GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Spectrum of variants associated with inherited retinal dystrophies in Northeast Mexico.

BACKGROUND: Inherited retinal dystrophies are hereditary diseases which have in common the progressive degeneration of photoreceptors. They are a group of diseases with clinical, genetic, and allelic heterogeneity. There is limited information regarding the genetic landscape of inherited retinal diseases in Mexico, therefore, the present study was conducted in the northeast region of the country. METHODS: Patients with inherited retinal dystrophies were included. A complete history, full ophthalmological and medical genetics evaluations, and genetic analysis through a targeted NGS panel for inherited retinal dystrophies comprising at least 293 genes were undertaken. RESULTS: A total of 126 patients were included. Cases were solved in 74.6% of the study's population. Retinitis pigmentosa accounted for the most found inherited retinal disease. Ninety-nine causal variants were found, being USH2A and ABCA4 the most affected genes (26 and 15 cases, respectively). CONCLUSIONS: The present study documents the most prevalent causative genes in IRDs, as USH2A, in northeastern Mexico. This contrasts with previous reports of IRDs in other zones of the country. Further studies, targeting previously unstudied populations in Mexico are important to document the genetic background of inherited retinal dystrophies in the country.

Impact of genetic polymorphisms related to innate immune response on respiratory syncytial virus infection in children.

Respiratory syncytial virus (RSV) causes lower respiratory tract infections and bronchiolitis, mainly affecting children under 2 years of age and immunocompromised patients. Currently, there are no available vaccines or efficient pharmacological treatments against RSV. In recent years, tremendous efforts have been directed to understand the pathological mechanisms of the disease and generate a vaccine against RSV. Although RSV is highly infectious, not all the patients who get infected develop bronchiolitis and severe disease. Through various sequencing studies, single nucleotide polymorphisms (SNPs) have been discovered in diverse receptors, cytokines, and transcriptional regulators with crucial role in the activation of the innate immune response, which is implicated in the susceptibility to develop or protect from severe forms of the infection. In this review, we highlighted how variations in the key genes affect the development of innate immune response against RSV. This data would provide crucial information about the mechanisms of viral infection, and in the future, could help in generation of new strategies for vaccine development or generation of the pharmacological treatments.

Colorectal cancer. Genetic variants in BMP signaling pathway and ancestry in the Mexican population.

INTRODUCTION: Genetic variants related to bone morphogenetic proteins (BMP2, BMP4, GREM1, SMAD7) signaling pathway have been associated with colorectal cancer, mainly in Caucasian populations. OBJECTIVE: To describe the association of variants in members of the BMP signaling pathway in a Mexican population, characterized by its indigenous American and Caucasian ancestry. METHODS: Genotyping of 1,000 colorectal cancer cases and 1,043 control individuals recruited in Mexico City, Monterrey, and Torreón was carried out using the Sequenom platform. Associations between colorectal cancer and variants were studied with univariate and multivariate analyses. RESULTS: Variants rs4444235, rs12953717 and rs4939827 replicated the association with the neoplasm (p ≤ 0.05). Caucasian ancestry showed association with the tumor. CONCLUSIONS: The study replicated the associations between colorectal cancer and SMAD7 and BMP4 variants, with an association being observed with the Caucasian component of the ethnic mix.

INTRODUCCIÓN: Variantes génicas relacionadas con la vía de señalización de las proteínas morfogenéticas óseas (BMP2, BMP4, GREM1, SMAD7) se han asociado a cáncer colorrectal, principalmente en poblaciones caucásicas. OBJETIVO: Describir la asociación de variantes en miembros de la vía BMP en población mexicana, caracterizada por su ancestría indoamericana y caucásica. MÉTODOS: Se realizó el genotipado de 1000 casos de cáncer colorrectal y 1043 individuos de control reclutados en la Ciudad de México, Monterrey y Torreón mediante la plataforma Sequenom. Con análisis univariados y multivariados se estudiaron las asociaciones entre cáncer colorrectal y variantes. RESULTADOS: Las variantes rs4444235, rs12953717 y rs4939827 replicaron la asociación con la neoplasia (p ≤ 0.05). La ascendencia caucásica mostró asociación con el tumor. CONCLUSIONES: El estudio mostró las asociaciones entre cáncer colorrectal y las variantes SMAD7 y BMP4, así como con el componente caucásico de la mezcla étnica.

Extending the allelic spectrum at noncoding risk loci of orofacial clefting.

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.

DNA Repair Genes as Drug Candidates for Early Breast Cancer Onset in Latin America: A Systematic Review.

The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3'-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

Differential admixture in Latin American populations and its impact on the study of colorectal cancer.

