Role Of Genetic Variation Research Articles

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

BackgroundProctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.MethodsWe investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369).ResultsIn prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.ConclusionsWe report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

Vascular homeostasis at high-altitude: role of genetic variants and transcription factors.

High-altitude pulmonary edema occurs most frequently in non-acclimatized low landers on exposure to altitude ≥2500 m. High-altitude pulmonary edema is a complex condition that involves perturbation of signaling pathways in vasoconstrictors, vasodilators, anti-diuretics, and vascular growth factors. Genetic variations are instrumental in regulating these pathways and evidence is accumulating for a role of epigenetic modification in hypoxic responses. This review focuses on the crosstalk between high-altitude pulmonary edema-associated genetic variants and transcription factors, comparing high-altitude adapted and high-altitude pulmonary edema-afflicted subjects. This approach might ultimately yield biomarker information both to understand and to design therapies for high-altitude adaptation.

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.

Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450.

Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating “Big Data”, a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. Pharmacogenomics of both somatic mutations in tumor cells and germline variants may help optimize targeted treatments and improve the response to conventional oncological therapy. In addition, integrative approaches combining copy number variations and long noncoding RNA profiling with germline and somatic variations seem to be a promising approach as well. In pharmacology, expression and enzyme activity are traditionally the more studied aspects of ATP-binding cassette transporters and cytochromes P450. In this review, we briefly introduce the field of pharmacogenomics and the advancements driven by next-generation sequencing and outline the possible roles of genetic variation in the two large pharmacogene superfamilies. Although the evidence needs further substantiation, somatic and copy number variants as well as rare variants and common polymorphisms in these genes could all affect response to cancer therapy. Regulation by long noncoding RNAs has also been shown to play a role. However, in all these areas, more comprehensive studies on larger sets of patients are needed.

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology.

In the past decades, new cancer treatments have been introduced in pediatric oncology leading to improvement in clinical outcomes and survival rates. However, due to inter-individual differences, some children experience severe chemotherapy-induced toxicities or a poor clinical outcome. An explanation for the diversity in response to chemotherapy is genetic variation, leading to differences in expression and activity of metabolizing and transport enzymes as well as drug targets. Pharmacogenetic testing has emerged as a promising tool to predict and limit acute and long-term adverse effects in patients. However, in pediatric oncology, limited number of patients and a considerable diversity in study results complicate the interpretation of test results and its clinical relevance. With this review, we provide an overview of new developments over the past four years regarding relevant polymorphisms related to toxicity in pediatric oncology. The following chemotherapeutics and associated toxicities are discussed: alkylating agents, anthracyclines, asparaginase, methotrexate, platinum compounds, steroids, thiopurines, topoisomerase inhibitors, and vinca alkaloids. Our review identifies several questions regarding the role of genetic variants in chemotherapy-induced toxicities. Ambiguities in the literature stem from small population sizes, differences in (statistical) interpretation and variations in sequencing technologies as well as different clinical outcome definitions. Standardization of clinical outcome data and toxicity definitions within electronic health records combined with the increased availability of genomic sequence techniques in clinical practice will help to validate these models in upcoming years.

Genetic diversity of rice germplasm (Oryza sativa L.) of java island, Indonesia

The role of genetic diversity in crop germplasm is an important concept within genetic conservation. In this research, 43 accessions were analyzed at the agro-morphological and genetic levels. Clustering based on the agro-morphological resulted in four sub-groups. Analysis at the genetic level was conducted using 22 microsatellites, which revealed a total number of alleles to be 203, with a range per allele between 2 and 17 and an average of 9.2 alleles per locus. The highest and lowest Polymorphic Information Content (PIC) values were found in RM431 and RM11, which were 0.95 and 0.67, respectively. The genetic diversity value ranged from 0.71 to 0.95. The genetic similarity among accessions ranged from 0.00 to 0.90. Clustering based on the genetic relatedness divided the Java rice samples into two major groups. The classification created through this research many inform future breeding programs aimed at improving the quality and quantity of yield production.

Genetics of synucleins in neurodegenerative diseases

The SNCA locus currently has an indisputable role in Parkinson's disease and other synucleinopathies. The role of genetic variability in the other members of the synuclein family (SNCB and SNCG) in disease is far less clear. In this review, we critically assess the pathogenicity, main characteristics, and roles of genetic variants in these genes reported to be causative of synucleinopathies. We also summarize the different association signals identified in the SNCA locus that have been associated with risk for disease. We take a bird's eye view of the variability currently reported in the general population for the three genes and use these data to infer on the potential relationship between each of the genes and human disease.

