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PLoS One ; 17(1): e0260897, 2022.
Article En | MEDLINE | ID: mdl-34995294

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.

COVID-19/genetics , COVID-19/mortality , Membrane Glycoproteins/genetics , Receptors, Interleukin-1/genetics , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Cohort Studies , Factor X/genetics , Factor X/metabolism , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Membrane Glycoproteins/metabolism , Middle Aged , Netherlands/epidemiology , Polymorphism, Single Nucleotide/genetics , Receptors, Interleukin-1/metabolism , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Treatment Outcome
BMC Genomics ; 23(1): 54, 2022 Jan 14.
Article En | MEDLINE | ID: mdl-35030994

BACKGROUND: The characterization of genetic diversity and population differentiation for maize inbred lines from breeding programs is of great value in assisting breeders in maintaining and potentially increasing the rate of genetic gain. In our study, we characterized a set of 187 tropical maize inbred lines from the public breeding program of the Universidade Federal de Viçosa (UFV) in Brazil based on 18 agronomic traits and 3,083 single nucleotide polymorphisms (SNP) markers to evaluate whether this set of inbred lines represents a panel of tropical maize inbred lines for association mapping analysis and investigate the population structure and patterns of relationships among the inbred lines from UFV for better exploitation in our maize breeding program. RESULTS: Our results showed that there was large phenotypic and genotypic variation in the set of tropical maize inbred lines from the UFV maize breeding program. We also found high genetic diversity (GD = 0.34) and low pairwise kinship coefficients among the maize inbred lines (only approximately 4.00 % of the pairwise relative kinship was above 0.50) in the set of inbred lines. The LD decay distance over all ten chromosomes in the entire set of maize lines with r2 = 0.1 was 276,237 kb. Concerning the population structure, our results from the model-based STRUCTURE and principal component analysis methods distinguished the inbred lines into three subpopulations, with high consistency maintained between both results. Additionally, the clustering analysis based on phenotypic and molecular data grouped the inbred lines into 14 and 22 genetic divergence clusters, respectively. CONCLUSIONS: Our results indicate that the set of tropical maize inbred lines from UFV maize breeding programs can comprise a panel of tropical maize inbred lines suitable for a genome-wide association study to dissect the variation of complex quantitative traits in maize, mainly in tropical environments. In addition, our results will be very useful for assisting us in the assignment of heterotic groups and the selection of the best parental combinations for new breeding crosses, mapping populations, mapping synthetic populations, guiding crosses that target highly heterotic and yielding hybrids, and predicting untested hybrids in the public breeding program UFV.

Genome-Wide Association Study , Zea mays , Brazil , Genotype , Hybrid Vigor , Plant Breeding , Polymorphism, Single Nucleotide , Zea mays/genetics
Neurosciences (Riyadh) ; 27(1): 24-30, 2022 Jan.
Article En | MEDLINE | ID: mdl-35017287

OBJECTIVES: To investigate catechol-O-methyltransferase (COMT) Val158Met gene polymorphism in MDMA use disorder (MUD) by comparing genotype distributions between MUD patients and healthy controls considering clinical parameters. METHODS: Eighty-two MUD patients' were consecutively admitted to the outpatient psychiatry clinic in May 2019-January 2020, and 95 healthy volunteers were included in the case-control study. We used the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) to determine COMT Val158Met polymorphism. RESULTS: The COMT Val158Met genotype distribution and allele frequencies of the MUD patient group were significantly different from the healthy control group. The Met/Met genotype (OR: 2.692; 95% Cl: 1.272-5.698; p=0.008) and Met allele frequencies (OR: 1.716; 95% Cl: 1.118-2.633; p=0.013) were significantly higher in the control group than in MUD patients. When the COMT Val158Met genotype and allele frequency distributions were compared between 2 groups according to the psychotic symptoms in the MUD patient group, the COMT Val158Met genotype distributions were significantly different between the groups of patients. The percentage of patients with the Val/Val genotype was significantly lower in MUD patients with a psychotic symptom than the MUD patients without a psychotic symptom (OR: 2.625; 95% Cl: 1.069-6.446; p=0.033). CONCLUSION: The COMT Val158Met gene polymorphism was found to be related to the MUD-diagnosed Turkish patients and MDMA-induced psychotic symptoms.

N-Methyl-3,4-methylenedioxyamphetamine , Psychotic Disorders , Case-Control Studies , Catechol O-Methyltransferase/genetics , Genotype , Humans , Polymorphism, Genetic , Polymorphism, Single Nucleotide/genetics
BMC Genomics ; 23(1): 26, 2022 Jan 06.
Article En | MEDLINE | ID: mdl-34991478