Genome-wide association studies focused on searching genes responsible for several diseases. Admixture mapping studies proposed a more efficient alternative capable of detecting polymorphisms contributing with a small effect on the disease risk. This method focuses on the higher values of linkage disequilibrium in admixed populations. To test this, we analyzed 10 genomic regions previously defined as related with colorectal cancer among nine populations and studied the variation pattern of haplotypic structures and heterozygosity values on seven categories of SNPs. Both analyses showed differences among chromosomal regions and studied populations. Admixed Latin-American samples generally show intermediate values. Heterozygosity of the SNPs grouped in categories varies more in each gene than in each population. African related populations have more blocks per chromosomal region, coherently with their antiquity. In sum, some similarities were found among Latin American populations, but each chromosomal region showed a particular behavior, despite the fact that the study refers to genes and regions related with one particular complex disease. This study strongly suggests the necessity of developing statistical methods to deal with di- or tri-hybrid populations, as well as to carefully analyze the different historic and demographic scenarios, and the different characteristics of particular chromosomal regions and evolutionary forces.

Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.

Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.

Advantages of adipose tissue stem cells over CD34+ mobilization to decrease hepatic fibrosis in Wistar rats.

INTRODUCTION AND OBJECTIVES: Chronic liver inflammation may lead to hepatic cirrhosis, limiting its regenerative capacity. The clinical standard of care is transplantation, although stem cell therapy may be an alternative option. The study aim was to induce endogenous hematopoietic stem cells (HSCs) with granulocyte colony stimulating factor (G-CSF) and/or intravenous administration of adipose tissue-derived mesenchymal stem cells (MSCs) to decrease hepatic fibrosis in an experimental model. MATERIAL AND METHODS: A liver fibrosis model was developed with female Wistar rats via multiple intraperitoneal doses of carbon tetrachloride. Three rats were selected to confirm cirrhosis, and the rest were set into experimental groups to evaluate single and combined therapies of G-CSF-stimulated HSC mobilization and intravenous MSC administration. RESULTS: Treatment with MSCs and G-CSF significantly improved alanine amino transferase levels, while treatment with G-CSF, MSCs, and G-CSF+MSCs decreased aspartate amino transferase levels. Hepatocyte growth factor (HGF) and interleukin 10 levels increased with MSC treatment. Transforming growth factor ß levels were lower with MSC treatment. Interleukin 1ß and tumor necrosis factor alpha levels decreased in all treated groups. Histopathology showed that MSCs and G-CSF reduced liver fibrosis from F4 to F2. CONCLUSIONS: MSC treatment improves liver function, decreases hepatic fibrosis, and plays an anti-inflammatory role; it promotes HGF levels and increased proliferating cell nuclear antigen when followed by MSC treatment mobilization using G-CSF. When these therapies were combined, however, fibrosis improvement was less evident.

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene.

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 vs 47 years, p=0.1), glucose levels (107 mg/dl vs 104 mg/dl, p=0.64), and body mass index (28 vs 29, p=0.14), respectively. Core biopsies were collected for histopathological diagnosis and gene expression analyses. Total RNA was isolated and expression profiling was performed. 40 genes showed differential expression pattern in TNBC tumors. Among these, 9 over-expressed genes (PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, and ANKRD11), and one under-expressed (ANX9) gene are involved in general metabolism. Based on this biochemical peculiarity, and the over-expression of BCL11A and FOXC1 (involved in tumor growth and metastasis, respectively) we validated by qPCR the expression profile of 7 genes out of the signature. In this report, a new gene signature for TNBC is proposed. To our knowledge, this is the first TNBC signature which describes genes involved in general metabolism. The findings may be pertinent for Mexican patients and require to be evaluated in further ethnic groups and populations.

Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer.

Breast cancer is the most common malignancy in women. Radiotherapy is frequently used in patients with breast cancer, but some patients may be more susceptible to ionizing radiation, and increased exposure to radiation sources may be associated to radiation adverse events. This susceptibility may be related to deficiencies in DNA repair mechanisms that are activated after cell-radiation, which causes DNA damage, particularly DNA double strand breaks. Some of these genetic susceptibilities in DNA-repair mechanisms are implicated in the etiology of hereditary breast/ovarian cancer (pathologic mutations in the BRCA 1 and 2 genes), but other less penetrant variants in genes involved in sporadic breast cancer have been described. These same genetic susceptibilities may be involved in negative radiotherapeutic outcomes. For these reasons, it is necessary to implement methods for detecting patients who are susceptible to radiotherapy-related adverse events. This review discusses mechanisms of DNA damage and repair, genes related to these functions, and the diagnosis methods designed and under research for detection of breast cancer patients with increased radiosensitivity.

[Association between genotype and allele frequencies of CYP2A6*12 and rs16969968 in CHRNA5 variants with smoking and body mass index in young subjects from Northeast Mexico]. / Análisis de frecuencias alélicas y genotípicas de las variantes CYP2A6*12 y rs16969968 de CHRNA5 y su asociación con el hábito de fumar y el índice de masa corporal (IMC) en sujetos jóvenes del noreste de México.