Abstract C045: Polymorphism in CYP1B1 increases CRC risk in Puerto Rican individuals that consume processed meats

Abstract Colorectal cancer (CRC) is the 1st cause of cancer-related deaths in Puerto Rico (PR). CRC is a heterogeneous disease with lifestyle and environmental factors shown to modify the risk to develop this disease. High intake of red and processed meats was determined to be a risk factor for increased risk of CRC. Genetic variations in genes involved in the metabolism of meat carcinogens have been found to be associated with CRC risk and to vary across racial/ethnic populations. The objective of this project was to determine the association of functional genetic variants in meat-carcinogen metabolism genes with CRC risk in the PR population. First, we analyzed the allelic frequencies of SNPs in key meat carcinogen metabolism genes (CYP1A1, CYP1B1, NAT2 and CYP2E1), that were previously reported to have an association with development of colorectal adenomas or CRC were evaluated in the 1000 Genomes Populations. The 1000 Genomes populations included AFR (African Populations), EUR (European Populations), CLM (Colombians from Medellin, Colombia), MXL (Mexican Ancestry from Los Angeles USA), PEL (Peruvians from Lima Peru) and PUR (Puerto Ricans from Puerto Rico). Then, we genotyped using TaqMan technology 5 functional SNPs localized at key meat carcinogen detoxifying genes, CYP1A1, CYP1B1, NAT1, NAT2 and CYP2E1 in Puerto Ricans (205 CRC cases and 218 controls). Our preliminary results showed that the allelic frequencies of the SNPs differ between PUR and the other 1000 Genomes populations, suggesting that these SNPs might have a distinct effect on the association of red/processed meat intake and CRC risk on Puerto Ricans. Furthermore, genotyping analysis showed that individuals with the AA genotype at the rs1800440 SNP (CYP1B1) who consume processed meat 2-4 times per week were at increased risk of CRC (p=0.008). These preliminary data support a role for genetic variants in genes that play key roles in the mechanisms of meat carcinogenesis as possible modifiers of the carcinogenic effects of meat. Citation Format: Julyann Perez-Mayoral, Maria E. Perez-Hernandez, Mariana Stern, Marcia R. Cruz-Correa. Polymorphism in CYP1B1 increases CRC risk in Puerto Rican individuals that consume processed meats [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C045.

Role of Genetic Variations in the Hepatic Handling of Drugs.

The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

A Munc18-1 mutant mimicking phosphorylation by Down Syndrome-related kinase Dyrk1a supports normal synaptic transmission and promotes recovery after intense activity

Phosphorylation of Munc18-1 (Stxbp1), a presynaptic organizer of synaptic vesicle fusion, is a powerful mechanism to regulate synaptic strength. Munc18-1 is a proposed substrate for the Down Syndrome-related kinase dual-specificity tyrosine phosphorylation-regulate kinase 1a (Dyrk1a) and mutations in both genes cause intellectual disability. However, the functional consequences of Dyrk1a-dependent phosphorylation of Munc18-1 for synapse function are unknown. Here, we show that the proposed Munc18-1 phosphorylation site, T479, is among the highly constrained phosphorylation sites in the coding regions of the gene and is also located within a larger constrained coding region. We confirm that Dyrk1a phosphorylates Munc18-1 at T479. Patch-clamp physiology in conditional null mutant hippocampal neurons expressing Cre and either wildtype, or mutants mimicking or preventing phosphorylation, revealed that synaptic transmission is similar among the three groups: frequency/amplitude of mEPSCs, evoked EPSCs, paired pulse plasticity, rundown kinetics upon intense activity and the readily releasable pool. However, synapses expressing the phosphomimic mutant responded to intense activity with more pronounced facilitation. These data indicate that Dyrk1a-dependent Munc18-1 phosphorylation has a minor impact on synaptic transmission, only after intense activity, and that the role of genetic variation in both genes in intellectual disability may be through different mechanisms.

Sex hormones and genetic variants in hormone metabolic pathways associated with the risk of colorectal cancer

ObjectiveThe different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. MethodsWe detected sex hormone levels in plasma from colorectal cancer patients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. ResultsWe found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10−19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3′-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. ConclusionThis is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes.

