Relationship between energy balance and reward system gene polymorphisms and appetitive traits in young Mexican subjects.

Introduction: Appetitive traits are influenced by the interplay between genetic and environmental factors. This study aimed to explore the relationship between gene polymorphisms involved in the regulation of energy balance and food reward and appetitive traits in young Mexican subjects. Methods: This cross-sectional study involved 118 university freshman undergraduates who completed the Adult Eating Behaviour Questionnaire for Spanish speakers (AEBQ-Esp) to assess their appetitive traits. A real-time PCR system was employed to determine gene polymorphisms involved in energy balance (LEP rs7799039, MC4R rs17782313, FTO rs9939609, GHRL rs696217), and reward system (DRD2/ANKK1 Taq1A rs1800497 and COMT rs4680). Results: The mean age of participants was 20.14 ± 3.95 years, 71.2% were women and their mean BMI was 23.52 ± 4.05 kg/m2. COMT Met allele carriers presented a significantly higher "Emotional overeating" mean score than Val allele carriers (2.63 ± 0.70 vs. 2.23 ± 0.70, p = 0.028). The MC4R CC + CT genotype correlated positively with "Emotional overeating" (Phi = 0.308, p = 0.01). The COMT MetMet+MetVal genotype correlated with higher "Emotional overeating" (r = 0.257, p = 0.028; Phi = 0.249, p = 0.033). The protective genotype FTO TT correlated positively with "Emotional undereating" (Phi = 0.298, p = 0.012). Carriers of the risk genotype MC4R CC + CT presented a higher risk of "Emotional overeating" than TT carriers (OR = 2.4, 95% CI 1.3-4.8, p = 0.034). Carriers of the risk genotype COMT MetMet+MetVal (OR = 3.4, 95% CI 1.1-10.3, p = 0.033), were associated with a higher risk of "Emotional overeating" than ValVal carriers. The protective FTO genotype TT was associated with "Emotional undereating" (OR = 1.8, 95% CI 1.1-9.1, p = 0.014). Discussion: The study found a relationship between the protective genotypes of FTO TT and "Emotional undereating" and risk genotypes of COMT Met/Met+Met/Val and MC4R CC + CT with "Emotional overeating." These genetic factors may increase weight gain by enhancing hedonic food consumption and reducing satiety control. Future studies should focus on replication studies in ethnically diverse young adults and life stages to explore the relationship between polymorphisms and appetitive traits and weight. This will help tailor personalized nutrigenetic strategies to counteract disordered eating patterns leading to obesity and associated co-morbidities.

FTO genotypes (rs9939609 T>A) are Associated with Increased Added Sugar Intake in Healthy Young Adults.

INTRODUCTION: Single-nucleotide polymorphism (SNP) rs9939609 in the FTO gene has been associated with dietary intake and appetite traits, mainly in participants with obesity; however, it remains widely unexplored in normal weight participants. Thus, the aims of this study were (1) to compare the changes in subjective appetite sensations, ghrelin, and insulin concentrations according to the SNP rs9939609 T>A in FTO and (2) to compare dietary intake between rs9939609 genotype groups in normal weight young participants. METHODS: We conducted a quasi-experimental study involving 88 normal weight participants to analyze subjective perception of appetite, hormonal response for hunger and satiety, and dietary intake according to the rs9939609 SNP. Participants received a standardized single breakfast. Visual analogue scales (VAS) were utilized for assessing the subjective perception of appetite at fasting and immediately after breakfast and at 30, 60, 90, and 120 min postprandially. Glucose, lipid profile, ghrelin, and insulin were measured at fasting and at 120 min after breakfast. Dietary intake was assessed with a 3-day food record. The SNP was determined by allelic discrimination with TaqMan probes. To compare dietetic, biochemical, and the subjective appetite sensations, Student t test, ANCOVA test, and the repeated measures ANOVA were used. The linear regression model and the linear mixed model were used for the association analysis. Pearson correlation was used to test the correlation between two quantitative variables. RESULTS: A total of 88 people participated, 81.8% were female, with a mean body mass index of 21.8 ± 2.0 kg/m2 and a mean age of 20.6 ± 2.0. Genotype frequencies of the rs9939609 SNP were 52% for the TT allele and 48% for the TA/AA. The subjective perception of appetite named hunger, fullness, satiety, desire to eat, and prospective food consumption were similar between genotypes of the rs9939609. Participants with the TA/AA genotype showed a higher intake of added sugar (p = 0.039) than TT participants. No differences were found in ghrelin, insulin, glucose, or lipid parameters between genotypes. CONCLUSION: Carriers of the A allele from FTO gene SNP rs9939609 may have an increased preference for foods, specifically for added sugars.

