Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

A 1 year course of starch- and sucrose-reduced diet used by irritable bowel syndrome patients with diarrhoea and the effect of genetic variants.

Background: Irritable bowel syndrome is a heterogeneous syndrome and it is difficult to find an effective treatment. Previously, a starch- and sucrose-reduced diet (SSRD) demonstrated promising short-term outcomes. It was proposed that genetic variants in the sucrose-isomaltase gene might influence this success. Our aim in this work was to extend the follow-up study to 1 year and to analyse the effect of the genetic variants of genes involved in starch and sucrose metabolism. Methods: IBS-SSS questionnaire, IBS-QoL questionnaire and questionnaires about adherence, difficulty and food assessment were sent to 34 patients after 6 months and 1 year after the end of the dietary intervention. In addition, 11 genes involved in sucrose and starch metabolism were sequenced. Results: Twenty-three participants responded to the 6 months follow-up and 16 to the 1 year follow-up. IBS-SSS total value increased 59.71% in the 6 months follow-up compared with the end of the intervention (p = 0.0018), and 55.39% in the 1 year follow-up (p = 0.0166); while IBS-QoL score decreased 24.09% (p = 0.0002) and 18.07% (p = 0.0022), respectively. The adherence decreased by 29.11% (p = 4.8 × 10-5) and 27.21% (p = 0.0054), respectively. In addition, carriers of pathogenic variants on the SI gene showed a slightly better performance than non-carriers. Finally, the participants showed less satisfaction over time with 18 allowed foods in the diet. Conclusion: Over time the SSRD is difficult to follow and the genotype might affect the performance of the diet. Since this diet could be a promising therapeutic option, a larger cohort needs to be analysed to validate the results and to compare it with other diets.

Genetic Variants as Predictors of the Success of Colorectal Cancer Treatments.

BACKGROUND: Some genetic polymorphisms (SNPs) have been proposed as predictors for different colorectal cancer (CRC) outcomes. This work aims to assess their performance in our cohort and find new SNPs associated with them. METHODS: A total of 833 CRC cases were analyzed for seven outcomes, including the use of chemotherapy, and stratified by tumor location and stage. The performance of 63 SNPs was assessed using a generalized linear model and area under the receiver operating characteristic curve, and local SNPs were detected using logistic regressions. RESULTS: In total 26 of the SNPs showed an AUC > 0.6 and a significant association (p < 0.05) with one or more outcomes. However, clinical variables outperformed some of them, and the combination of genetic and clinical data showed better performance. In addition, 49 suggestive (p < 5 × 10-6) SNPs associated with one or more CRC outcomes were detected, and those SNPs were located at or near genes involved in biological mechanisms associated with CRC. CONCLUSIONS: Some SNPs with clinical data can be used in our population as predictors of some CRC outcomes, and the local SNPs detected in our study could be feasible markers that need further validation as predictors.

From Omic Layers to Personalized Medicine in Colorectal Cancer: The Road Ahead.

Colorectal cancer is a major health concern since it is a highly diagnosed cancer and the second cause of death among cancers. Thus, the most suitable biomarkers for its diagnosis, prognosis, and treatment have been studied to improve and personalize the prevention and clinical management of colorectal cancer. The emergence of omic techniques has provided a great opportunity to better study CRC and make personalized medicine feasible. In this review, we will try to summarize how the analysis of the omic layers can be useful for personalized medicine and the existing difficulties. We will discuss how single and multiple omic layer analyses have been used to improve the prediction of the risk of CRC and its outcomes and how to overcome the challenges in the use of omic layers in personalized medicine.

LncRNA ARGI Contributes to Virus-Induced Pancreatic ß Cell Inflammation Through Transcriptional Activation of IFN-Stimulated Genes.

Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D-associated single nucleotide polymorphisms (SNPs) are located in non-coding regions of the human genome. Interestingly, SNPs in long non-coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus-induced T1D-associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic ß cells and binds to CTCF to interact with the promoter and enhancer regions of IFNß and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic ß cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D-related SNPs in lncRNAs influence pathogenesis at the pancreatic ß cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic ß cell inflammation in T1D.

The effect of starch- and sucrose-reduced diet accompanied by nutritional and culinary recommendations on the symptoms of irritable bowel syndrome patients with diarrhoea.