A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation

Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by affected individuals. We aimed to investigate the role of genetic variation of CLCN2 encoding the inwardly rectifying chloride channel ClC-2 as a risk factor for the development of familiar AF. The effect of the CLCN2 variant was evaluated by electrophysiological recordings on transiently transfected cells. We used quantitative PCR to assess CLCN2 mRNA expression levels in human atrial and ventricular tissue samples. The nucleotide deletion CLCN2 c.1041_1044del results in a frame-shift and premature stop codon. The truncated ClC-2 p.V347fs channel does not conduct current. Co-expression with wild-type ClC-2, imitating the heterozygote state of the patients, resulted in a 50% reduction in macroscopic current, suggesting an inability of truncated ClC-2 protein to form channel complexes with wild type channel subunits. Quantitative PCR experiments using human heart tissue from healthy donors demonstrated that CLCN2 is expressed across all four heart chambers. Our genetic and functional data points to a possible link between loss of ClC-2 function and an increased risk of developing AF.

Human Genetic Susceptibility of Leprosy Recurrence

Host genetic susceptibility to leprosy has been intensively investigated over the last decades; however, there are no studies on the role of genetic variants in disease recurrence. A previous initiative identified three recurrent cases of leprosy for which none of the M. leprae strains, as obtained in the first and the second diagnosis, had any known genomic variants associated to resistance to Multidrug therapy; in addition, whole genome sequencing indicated that the same M. leprae was causing two out of the three recurrences. Thus, these individuals were suspected of being particularly susceptible to M. leprae infection, either as relapse or reinfection. To verify this hypothesis, 19 genetic markers distributed across 11 loci (14 genes) classically associated with leprosy were genotyped in the recurrent and in three matching non-recurrent leprosy cases. An enrichment of risk alleles was observed in the recurrent cases, suggesting the existence of a particularly high susceptibility genetic profile among leprosy patients predisposing to disease recurrence.

Comparison of multiple algorithms to reliably detect structural variants in pears

BackgroundStructural variations (SVs) have been reported to play an important role in genetic diversity and trait regulation. Many computer algorithms detecting SVs have recently been developed, but the use of multiple algorithms to detect high-confidence SVs has not been studied. The most suitable sequencing depth for detecting SVs in pear is also not known.ResultsIn this study, a pipeline to detect SVs using next-generation and long-read sequencing data was constructed. The performances of seven types of SV detection software using next-generation sequencing (NGS) data and two types of software using long-read sequencing data (SVIM and Sniffles), which are based on different algorithms, were compared. Of the nine software packages evaluated, SVIM identified the most SVs, and Sniffles detected SVs with the highest accuracy (> 90%). When the results from multiple SV detection tools were combined, the SVs identified by both MetaSV and IMR/DENOM, which use NGS data, were more accurate than those identified by both SVIM and Sniffles, with mean accuracies of 98.7 and 96.5%, respectively. The software packages using long-read sequencing data required fewer CPU cores and less memory and ran faster than those using NGS data. In addition, according to the performances of assembly-based algorithms using NGS data, we found that a sequencing depth of 50× is appropriate for detecting SVs in the pear genome.ConclusionThis study provides strong evidence that more than one SV detection software package, each based on a different algorithm, should be used to detect SVs with higher confidence, and that long-read sequencing data are better than NGS data for SV detection. The SV detection pipeline that we have established will facilitate the study of diversity in other crops.

Enteric infection induces Lark-mediated intron retention at the 5\u2032 end of Drosophila genes

BackgroundRNA splicing is a key post-transcriptional mechanism that generates protein diversity and contributes to the fine-tuning of gene expression, which may facilitate adaptation to environmental challenges. Here, we employ a systems approach to study alternative splicing changes upon enteric infection in females from classical Drosophila melanogaster strains as well as 38 inbred lines.ResultsWe find that infection leads to extensive differences in isoform ratios, which results in a more diverse transcriptome with longer 5′ untranslated regions (5′UTRs). We establish a role for genetic variation in mediating inter-individual splicing differences, with local splicing quantitative trait loci (local-sQTLs) being preferentially located at the 5′ end of transcripts and directly upstream of splice donor sites. Moreover, local-sQTLs are more numerous in the infected state, indicating that acute stress unmasks a substantial number of silent genetic variants. We observe a general increase in intron retention concentrated at the 5′ end of transcripts across multiple strains, whose prevalence scales with the degree of pathogen virulence. The length, GC content, and RNA polymerase II occupancy of these introns with increased retention suggest that they have exon-like characteristics. We further uncover that retained intron sequences are enriched for the Lark/RBM4 RNA binding motif. Interestingly, we find that lark is induced by infection in wild-type flies, its overexpression and knockdown alter survival, and tissue-specific overexpression mimics infection-induced intron retention.ConclusionOur collective findings point to pervasive and consistent RNA splicing changes, partly mediated by Lark/RBM4, as being an important aspect of the gut response to infection.

