners, and academics in LA. In this editorial, we state the need for alterations in the attitudes of the integral players involved in this situation. A recognition shift could help to create preventive strategies of viral hepatitis and to advocate for accessibility to new HCV treatments.

Differential distribution of gene polymorphisms associated with hypercholesterolemia,hypertriglyceridemia,and hypoalphalipoproteinemia among Native American and Mestizo Mexicans

BACKGROUND Dyslipidemias are metabolic abnormalities associated with chronic diseases caused by genetic and environmental factors.The Mexican population displays regional differences according to ethnicity with an impact on the type of dyslipidemia.AIM To define the main dyslipidemias,the frequency of lipid-related risk alleles,and their association with hyperlipidemic states among different ethnic groups in West Mexico.METHODS In a retrospective study,1324 adults were selected to compare dyslipidemias and lipid-related gene polymorphisms.Demographic,clinical,and laboratory data were collected.A subgroup of 196 normal weight subjects without impaired glucose was selected for the association analyses.Genotyping was determined by allelic discrimination assay.RESULTS Hypercholesterolemia was the most prevalent dyslipidemia(42.3%).The frequency of the risk alleles associated with hypoalphalipoproteinemia(ABCA1)and hypercholesterolemia(APOE,LDLR)was higher in the Native Americans(P=0.047).In contrast,the Mestizos with European ancestry showed a higher frequency of the risk alleles for hypertriglyceridemia(APOE2,MTTP)(P=0.045).In normal weight Mestizo subjects,the APOB TT and LDLR GG genotypes were associated risk factors for hypercholesterolemia(OR=5.33,95%CI:1.537-18.502,P=0.008 and OR=3.90,95%CI:1.042-14.583,P=0.043,respectively),and displayed an increase in low-density lipoprotein cholesterol levels(APOB:β=40.39,95%CI:14.415-66.366,P=0.004;LDLR:β=20.77,95%CI:5.763-35.784,P=0.007).CONCLUSION Gene polymorphisms and dyslipidemias showed a differential distribution.Regional primary health care strategies are required to mitigate their prevalence considering the genetic and environmental features which could have important implications for personalized medicine within the new era of precision medicine.

High Frequency of Antiviral Resistance Mutations in HBV Genotypes A2 and H: Multidrug Resistance Strains in Mexico

Background and Aims:Lamivudine(3TC),telbivudine(LdT),entecavir(ETV),adefovir(ADF),and tenofovir(TFV)are drugs used to treat hepatitis B virus(HBV)infection,but specific mutations allow some viruses to become resistant to antiviral drugs or to acquire immune escape capacities.These mutations have not been thoroughly investigated in Mexico.This study aimed to estimate the prevalence of HBV antiviral resistance and escape mutations.Methods:This cross-sectional study analyzed 158 samples.HBV DNA was extracted,amplified,and sequenced in serum samples using the spin column method,PCR assay,and Sanger’s sequencing,respectively.HBV genotypes were determined,and HBV mutations were tested using the Geno2pheno tool.Results:Overall,68.4%(108/158)of HBV patients were infected with genotype H,followed by G(11.4%,18/158),A2(10.8%,17/158),F1b(6.9.0%,11/158),D(1.9%,3/158),and E(0.6%,1/158),and 5.1%(8/158)had evidence of recombination.The prevalence of resistance mutations was 8.2%(13/158)and the most common combined mutation was rt180M+rt204V.Notably,we found the combinations rt180M+rt204V+rt173L(n=2)and rt180M+rt204V+rt202G(n=1)that confer multidrug resistance to 3TC,LdT,and ETV.Resistance mutations were found in genotypes A2(11.8%,2/17),and H(10.2%,11/108),and escape mutations were detected in HBV genotypes A2(11.8%,2/17),H(10.2%,11/108),F1b(9.1%,1/11)and G(5.6%,1/18).Conclusions:The highest prevalence of antiviral resistance mutations or escape mutations was detected in HBV genotypes A2 and H.The earliest cases of HBV multidrug resistance were detected in Mexico.