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal condition which entails a high burden in the quality of life (QoL) of patients. Nutritional interventions have been proposed to alleviate symptoms, since still no effective treatments exist for IBS. Objectives: Our aim is to analyse the feasibility of the use of starch- and sucrose-reduced diet (SSRD). Design: In this study, we used a SSRD accompanied by nutritional and culinary recommendations to measure the effects in IBS patients with diarrhoea. Methods: In all, 34 participants completed a 4-week nutritional intervention based on SSRD. Symptoms, QoL and dietary habits were assessed by several questionnaires that were completed at the beginning, daily, after 2 weeks, at the end, and after 2 months. Results: 85.29% of the participants reached the primary endpoint [reduction of 50 points or more in IBS-symptom severity scale (SSS)], and 58.82% the secondary endpoint (reduction of 50% or more in IBS-SSS). The relief of symptoms and improvement of the QoL were significant after 2 weeks of intervention, at the end and after 2 months. Dietary habits were consistent with the diet and high adherence was achieved. Conclusions: SSRD and individualized nutritional and culinary guidance improved symptoms and QoL of IBS patients with diarrhoea, with a high adherence.

Identification of taxonomic changes in the fecal bacteriome associated with colorectal polyps and cancer: potential biomarkers for early diagnosis.

Colorectal cancer (CRC) commonly arises in individuals with premalignant colon lesions known as polyps, with both conditions being influenced by gut microbiota. Host-related factors and inherent characteristics of polyps and tumors may contribute to microbiome variability, potentially acting as confounding factors in the discovery of taxonomic biomarkers for both conditions. In this study we employed shotgun metagenomics to analyze the taxonomic diversity of bacteria present in fecal samples of 90 clinical subjects (comprising 30 CRC patients, 30 with polyps and 30 controls). Our findings revealed a decrease in taxonomic richness among individuals with polyps and CRC, with significant dissimilarities observed among the study groups. We identified significant alterations in the abundance of specific taxa associated with polyps (Streptococcaceae, Lachnoclostridium, and Ralstonia) and CRC (Lactobacillales, Clostridiaceae, Desulfovibrio, SFB, Ruminococcus, and Faecalibacterium). Clostridiaceae exhibited significantly lower abundance in the early stages of CRC. Additionally, our study revealed a positive co-occurrence among underrepresented genera in CRC, while demonstrating a negative co-occurrence between Faecalibacterium and Desulfovibrio, suggesting potential antagonistic relationships. Moreover, we observed variations in taxonomic richness and/or abundance within the polyp and CRC bacteriome linked to polyp size, tumor stage, dyslipidemia, diabetes with metformin use, sex, age, and family history of CRC. These findings provide potential new biomarkers to enhance early CRC diagnosis while also demonstrating how intrinsic host factors contribute to establishing a heterogeneous microbiome in patients with CRC and polyps.

Host Genetics and Microbiota Interactions in Colorectal Cancer: Shared or Independent Risk?

The role of microbiota in colorectal cancer has been studied since alterations in its composition were observed. In addition, there are more and more pieces of evidence that microbiota could be implicated in colorectal cancer progression. Thus, the components of the microbiota could be biomarkers for the diagnosis and prognosis of colorectal cancer. In addition, it is important to address how the microbiota interacts with the host and how the host shapes the microbiota, in order to understand the biological pathways and mechanisms involved in their relationship and the consequences of their interactions in colorectal cancer. Thereby, it could be possible to find feasible measures and treatments to prevent or better diagnose colorectal cancer. In this review, we will try to summarize the role of the microbiota in colorectal cancer and its interactions with the host and the host genetics, coming to some conclusions that could be useful to find the gaps in our knowledge and propose future steps in this field.

Performance of the Use of Genetic Information to Assess the Risk of Colorectal Cancer in the Basque Population.

Although the genetic contribution to colorectal cancer (CRC) has been studied in various populations, studies on the applicability of available genetic information in the Basque population are scarce. In total, 835 CRC cases and 940 controls from the Basque population were genotyped and genome-wide association studies were carried out. Mendelian Randomization analyses were used to discover the effect of modifiable risk factors and microbiota on CRC. In total, 25 polygenic risk score models were evaluated to assess their performance in CRC risk calculation. Moreover, 492 inflammatory bowel disease cases were used to assess whether that genetic information would not confuse both conditions. Five suggestive (p < 5 × 10−6) loci were associated with CRC risk, where genes previously associated with CRC were located (e.g., ABCA12, ATIC or ERBB4). Moreover, the analyses of CRC locations detected additional genes consistent with the biology of CRC. The possible contribution of cholesterol, BMI, Firmicutes and Cyanobacteria to CRC risk was detected by Mendelian Randomization. Finally, although polygenic risk score models showed variable performance, the best model performed correctly regardless of the location and did not misclassify inflammatory bowel disease cases. Our results are consistent with CRC biology and genetic risk models and could be applied to assess CRC risk in the Basque population.