P755 Congenital chloride diarrhoea and inflammatory bowel disease: an emerging association

Abstract Background Congenital chloride diarrhea (CLD) is a rare autosomal recessive disease caused by the mutation in member 3 of the solute carrier 26 (SLC26A3). The phenotypic expression is a life-long severe watery Chloride rich diarrhea. Anecdotal association with inflammatory bowel disease (IBD) has been reported suggesting that underlying molecular mechanisms could represent part of an evolving association between IBD and channelopathies. We aimed to investigate this association in a cohort of CLD pediatric patients. Methods A European-based call for cases was made in CLD patients followed up in five different countries. A case report form for each patient was then completed. Results A total of 74 patients with CLD with a range of different CLD mutations were enrolled in the study. Twelve patients of 64 (16%) demonstrated colonic inflammation and were finally diagnosed with IBD: 8 patients with Crohn’s Disease, 2 with Ulcerative Colitis, and 2 IBD-like colitis (IBD-U). The diagnosis was made at a median of 12 years old (IQR: 6–30). Patients had different ethnicities (7 European, 2 Middle East, 1 North Africa, 1 Pakistan, 1 Central Africa). Among the 12 IBD, 2 had a 5-ASA-based treatment, 3 required immunosuppressant and 6 had biologics (Infliximab, Adalimumab and Vedolizumab). Three patients underwent surgery for ileostomy formation for CD that was non-responsive to multiple line of biologics (anti-TNF and anti-integrin): one had colectomy the remnant two colon preservation. Clinical characteristics, such as premature delivery, low weight at birth, fecal Cl- at diagnosis and amount of Cl- supplementation (mmol/kg) did not differ between patients with or without IBD. All patients underwent genotyping for CLD diagnosis and we did not find any specific genetic mutation linked to the development of IBD. Conclusion Sixteen percent of patients enrolled with CLD in our cohort developed IBD. Despite different presentations (CD, UC, IBD-U) all patients had colonic without ileal/small bowel involvement, in line with preliminary murine models of CLD demonstrating a role of colonic mucous layer in the development of colonic inflammation (Xiao et al Acta Physiol Oxf Engl 2014; 211:161–175). Patients’ IBD treatment included a wide range with variable success. Patients with IBD did not differ in their clinical characteristics or genetic mutations compared with non-IBD CLD patients. The role of genetic variants outside the CLD-gene and the microbiome in this association are under investigation.

The Association between Vitamin D-Related Gene Polymorphisms and Serum 25-Hydroxyvitamin D Concentration: A Prospective Cohort Study in Pregnant Minangkabau Women, Indonesia.

Several candidate genes in vitamin D synthesis and metabolism have been reported to have a significant association with 25-hydroxyvitamin D (25(OH)D) in Caucasians and African Americans. Few studies have indicated this relationship among Asians, especially in pregnant Minangkabau women, Indonesia. This study was conducted among 180 singleton pregnant women of West Sumatran Vitamin D Pregnant Mother (VDPM) cohort study. Serum 25(OH)D obtained in the third trimester (T3). Genetic risk scores (GRS) were created based on six vitamin D-related SNPs and their association with 25(OH)D levels were tested. Informations on demographics, lifestyle, pregnancy profile, and physical activity were collected using questionnaire. The average of 25(OH)D concentration was 21.21±10.41 ng/mL respectively. Vitamin D-GRS has significantly associated with serum 25(OH)D levels in the third trimester (p=0.006). However, the synthesis-GRS and metabolism-GRS group of vitamin D-related gene polymorphisms had no association with 25(OH)D concentration at T3 (p>0.05). A high prevalence of insufficient-deficient vitamin D status at T3 was common. We observed an association between vitamin D-GRS and 25(OH)D concentration. The results of this study provides additional support for possible role of genetic variants in vitamin D-related gene polymorphisms on 25(OH)D concentration during pregnancy. Further replication studies with larger sample sizes are needed to confirm thefindings.