A systematic review and functional bioinformatics analysis of genes associated with Crohn's disease identify more than 120 related genes.

BACKGROUND: Crohn's disease is one of the two categories of inflammatory bowel diseases that affect the gastrointestinal tract. The heritability estimate has been reported to be 0.75. Several genes linked to Crohn's disease risk have been identified using a plethora of strategies such as linkage-based studies, candidate gene association studies, and lately through genome-wide association studies (GWAS). Nevertheless, to our knowledge, a compendium of all the genes that have been associated with CD is lacking. METHODS: We conducted functional analyses of a gene set generated from a systematic review where genes potentially related to CD found in the literature were analyzed and classified depending on the genetic evidence reported and putative biological function. For this, we retrieved and analyzed 2496 abstracts comprising 1067 human genes plus 22 publications regarding 133 genes from GWAS Catalog. Then, each gene was curated and categorized according to the type of evidence associated with Crohn's disease. RESULTS: We identified 126 genes associated with Crohn's disease risk by specific experiments. Additionally, 71 genes were recognized associated through GWAS alone, 18 to treatment response, 41 to disease complications, and 81 to related diseases. Bioinformatic analysis of the 126 genes supports their importance in Crohn's disease and highlights genes associated with specific aspects such as symptoms, drugs, and comorbidities. Importantly, most genes were not included in commercial genetic panels suggesting that Crohn's disease is genetically underdiagnosed. CONCLUSIONS: We identified a total of 126 genes from PubMed and 71 from GWAS that showed evidence of association to diagnosis, 18 to treatment response, and 41 to disease complications in Crohn's disease. This prioritized gene catalog can be explored at http://victortrevino.bioinformatics.mx/CrohnDisease .

Influence of a Nutrigenetic Intervention on Self-Efficacy, Emotions, and Rewarding Behaviors in Unhealthy Eating among Mexicans: An Exploratory Pilot Study.

The Genome-based Mexican (GENOMEX) diet is a strategy for preventing and managing obesity. Emotion and eating behavior in the context of a nutrigenetic intervention have not been thoroughly studied. We aimed to explore the influence of the GENOMEX diet on emotions, self-efficacy, and rewarding behaviors in unhealthy eating among subjects with risk factors for obesity-related chronic diseases. Twenty-eight subjects included in the six-month GENOMEX intervention answered questions regarding emotions that influence food consumption. Additionally, the Patient Health Questionnaire (PHQ-9) and the Reward-based eating drive scale (RED) were applied. In the study, minimal, mild, moderate, and severe depression were present in 46.4%, 39.3%, 10.7%, and 3.6%, respectively. RED did not change, but it correlated with a higher intake of fats (r2 = 0.684, ß = 2.066, p = 0.003). Mood influenced unhealthy eating in 71.7% of subjects, and 76.9% experienced binge episodes triggered by anxiety. Sugars were the most consumed foods during binge episodes (42.2%). Both low self-efficacy levels and binge episodes were associated with high consumption of unhealthy foods. After the intervention, 10.7% of subjects reported a high level of self-efficacy. In conclusion, a culturally acceptable and genetically compatible regional Mexican food diet reduced negative emotions and unhealthy eating while increasing self-efficacy.

Evidence for Increased Inflammatory Cytokine Profile in Hepatitis E Virus-Infected Obese Patients: Implications for Chronic Liver Disease.