Applicability of polygenic risk scores in endometriosis clinical presentation.

BACKGROUND: Risk prediction is an essential part of preventative medicine and in recent years genomic information has become an interesting factor in risk models. Polygenic risk scores (PRS) combine the effect of many genetic variations into a single score which has been shown to have predictive value for many diseases. This study aimed to investigate the association between PRS for endometriosis and the clinical presentation of the disease. METHODS: Women with endometriosis (N = 172) were identified at the Department of Gynecology. All participants answered questionnaires regarding sociodemographic factors, lifestyle habits and medical history, registered bowel symptoms on the Visual Analog Scale for Irritable Bowel Syndrome and passed blood samples. DNA was extracted and samples were genotyped, and a PRS was calculated based on previous genome-wide association studies of endometriosis. Inflammatory proteins and TSH receptor antibodies (TRAb) in serum were analyzed. RESULTS: Inverse associations were identified between PRS and spread of endometriosis, involvement of the gastrointestinal tract and hormone treatment. However, significance was lost when calculated as p for trend and the specificity and sensitivity were low. There were no correlations between PRS and TRAb or inflammatory proteins. CONCLUSION: The findings indicate that specific PRS should be developed to predict clinical presentations in patient with endometriosis.

Local genetic variation of inflammatory bowel disease in Basque population and its effect in risk prediction.

Inflammatory bowel disease (IBD) is characterised by chronic inflammation of the gastrointestinal tract. Although its aetiology remains unknown, environmental and genetic factors are involved in its development. Regarding genetics, more than 200 loci have been associated with IBD but the transferability of those signals to the Basque population living in Northern Spain, a population with distinctive genetic background, remains unknown. We have analysed 5,411,568 SNPs in 498 IBD cases and 935 controls from the Basque population. We found 33 suggestive loci (p < 5 × 10-6) in IBD and its subtypes, namely Crohn's Disease (CD) and Ulcerative Colitis (UC), detecting a genome-wide significant locus located in HLA region in patients with UC. Those loci contain previously associated genes with IBD (IL23R, JAK2 or HLA genes) and new genes that could be involved in its development (AGT, BZW2 or FSTL1). The overall genetic correlation between European populations and Basque population was high in IBD and CD, while in UC was lower. Finally, the use of genetic risk scores based on previous GWAS findings reached area under the curves > 0.68. In conclusion, we report on the genetic architecture of IBD in the Basque population, and explore the performance of European-descent genetic risk scores in this population.

A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross-disease analyses.

BACKGROUND: Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated. METHODS: Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry. KEY RESULTS: In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10-300 ), anxiety disorders (OR = 2.3, p < 1.4 × 10-27 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10-76 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10-73 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% ( hSNP2  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (rg  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10-6 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients. CONCLUSIONS & INFERENCES: FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.

Interplay between Genome, Metabolome and Microbiome in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC), a major health concern, is developed depending on environmental, genetic and microbial factors. The microbiome and metabolome have been analyzed to study their role in CRC. However, the interplay of host genetics with those layers in CRC remains unclear. METHODS: 120 individuals were sequenced and association analyses were carried out for adenoma and CRC risk, and for selected components of the microbiome and metabolome. The epistasis between genes located in cholesterol pathways was analyzed; modifiable risk factors were studied using Mendelian randomization; and the three omic layers were used to integrate their data and to build risk prediction models. RESULTS: We detected genetic variants that were associated to components of metabolome or microbiome and adenoma or CRC risk (e.g., in LINC01605, PROKR2 and CCSER1 genes). In addition, we found interactions between genes of cholesterol metabolism, and HDL cholesterol levels affected adenoma (p = 0.0448) and CRC (p = 0.0148) risk. The combination of the three omic layers to build risk prediction models reached high AUC values (>0.91). CONCLUSIONS: The use of the three omic layers allowed for the finding of biological mechanisms related to the development of adenoma and CRC, and each layer provided complementary information to build risk prediction models.

GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome.

Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.

