Karina Gonzalez-Aldaco

Association with Spontaneous Hepatitis C Viral Clearance and Genetic Differentiation of IL28B/IFNL4 Haplotypes in Populations from Mexico

Aim To analyze the genetic heterogeneity of the Amerindian and admixed population (Mestizos) based on the IL28B (rs12979860, rs8099917) and IFNL4 (rs368234815) haplotypes, and their association with spontaneous clearance (SC) and liver damage in patients with hepatitis C infection from West Mexico. Methods A total of 711 subjects from West Mexico (181 Amerindians and 530 Mestizos) were studied for the prevalence of IL28B (rs12979860C/T, rs8099917G/T) and IFNL4 (rs368234815∆G/TT) genotypes. A case-control study was performed in 234 treatment-naïve HCV Mestizos (149 chronic hepatitis C and 85 with SC) for the association of haplotypes with SC and liver damage. A real-time PCR assay was used for genotyping, and transitional elastography staged liver damage. Results Significant Fst-values indicated differentiation between the studied populations. The frequencies of the protective C, T, TT alleles were significantly lower in the Amerindians than in Mestizos (p<0.05). The r2 measure of linkage disequilibrium was significant for all variants and the T/G/ΔG risk haplotype predominated in Amerindians and secondly in Mestizos. The protective C/T/TT haplotype was associated with SC (OR = 0.46, 95% IC 0.22–0.95, p = 0.03) and less liver damage (OR = 0.32, 95% IC 0.10–0.97, p = 0.04) in chronic patients. The Structure software analysis demonstrated no significant differences in ancestry among SC and chronic patients. Conclusions West Mexico´s population is genetically heterogeneous at the IL28B/IFNL4 polymorphisms. The T/G/ΔG high-risk haplotype predominated in Amerindians and the beneficial alternative haplotype in Mestizos. The C/T/TT haplotype was associated with SC and less liver damage in chronically infected Mestizo patients.

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 of numerous 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.

High frequency of the DRD2/ANKK1 A1 allele in Mexican Native Amerindians and Mestizos and its association with alcohol consumption

BACKGROUND Mexico has an ancient tradition of alcohol drinking influenced by genetic and sociocultural factors. This study aimed to determine the distribution of the DRD2/ANKK1 TaqIA polymorphism in Mexican populations and to analyze its association with heavy drinking. METHODS In a cross-sectional and analytical study, 680 unrelated subjects including two Native Amerindians groups (87 Nahuas and 139 Huicholes), and two Mestizos groups (158 subjects from Tepic, Nayarit and 296 subjects from Guadalajara, Jalisco) were enrolled. DRD2/ANKK1 genotyping was performed by PCR-RFLP and allelic discrimination assays. Genetic analyses were conducted by Arlequin and Structure software. Heavy drinking was defined as ≥300g alcohol/week. The association of the DRD2/ANKK1 TaqIA polymorphism with heavy drinking was estimated. RESULTS Heavy drinking was prevalent in 64.7% of the study population. The DRD2/ANKK1 A1 allele prevailed in 67% and 65% of Nahuas and Huicholes, respectively and 51% and 47.3% in Mestizos from Tepic and Guadalajara, respectively. Heavy drinking was associated with the A1A1 genotype in the Mestizos of Guadalajara (A1A1 vs. A1A2 OR=4.79, 95%CI 1.81-12.68, p=0.0006; A1A1 vs. A1A2+A2A2, OR=4.09, 95%CI 1.56-10.68, p=0.0021) and in the Mestizos from Tepic (A1A1 vs. A1A2, OR=5.92, 95%CI 2.12-16.49, p=0.0002); A2A2, OR=14.56, 95%CI 3.57-59.24, p=0.00004); A1A2+A2A2, OR=6.68, 95%CI 2.42-18.42, p=0.00005). In Native Amerindians, a lack of association was found. CONCLUSIONS High frequencies of the DRD2/ANKK1 A1 allele were present in Mexican populations. Native Amerindians exhibited the highest frequencies of the A1 allele documented worldwide to date. The A1A1 genotype was associated with heavy drinking in Mestizos.

Spontaneous hepatitis C viral clearance and hepatitis C chronic infection are associated with distinct cytokine profiles in Mexican patients

The mechanisms related to the spontaneous clearance of hepatitis C virus (HCV) have been primarily studied in regions where the infection is endemic. Results of prior studies have been extrapolated to populations with low endemicity, such as Mexico. Herein, we determined the cytokine profiles in serum samples from Mexican patients who spontaneously cleared HCV and patients chronically infected with HCV genotype 1a. Chronic HCV-infected patients displayed increased interleukin (IL)-8 and regulated upon activation, normal T-cell expressed and secreted (CCL-5) secretion, whereas patients who spontaneously cleared HCV showed augmented levels of IL-1 alpha, tumour necrosis factor-alpha, transforming growth factor-beta, monocyte chemoattractant protein-2 (CCL-8), IL-13 and IL-15. Our study suggeststhat cytokine profiles may predict disease outcome during HCV infection.