We aimed to characterize the contribution of hepatitis E virus (HEV) in perpetuating the cytokine-mediated inflammatory setting related to liver damage in the context of obesity. Herein, serum samples from patients with liver disease were retrospectively analyzed and categorized as normal-weight patients (NW), overweight patients (OW), obese patients (ObP), and high alcohol consumer patients (HAC), and biochemical, anthropometrical, and transient elastography measurements were obtained. The positivity for immunoglobulin M (IgM) and immunoglobulin G (IgG) anti-HEV antibodies in samples was determined by enzyme-linked immunosorbent assay. Available samples from ObP were tested by reverse transcription-nested polymerase chain reaction for the presence of HEV-RNA. Cytokine profile in the serum of ObP was identified using a multiplexed immune assay. Globally, the highest frequency of IgG anti-HEV was found in ObP (57.5%), followed by HAC (20%), OW (15%), and NW (7.5%). A strong association between HEV serology and obesity was found (odds ratio = 4.21, confidence interval = 1.91.9.27) with a cutoff of 29.3 kg/m2 (area under curve [AUC] = 0-66; p = 0.003) and, a 23.7% of available samples of ObP provided amplification of HEV genome. Cytokine analysis revealed significantly higher levels of proinflammatory cytokines (interleukin [IL]-12, interferon [IFN]-γ, and IL-1ß) in IgG anti-HEV-positive ObP than in IgG anti-HEV-negative ObP. Moreover, a high proportion of patients with positive serology showed advanced liver damage. In conclusion, the high percentage of anti-HEV antibodies and viral RNA detection in the setting of an excess of fat, along with an associated proinflammatory cytokine profile found in IgG anti-HEV-positive ObP with more severe liver disease, support an interplay between HEV and obesity.

A systematic review of genes affecting mitochondrial processes in cancer.

Malignant conversion of cancer cells requires efficient mitochondria reprogramming orchestrated by hundreds of genes. The transformation includes increased energy demand, biosynthesis of precursors, and reactive oxygen species needed to accelerate cell growth, proliferation, and survival. Reprogramming involves complex gene alterations that have not been methodically curated. Therefore, we systematically analyzed the literature of cancer-related genes in mitochondria. Through the analysis of >2500 PubMed abstracts and >1600 human genes, we identified 228 genes showing clear roles in cancer. Each gene was classified according to their homeostatic function, together with the pathological transitions that contribute to specific cancer hallmarks. The potential clinical relevance of these hallmarks and genes is discussed by representative examples and validated by detecting differences in gene expression levels across 16 different types of cancer. A compendium, including the gene functions and alterations underpinning cancer progression, can be explored at http://bioinformatica.mty.itesm.mx/MitoCancer.

A Regionalized Genome-Based Mexican Diet Improves Anthropometric and Metabolic Parameters in Subjects at Risk for Obesity-Related Chronic Diseases.

Obesity-related chronic diseases (CD) are highly prevalent in Mexicans who show moderate to high frequencies of diet-related adaptive gene (DRAG) polymorphisms and recent shifts in traditional dietary habits and lifestyles. This study first evaluated the effects of a regionalized genome-based Mexican (GENOMEX) diet on anthropometric and biochemical parameters and, subsequently their relationship with the genetic profile of DRAG polymorphisms in subjects with metabolic risk factors for obesity-related CD. Thirty-seven eligible subjects underwent a 24-week dietary intervention with a GENOMEX diet. The DRAG polymorphisms were determined by an allelic discrimination real-time assay to evaluate their association with the clinical response to diet. The GENOMEX diet significantly improved anthropometric parameters such as total weight, body mass index, waist circumference, and body fat percentage, with an average weight loss of 6.6% (5.3 ± 5.3 kg). The frequency of subjects with insulin resistance, hypertriglyceridemia and elevated VLDL-c (48.5% vs. 24.2%, p = 0.041; 45.5% vs. 12.1%, p = 0.003; and 39.4% vs. 15.2%, p = 0.027, baseline vs. 24-weeks, respectively) was reduced. A more significant favorable effect in HOMA-IR and insulin was observed in MTHFR 677T adaptive allele carriers, but no other DRAG polymorphism was associated with clinical changes. The GENOMEX diet improved the metabolic risk factors for obesity-related CD. The recommendation and habitual consumption of a traditional Mexican diet based on knowledge of the population´s genetic and cultural history may be effective in preventing current obesity-related CD.