Association of Polygenic Risk Score and Bacterial Toxins at Screening Colonoscopy with Colorectal Cancer Progression: A Multicenter Case-Control Study.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and its incidence is correlated with infections, chronic inflammation, diet, and genetic factors. An emerging aspect is that microbial dysbiosis and chronic infections triggered by certain bacteria can be risk factors for tumor progression. Recent data suggest that certain bacterial toxins implicated in DNA attack or in proliferation, replication, and death can be risk factors for insurgence and progression of CRC. In this study, we recruited more than 300 biopsy specimens from people undergoing colonoscopy, and we analyzed to determine whether a correlation exists between the presence of bacterial genes coding for toxins possibly involved in CRC onset and progression and the different stages of CRC. We also analyzed to determine whether CRC-predisposing genetic factors could contribute to bacterial toxins response. Our results showed that CIF toxin is associated with polyps or adenomas, whereas pks+ seems to be a predisposing factor for CRC. Toxins from Escherichia coli as a whole have a higher incidence rate in adenocarcinoma patients compared to controls, whereas Bacteroides fragilis toxin does not seem to be associated with pre-cancerous nor with cancerous lesions. These results have been obtained irrespectively of the presence of CRC-risk loci.

Gene-Diet Interactions in Colorectal Cancer: Survey Design, Instruments, Participants and Descriptive Data of a Case-Control Study in the Basque Country.

Epidemiologic studies have revealed inconsistent evidence of gene-diet interaction in relation to colorectal cancer (CRC). The aim of this study was to analyze them in a sample of cases and controls from the population-based bowel cancer screening program of the Osakidetza/Basque Health Service. This study analyzed dietetic, genetic, demographic, socioeconomic factors and lifestyles. In the present manuscript, the survey design, sampling, instruments, measurements and related quality management were presented. Moreover, we analyze differences between cases and controls in some data, especially those related to diet. The participants were 308 cases and 308 age- and sex-matched subjects as controls. Cases were more likely than controls to have overweight/obesity (67.5% vs. 58.1%, p < 0.05), a lower intake of vitamin B2 (0.86 ± 0.23 vs. 0.92 ± 0.23 mg/1000 kcal, p < 0.01) and calcium:phosphorus ratio (0.62 ± 0.12 vs. 0.65 ± 0.13, p < 0.01). A higher proportion of cases than controls did not meet the Nutritional Objectives for saturated fatty acids (85.7% vs. 67.5%, p < 0.001) or cholesterol (35.4% vs. 25.0%, p < 0.01). In conclusion, the present study provides valuable data for analyzing the complexity of gene-diet interaction in relation to CRC. The results presented here suggest that overweight/obesity and a high intake of certain dietary components, especially saturated fatty acids and cholesterol, are more frequent in cases than in controls.

Food groups, diet quality and colorectal cancer risk in the Basque Country.

BACKGROUND: The results obtained to date concerning food groups, diet quality and colorectal cancer (CRC) risk vary according to criteria used and the study populations. AIM: To study the relationships between food groups, diet quality and CRC risk, in an adult population of the Basque Country (North of Spain). METHODS: This observational study included 308 patients diagnosed with CRC and 308 age- and sex-matched subjects as controls. During recruitment, dietary, anthropometric, lifestyle, socioeconomic, demographic and health status information was collected. Adherence to the dietary recommendations was evaluated utilizing the Healthy Eating Index for the Spanish Diet and the MedDietScore. Conditional logistic regressions were used to evaluate the associations of food group intakes, diet quality scores, categorized in tertiles, with CRC risk. RESULTS: The adjusted models for potential confounding factors showed a direct association between milk and dairy products consumption, in particular high-fat cheeses [odds ratio (OR) third tertile vs first tertile = 1.87, 95% confidence intervals (CI): 1.11-3.16], and CRC risk. While the consumption of fiber-containing foods, especially whole grains (OR third tertile vs first tertile = 0.62, 95%CI: 0.39-0.98), and fatty fish (OR third tertile vs first tertile = 0.53, 95%CI: 0.27-0.99) was associated with a lower risk for CRC. Moreover, higher MD adherence was associated with a reduced CRC risk in adjusted models (OR third tertile vs first tertile = 0.40, 95%CI: 0.20-0.80). CONCLUSION: Direct associations were found for high-fat cheese, whereas an inverse relation was reported for fiber-containing foods and fatty fish, as well as adherence to a Mediterranean dietary pattern.

A Two-Sample Mendelian Randomization Analysis Investigates Associations Between Gut Microbiota and Celiac Disease.

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.