Genetic variation among common beans cultivars (Phaseolus vulgaris L.) as revealed by morphological, protein and molecular markers

The role of genetic diversity is crucial for future improvements to meet societal demand for food security under a climate change scenario. Morphological, biochemical and molecular analyses have been suggested for the evaluation of genetic diversity in common bean (Phaseolus vulgaris L.) from Egypt. Twelve cultivars were collected from different five geographical isolated locations. These cultivars were evaluated using 20 morphological traits (15 qualitative and 5quantitative). The two cultivars P9 and P14 which were collected from Quesna and New Valley, respectively exhibited partially different morphologically features from other cultivars. The electrophoretic pattern of seed storage proteins indicated 45 different molecular weight bands, ranging from 309.7 kDa to 44.3 kDa with the presence of 4 unique bands and 41 polymorphic bands. ISSR results revealed a high level of polymorphism (69.1%) using six ISSR primers, which produced a total of 117 bands; out of them 85 bands are polymorphic, 25 monomorphic and 7 unique. Cluster analysis using CAP software program based on combined data revealed two groups. The obtained data confirmed that morphological, SDS-protein and ISSR markers are important tools for genetic analysis for common bean and recommended to give accurate results.

Association between Hepatitis C Virus Viremia and the rs12979860, rs2228145 and rs1800795 SNP (CT/AC/GG) Genotype in Saudi Kidney Transplant Recipients.

Background:Hepatitis C virus (HCV) is a major health problem, particularly in high-risk groups such as kidney transplant recipients, where it can adversely affect graft survival and increase the relative risk for mortality. Recently, the role of genetic variation among HCV patients in determining the outcome of infections has been under investigation.Objective:To investigate the association of single-nucleotide polymorphisms (SNPs) rs12979860 (located within the interleukin-28B locus), rs2228145 (interleukin-6 receptor) and rs1800795 (interleukin-6 promoter) with HCV viremia in renal transplant patients.Materials and Methods:In this analytical cross-sectional study, 149 kidney transplant recipients, 82 males (median age: 41 years) and 67 females (median age: 45 years), were screened for HCV RNA in blood using real-time polymerase chain reaction and genotyped by sequencing (rs12979860) and restriction fragment length polymorphism (rs2228145 and rs1800795).Results:HCV RNA was detected in 17 (11.41%) of the 149 patients. There was no statistically significant association between the studied SNPs and HCV viremia. However, a combination of the CT/AC/GG genotype was significantly associated with HCV viremia (odds ratio: 5.4). The genotype AA of rs2228145 in the IL-6 receptor was associated with viremia levels of >105 copies/ml (odds ratio: 5.96).Conclusion:To the best of the authors' knowledge, this is the first study that has shown that the CT/AC/GG genotype has an impact on HCV viremia in kidney transplant patients. Therefore, such SNP genotypes may potentially be used to identify transplant patients at risk of HCV infection.

139 Nutrigenetics/Nutrigenomics: Nutrient-gene interactions in humans and animals

Abstract Human beings evolved on a diet that was balanced in the omega-6 and omega-3 essential fatty acids to which their genes were programmed to respond. Studies on gene-nutrient interactions using methods from molecular biology and genetics have clearly shown that there are genetic differences in the population, as well as differences in the frequency of genetic variations that interact with diet and influence the growth and development of humans and animals, as well as overall health and chronic disease. Nutrigenetics refers to studies on the role of genetic variants and their response to diet. For example, persons with genetic variants in the metabolism of omega-6 and omega-3 fatty acids have different levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) based on the type of genetic variant in the Fatty Acid Desaturase 1 (FADS1) and Fatty Acid Desaturase 2 (FADS2). At the same level of linoleic acid (LA) and alpha-linolenic acid (ALA) a person with a genetic variant that increases the activity of the FADS1 will have a higher AA in the red cell membrane phospholipids and a higher risk for obesity and cardiovascular disease. Nutrigenomics refers to how nutrients (diets) influence the expression of genes. For example, diets rich in omega-3 fatty acids, EPA and DHA decrease the expression of inflammatory genes and as a result decrease the risk of obesity and cardiovascular disease. Thus, through studies on Nutrigenetics/Nutrigenomics nutritional science stands at its “golden threshold” where personalized nutrition is the future, to improve an individual’s health.