Identification and analysis of 35 genes associated with vitamin D deficiency: A systematic review to identify genetic variants.

Vitamin D deficiency is a public health concern associated with, but not limited to, skeletal anomalies, chronic diseases, immune conditions, and cancer, among others. Hypovitaminosis D is mainly associated with environmental and lifestyle factors that affect sunlight exposure. However, genetic factors also influence 25-hydroxyvitamin D (25[OH]D) serum concentration. Although there is available information of genes with clear biological relevance or markers identified by Genome-Wide Association Studies, an overall view and screening tool to identify known genetic causes of altered serum levels of 25(OH)D is lacking. Moreover, there are no studies including the total genetic evidence associated with abnormal serum concentration of 25(OH)D. Therefore, we conducted a de-novo systematic literature review to propose a set of genes comprehensive of all genetic variants reported to be associated with deficiency of vitamin D. Abstracts retrieved from PubMed search were organized by gene and curated one-by-one using the PubTerm web tool. The genes identified were classified according to the type of genetic evidence associated with serum 25(OH)D levels and were also compared with the few commonly screened genes related to vitamin D status. This strategy allowed the identification of 35 genes associated with serum 25(OH)D concentrations, 27 (75%) of which are not commercially available and are not, therefore, analyzed in clinical practice for genetic counseling, nor are they sufficiently studied for research purposes. Functional analysis of the genes identified confirmed their role in vitamin D pathways and diseases. Thus, the list of genes is an important source to understand the genetic determinants of 25(OH)D levels. To further support our findings, we provide a map of the reported functional variants and SNPs not included in ClinVar, minor allelic frequencies, SNP effect sizes, associated diseases, and an integrated overview of the biological role of the genes. In conclusion, we identified a comprehensive candidate list of genes associated with serum 25(OH)D concentrations, most of which are not commercially available, but would prove of importance in clinical practice in screening for patients that should respond to supplementation because of alterations in absorption, patients that would have little benefit because alterations in the downstream metabolism of vitamin D, and to study non-responsiveness to supplementation with vitamin D.

High prevalence of nonalcoholic steatohepatitis and abnormal liver stiffness in a young and obese Mexican population.

OBJECTIVE: To identify nonalcoholic steatohepatitis (NASH) and liver stiffness in Mexican subjects with different body mass index (BMI). METHODS: A cross-sectional study was conducted in 505 adults. Risk for NASH was defined as the presence of one or more of the following biochemical and metabolic parameters (BMPs): fasting glucose ≥100 mg/dl, triglycerides (TG) ≥150 mg/dl, homeostatic model assessment of insulin resistance (HOMA-IR) ≥2.5, aspartate aminotransferase (AST) >54 IU/L and alanine aminotransferase (ALT) >42 IU/L. Body mass index measurement and nutritional assessment were performed by standard procedures. Liver fibrosis stage was determined by liver stiffness measurement using transitional elastography (TE) or by liver biopsy (LB). RESULTS: Risk for NASH was 57% (290/505). Most BMPs values incremented by BMI category. Among 171 at-risk patients, 106 subjects were evaluated by TE and 65 subjects by LB. Abnormal liver stiffness (≥6.0 kPa) was prevalent in 54% (57/106) of the cases, whereas by LB, 91% (59/65) of patients with obesity had NASH and liver fibrosis. Furthermore, liver fibrosis was prevalent in 46% (6/13) in normal weight individuals, whereas 4.6% (3/65) of patients with a BMI ≥ 35 kg/m2 showed no histopathological abnormalities. Overall, 67.8% (116/171) of the patients had abnormal liver stiffness or NASH. The normal weight patients with liver damage consumed relatively a higher fat-rich diet compared to the other groups whereas the remaining subgroups shared a similar dietary pattern. CONCLUSION: Young patients with overweight and obesity showed a high prevalence of altered BMPs related to abnormal liver stiffness assessed by TE and NASH by LB. Early diagnostic strategies are required to detect the risk for NASH and avoid further liver damage in populations with a rising prevalence of obesity by defining the risk factors involved in the onset and progression of NASH.