BACKGROUND: Several studies have reported that variants rs16969968 G>A of the CHRNA5 gene and CYP2A6*12 of the CYP2A6 gene are associated with smoking and smoking refusal, respectively. In addition, some studies report that a higher cigarette consumption is associated with low body mass index (BMI). AIM: To analyze the allele and genotypic frequencies of these variants and their impact on smoking and BMI. MATERIAL AND METHODS: A blood sample was obtained and a survey about smoking habits was answered by 319 university students aged 18 to 35 years (127 women, 171 smokers), living in Northeastern Mexico. Genetic variants were studied by polymerase chain reaction/restriction fragment length polymorphism and their frequencies were associated with smoking and BMI. RESULTS: No associations were found between the analyzed variants and smoking in the study groups. However, there was an association among non-smoking subjects between the A allele of rs16969968 and high a BMI (p < 0.01). CONCLUSIONS: This last variant may be involved in food-addiction disorders.

Evaluating eight newly identified susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a Mesoamerican population.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is among the most frequently occurring congenital malformations worldwide. The number of genetic loci identified as being involved in NSCL/P etiology was recently increased by a large genome-wide meta-analysis of European and Asian samples. This meta-analysis confirmed all six previously recognized genetic susceptibility loci and identified six novel ones. METHODS: To investigate which of these 12 loci contribute to NSCL/P risk in an independent sample of distinct ethnicity, we performed a case-control association analysis in a sample of the Mesoamerican population. A total of 153 individuals with NSCL/P (cases) and 337 unaffected controls were included. Top single-nucleotide polymorphisms (SNPs) at 8 of the 12 loci (1p22.1, 1p36, 2p21, 3p11.1, 8q21.3, 13q31.1, 15q22, and 20q12) were analyzed using mass spectroscopy and restriction-length-fragment polymorphism analyses. In a previous study, we had analyzed the remaining four NSCL/P susceptibility regions (IRF6, 8q24, 10q25, and 17q22) in the same sample. RESULTS: Single-marker association analyses applying allelic, dominant, and recessive models revealed nominal significant associations for four of the eight loci, with two additional loci showing at least a trend of association in the hypothesized direction. CONCLUSION: In combination with results from our previous study using the same sample, our data suggest that the majority of the known NSCL/P susceptibility regions identified to date also confer risk for this malformation in the Mesoamerican population. Birth Defects Research (Part A) 100:43-47, 2014. © 2013 Wiley Periodicals, Inc.

A tribute to josé maría ("chema") cantú.

José María ("Chema") Cantú (1938-2007), born in Mexico, was a pioneering, loved and respected leader in medical and human genetics and bioethics in Latin America. He graduated as a physician in Mexico and then trained in medical and human genetics in France and the United States. He was instrumental in developing a first-rate research, training and genetic services program in medical and human genetics in Guadalajara, in northwestern Mexico. He acted forcefully at national, regional and international levels to promote scientific development through collaboration and education in science and humanities, while he simultaneously strived for justice, peace, love and human rights. He attained some of the highest honors a scientist and humanist could aspire to as well as the recognition of the communities he served. Hundreds of disciples throughout Latin America and the world have been inspired by his vision of a better world through the conjunction of science, respect for humankind, ethics and love.

RELAGH - The challenge of having a scientific network in Latin America: An account from the presidents.

Latin America and the Caribbean region make up one of the largest areas of the world, and this region is characterized by a complex mixture of ethnic groups sharing Iberian languages. The area is comprised of nations and regions with different levels of social development. This region has experienced historical advances in the last decades to increase the minimal standards of quality of life; however, several factors, such as concentrated populations in large urban centers and isolated and poor communities, still have an important impact on medical services, particularly genetics services. Latin American researchers have greatly contributed to the development of human genetics and historic inter-ethnic diversity, and the multiplicity of geographic areas are unique for the study of gene-environment interactions. As a result of regional developments in the fields of human and medical genetics, the Latin American Network of Human Genetics (Red Latinoamericana de Genética Humana - RELAGH) was created in 2001 to foster the networking of national associations and societies dedicated to these scientific disciplines. RELAGH has developed important educational activities, such as the Latin American School of Human and Medical Genetics (ELAG), and has held three biannual meetings to encourage international research cooperation among the member countries and international organizations. Since its foundation, RELAGH has been admitted as a full regional member to the International Federation of Human Genetics Societies. This article describes the historical aspects, activities, developments, and challenges that are still faced by the Network.

[Pharmacogenomics of the first-line treatment for gastric cancer: advances in the identification of genomic biomarkers for clinical response to chemotherapy]. / Farmacogenómica del tratamiento de primera linea en el cáncer gástrico: avances en la identificación de los biomarcadores genómicos de respuesta clínica.

Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.