BACKGROUND: Valgus-varus deformity (VVD) is a lateral or middle deviation of the tibiotarsus or tarsometatarsus, which is associated with compromised growth, worse bone quality and abnormal changes in serum indicators in broilers. To investigate the genetic basis of VVD, a genome wide association study (GWAS) was performed to identify candidate genes and pathways that are responsible for VVD leg disease, serum indicators and growth performance in broilers. RESULTS: In total, VVD phenotype, seven serum indicators and three growth traits were measured for 126 VVD broilers (case group) and 122 sound broilers (control group) based on a high throughput genome wide genotyping-by-sequencing (GBS) method. After quality control 233 samples (113 sound broilers and 120 VVD birds) and 256,599 single nucleotide polymorphisms (SNPs) markers were used for further analysis. As a result, a total of 5 SNPs were detected suggestively significantly associated with VVD and 70 candidate genes were identified that included or adjacent to these significant SNPs. In addition, 43 SNPs located on Chr24 (0.22 Mb - 1.79 Mb) were genome-wide significantly associated with serum alkaline phosphatase (ALP) and 38 candidate genes were identified. Functional enrichment analysis showed that these genes are involved in two Gene Ontology (GO) terms related to bone development (cartilage development and cartilage condensation) and two pathways related to skeletal development (Toll-like receptor signaling pathway and p53 signaling pathway). BARX2 (BARX homeobox 2) and Panx3 (Pannexin 3) related to skeleton diseases and bone quality were obtained according to functional analysis. According to the integration of GWAS with transcriptome analysis, HYLS1 (HYLS1 centriolar and ciliogenesis associated) was an important susceptibility gene. CONCLUSIONS: The results provide some reference for understanding the relationship between metabolic mechanism of ALP and pathogenesis of VVD, which will provide a theoretical basis for disease-resistant breeding of chicken leg soundness.

Chickens , Genome-Wide Association Study , Animals , Chickens/genetics , Gene Expression Profiling , Phenotype , Polymorphism, Single Nucleotide
Trop Anim Health Prod ; 54(1): 50, 2022 Jan 12.
Article En | MEDLINE | ID: mdl-35022894

The Bos indicus zebu cattle Butana is the most commonly used indigenous dairy cattle breed in Sudan. In the last years, high-yielding Holstein dairy cattle were introgressed into Butana cattle to improve their milk yield and simultaneously keep their good adaption to extreme environmental conditions. With the focus on the improvement of milk production, other problems arose such as an increased susceptibility to mastitis. Thus, genetic selection for mastitis resistance should be considered to maintain healthy and productive cows. In this study, we tested 10 single nucleotide polymorphisms (SNPs) which had been associated with somatic cell score (SCS) in Holstein cattle for association with SCS in 37 purebred Butana and 203 Butana × Holstein crossbred cattle from Sudan. Animals were genotyped by competitive allele-specific PCR assays and association analysis was performed using a linear mixed model. All 10 SNPs were segregating in the crossbred Butana × Holstein populations, but only 8 SNPs in Sudanese purebred Butana cattle. The SNP on chromosome 13 was suggestively associated with SCS in the Butana × Holstein crossbred population (rs109441194, 13:79,365,467, PBF = 0.054) and the SNP on chromosome 19 was significantly associated with SCS in both populations (rs41257403, 19:50,027,458, Butana: PBF = 0.003, Butana × Holstein: PBF = 6.2 × 10-16). The minor allele of both SNPs showed an increase in SCS. Therefore, selection against the disadvantageous minor allele could be used for genetic improvement of mastitis resistance in the studied populations. However, investigations in a bigger population and across the whole genome are needed to identify additional genomic loci.

Milk , Polymorphism, Single Nucleotide , Alleles , Animals , Cattle/genetics , Female , Genomics , Genotype
BMC Infect Dis ; 22(1): 47, 2022 Jan 12.
Article En | MEDLINE | ID: mdl-35022007

BACKGROUND: COVID-19, caused by SARS-CoV-2 has become the most threatening issue to all populations around the world. It is, directly and indirectly, affecting all of us and thus, is an emerging topic dealt in global health. To avoid the infection, various studies have been done and are still ongoing. COVID-19 cases are reported all over the globe, and among the millions of cases, genetic similarity may be seen. The genetical common features seen within confirmed cases may help outline the tendency of infection and degree severity of the disease. Here, we reviewed multiple papers on SNPs related to SARS-CoV-2 infection and analyzed their results. METHODS: The PubMed databases were searched for papers discussing SNPs associated with SARS-CoV-2 infection and severity. Clinical studies with human patients and statistically showing the relevance of the SNP with virus infection were included. Quality Assessment of all papers was done with Newcastle Ottawa Scale. RESULTS: In the analysis, 21 full-text literature out of 2956 screened titles and abstracts, including 63,496 cases, were included. All were human-based clinical studies, some based on certain regions gathered patient data and some based on big databases obtained online. ACE2, TMPRSS2, and IFITM3 are the genes mentioned most frequently that are related to SARS-CoV-2 infection. 20 out of 21 studies mentioned one or more of those genes. The relevant genes according to SNPs were also analyzed. rs12252-C, rs143936283, rs2285666, rs41303171, and rs35803318 are the SNPs that were mentioned at least twice in two different studies. CONCLUSIONS: We found that ACE2, TMPRSS2, and IFITM3 are the major genes that are involved in SARS-CoV-2 infection. The mentioned SNPs were all related to one or more of the above-mentioned genes. There were discussions on certain SNPs that increased the infection and severity to certain groups more than the others. However, as there is limited follow-up and data due to a shortage of time history of the disease, studies may be limited.