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.

Early Detection of Liver Damage in Mexican Patients with Chronic Liver Disease.

BACKGROUND AND OBJECTIVE: Liver cirrhosis is usually detected at the later stages of disease. This study is aimed to detect liver damage in patients with chronic liver disease using transitional elastography (TE) and to assess the biochemical parameters associated with liver damage. METHODS: In 578 patients, chronic liver disease based on etiology was diagnosed by clinical and laboratory tests. Liver damage was evaluated with TE (FibroScan®), while its association with biochemical parameters was performed using the logistic regression tests. RESULTS: Overall, the main etiologies of liver damage were hepatitis C virus (HCV) (37%), alcoholic liver disease (ALD) (33%) and non-alcoholic steatohepatitis (NASH) (26%). Patients were 40 to 50 years of age. ALD and hepatitis B prevailed in men, whereas HCV and NASH in women. The stages of fibrosis were F0 (n = 121, 21%), F1 (n = 122, 21%), F2 (n = 58, 10%), F3 (n = 46, 8%) and F4 (n = 87, 15%). In patients with liver cirrhosis, ALD (n = 96/217, 45%), HCV (n = 94/217, 43%) and NASH (n = 21/217, 10%) were the leading etiologies. Platelets count (OR=3.31, 95%CI 1.61-6.78), glucose (OR=3.07, 95%CI 1.50-6.26), gamma-glutamyl-transferase (OR=3.60, 95%CI 1.79-7.25), albumin (OR=3.89, 95%CI 1.61-9.36), and total bilirubin (OR=3.93, 95%CI 1.41-10.91) were associated to advanced stages of fibrosis (F3-F4) regardless of etiology. The concordance and positive predictive values of these parameters were higher as compared to other scores. CONCLUSION: Asymptomatic liver disease due to HCV, ALD and NASH prevailed in young adults. Advanced liver damage assessed by TE was associated with five biochemical parameters. In conjunction, both methodologies may be useful for the early detection of fibrosis and cirrhosis in Latin America.

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 neural-neuroendocrine 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.

Association of a novel TAS2R38 haplotype with alcohol intake among Mexican-Mestizo population.

BACKGROUND: Alcohol intake has been associated with the bitter taste receptor T2R38. TAS2R38 gene expresses two common haplotypes: PAV and AVI. It has been reported that AVI homozygotes consume more alcohol than heterozygotes and PAV homozygotes. The aim of this study was to determine the prevalence of the TAS2R38 haplotypes among Mexican-Mestizo population and to analyze its association with alcohol intake. MATERIAL AND METHODS: In a cross-sectional study, a total of 375 unrelated Mestizo individuals were genotyped for TAS2R38 polymorphisms (A49P, V262A and I296V) by a Real-Time PCR System (TaqMan). Haplotype frequencies were calculated. Association of TAS2R38 haplotypes with alcohol intake was estimated in drinkers (DRS) and nondrinkers (NDRS). RESULTS: Two haplotypes accounted for over 96% of all haplotypes(AVV, 60%, and PAI, 36.5%). The frequency of AVV homozygotes was significantly higher in DRS than NDRS(47.2 vs. 32.2%, respectively; p < 0.05). Additionally, the AVV/AVV genotype was associated with alcohol intake when compared with heterozygotes and PAI homozygotes (OR = 1.79, 95% CI 1.13-2.84, p < 0.05 and OR = 2.23, 95% CI 1.11-4.48; p < 0.05, respectively). CONCLUSIONS: In conclusion, two TAS2R38 haplotypes(AVV and PAI) prevailed in Mexican-Mestizo population. The novel AVV haplotype was associated with alcohol intake. The high prevalence of this allelic profile in our population could help to explain, at least in part, the preference for alcohol among the Mexicans.