Association of Lactase Persistence Genotypes with High Intake of Dairy Saturated Fat and High Prevalence of Lactase Non-Persistence among the Mexican Population

Background/Aim: Lactase (LCT) -13910 C>T and -22018 G>A polymorphisms associated with the lactase non-persistence (LNP)/persistence (LP) phenotypes vary globally. LP has been associated with obesity in Europeans. However, it has not been genetically evaluated in Mexico, a country with admixed population, recent introduction of dairy, and a high prevalence of obesity. Thus, we aimed to determine the distribution of the LCT polymorphisms and their association with the nutritional profile of West Mexicos populations. Methods: Genotyping of 1,196 individuals (natives and mestizos) was carried out by a Taqman allelic discrimination assay. Descriptive statistics and interpopulation analyzes were performed by SPSS, Arlequin, and Structure software. Demographic, anthropometric, biochemical and dietary data were analyzed in 212 mestizos. Results: LNP genotypes mainly prevailed (CC 68.7% and GG 68.2%); both predominated in native Huicholes and Nahuas (>97.7%). Among the mestizos, the LP genotypes were associated with a higher intake of saturated fat (9.9 ± 3.9% vs. 8.5 ± 4.0%, p = 0.018; OR = 2.55, 95% CI 1.29-5.03, p = 0.006) and a daily/more frequent consumption of dairy (88.8 vs. 78.0%; p = 0.049) than LNP genotypes. Conclusion: The LNP trait was predominant in Mexicans with a major Amerindian ancestry. A daily consumption of dairy was associated with a higher intake of saturated fat in LP individuals.

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 TaqMan 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.

The Immune System and Viral Hepatitis

Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus are viruses with hepatotropic lifecycles. Numerous studies have demonstrated the prominent role of the immune system in liver damage caused by these viruses. This chapter introduces the concept that differences in the host immune response dictate the distinct outcomes to these infections. It starts by presenting the natural history of these viral illnesses. A high-level perspective of the cellular immune responses against HAV, HBV, and HCV is included. Recent data pointing at the host (genetic), viral (genotype), and environmental factors that may account for the differential immune response in the admixed Mexican population are underlined. At the end of the chapter, the immune cells, cytokines, and metabolites with immunomodulatory functions related to liver injury are explained. We focus on discoveries that hold promise for identifying immunologic features in the resolution of viral hepatitis.

Tailoring Nutritional Advice for Mexicans Based on Prevalence Profiles of Diet-Related Adaptive Gene Polymorphisms

Diet-related adaptive gene (DRAG) polymorphisms identified in specific populations are associated with chronic disorders in carriers of the adaptive alleles due to changes in dietary and lifestyle patterns in recent times. Mexico’s population is comprised of Amerindians (AM) and Mestizos who have variable AM, European (EUR) and African genetic ancestry and an increased risk of nutrition-related chronic diseases. Nutritional advice based on the Mexican genome and the traditional food culture is needed to develop preventive and therapeutic strategies. Therefore, we aimed to provide a prevalence profile of several DRAG polymorphisms in the Mexican population, including Central West (CW) Mexico subpopulations. Geographic heat maps were built using ArcGIS10 (Esri, Redlands, CA, USA) software, based on the published data of the MTHFR C677T (rs1801133), ABCA1 Arg230Cys (rs9282541), APOE T388C (rs429358)/C526T (rs7412), LCT C-13910T (rs4988235) polymorphisms and AMY1 copy number variation (CNV). Also, new data obtained by allelic discrimination-real-time polymerase chain reaction (RT-PCR) assays for the MTHFR, ABCA1, and APOE polymorphisms as well as the AMY1 CNV in the CW Mexico subpopulations with different proportions of AM and EUR ancestry were included. In the CW region, the highest frequency of the MTHFR 677T, ABCA1 230C and APOE ε4 adaptive alleles was observed in the AM groups, followed by Mestizos with intermediate AM ancestry. The LCT-13910T allele frequency was highest in Mestizos-EUR but extremely low in AM, while the AMY1 diploid copy number was 6.82 ± 3.3 copies. Overall, the heat maps showed a heterogeneous distribution of the DRAG polymorphisms, in which the AM groups revealed the highest frequencies of the adaptive alleles followed by Mestizos. Given these genetic differences, genome-based nutritional advice should be tailored in a regionalized and individualized manner according to the available foods and Mexican traditional food culture that may lead to a healthier dietary pattern.

High Prevalence of ITPA Alleles Associated with Ribavirin-Induced Hemolytic Anemia Among Mexican Population

BACKGROUND The prevalence of two functional polymorphisms (rs1127354 and rs7270101) of the inosine triphosphatase (ITPA) gene associated with ribavirin-induced hemolytic anemia (RIHA) during antiviral therapy for hepatitis C virus (HCV) infection varies by ethnicity. In Mexico, the distribution of these polymorphisms among Native Amerindians (NA) and admixed population (Mestizos) is unknown. This study aimed to determine the prevalence of the ITPA polymorphisms among healthy NA and Mestizos, as well as in HCV patients from West Mexico. MATERIAL AND METHODS In a cross-sectional study, 600 unrelated subjects (322 Mestizos, 100 NA, and 178 treatment-naïve, HCV-infected Mestizos patients) were enrolled. A medical history was registered. ITPA genotype was determined by Real-Time PCR. Fst-values and genetic relatedness between study and reference populations were assessed. RESULTS The frequency of the risk genotypes rs1127354CC and rs7270101AA was higher among NA (98-100%) than in Mestizos (87-92.9%), (p < 0.05). The NA presented the highest prevalence of the rs1127354CC genotype reported worldwide. The Fst-values revealed a genetic relatedness among Mexican NA, South Americans and African populations (p > 0.05). The frequency of the predicted risk for RIHA was higher among NA (98%) than in Mestizos (80.5%) and HCV-infected patients (81.5%) (p < 0 .01). The CC/AA alleles were associated with lower values of total bilirubin, aspartate/alanine aminotransferases, and aspartate-to-platelet-ratio-index score among HCV-patients. CONCLUSION A high prevalence of the ITPA polymorphisms associated with RIHA was found in Mexican NA. These polymorphisms could be a useful tool for evaluating potential adverse effects and the risk or benefit of antiviral therapy in Mexicans and other admixed populations.BACKGROUND Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. OBJECTIVE To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. MATERIAL AND METHODS This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. RESULTS No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treat-ment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. CONCLUSION Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.