COVID-19 , Population Health , Humans , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins , SARS-CoV-2
BMC Bioinformatics ; 23(1): 30, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-35012448

BACKGROUND: Plant variety identification is the one most important of agricultural systems. Development of DNA marker profiles of released varieties to compare with candidate variety or future variety is required. However, strictly speaking, scientists did not use most existing variety identification techniques for "identification" but for "distinction of a limited number of cultivars," of which generalization ability always not be well estimated. Because many varieties have similar genetic backgrounds, even some essentially derived varieties (EDVs) are involved, which brings difficulties for identification and breeding progress. A fast, accurate variety identification method, which also has good performance on EDV determination, needs to be developed. RESULTS: In this study, with the strategy of "Divide and Conquer," a variety identification method Conditional Random Selection (CRS) method based on SNP of the whole genome of 3024 rice varieties was developed and be applied in essentially derived variety (EDV) identification of rice. CRS is a fast, efficient, and automated variety identification method. Meanwhile, in practical, with the optimal threshold of identity score searched in this study, the set of SNP (including 390 SNPs) showed optimal performance on EDV and non-EDV identification in two independent testing datasets. CONCLUSION: This approach first selected a minimal set of SNPs to discriminate non-EDVs in the 3000 Rice Genome Project, then united several simplified SNP sets to improve its generalization ability for EDV and non-EDV identification in testing datasets. The results suggested that the CRS method outperformed traditional feature selection methods. Furthermore, it provides a new way to screen out core SNP loci from the whole genome for DNA fingerprinting of crop varieties and be useful for crop breeding.

Oryza , DNA Fingerprinting , Genetic Markers , Genome, Plant , Nucleotides , Oryza/genetics , Polymorphism, Single Nucleotide
BMC Genomics ; 23(1): 43, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-35012465

BACKGROUND: Miscanthus, which is a leading dedicated-energy grass in Europe and in parts of Asia, is expected to play a key role in the development of the future bioeconomy. However, due to its complex genetic background, it is difficult to investigate phylogenetic relationships in this genus. Here, we investigated 50 Miscanthus germplasms: 1 female parent (M. lutarioriparius), 30 candidate male parents (M. lutarioriparius, M. sinensis, and M. sacchariflorus), and 19 offspring. We used high-throughput Specific-Locus Amplified Fragment sequencing (SLAF-seq) to identify informative single nucleotide polymorphisms (SNPs) in all germplasms. RESULTS: We identified 257,889 SLAF tags, of which 87,162 were polymorphic. Each tag was 264-364 bp long. The obtained 724,773 population SNPs were used to investigate genetic relationships within three species of Miscanthus. We constructed a phylogenetic tree of the 50 germplasms using the obtained SNPs and grouped them into two clades: one clade comprised of M. sinensis alone and the other one included the offspring, M. lutarioriparius, and M. sacchariflorus. Genetic cluster analysis had revealed that M. lutarioriparius germplasm C3 was the most likely male parent of the offspring. CONCLUSIONS: As a high-throughput sequencing method, SLAF-seq can be used to identify informative SNPs in Miscanthus germplasms and to rapidly characterize genetic relationships within this genus. Our results will support the development of breeding programs with the focus on utilizing Miscanthus cultivars with elite biomass- or fiber-production potential for the developing bioeconomy.

Poaceae , Polymorphism, Single Nucleotide , Asia , High-Throughput Nucleotide Sequencing , Phylogeny , Poaceae/genetics
J Appl Oral Sci ; 29: e20210262, 2022.
Article En | MEDLINE | ID: mdl-35019025

This study aimed to investigate if SNP rs6313, SNP rs2770304, SNP rs4941573, and SNP rs1923884 of the 5-HT2A receptor gene and SNP rs6295 of the 5-HT1A receptor gene are associated with bruxism etiology. METHODOLOGY: This systematic review was registered in PROSPERO (CRD42018094561). A search was conducted for articles published in or before May 2021. To qualify for eligibility in this review, the studies had to be case-controls, cohort or cross-sectional. The inclusion criteria were the articles with a group of patients with bruxism and a control group in which the presence of these SNPs was evaluated. The exclusion criteria were the investigations of other polymorphisms, the studies that did not consider a control group for comparison, case reports, and reviews. The NOS and JBI were used to evaluate the methodological quality of studies. RESULTS: We conducted this study with databases, such as Web of Science, Scopus, Embase, PubMed/MEDLINE, and ProQuest. We considered four studies eligible. A total of 672 participants were included,187 with sleep bruxism, 105 with awake bruxism, 89 with sleep and awake bruxism, and 291 controls. One study found a strong association between the SNPs rs6313, rs2770304 and rs4941573 of the 5-HT2A receptor gene and sleep bruxism. In one study, we considered the C allele of the SNP rs2770304 a risk factor for sleep bruxism. We found no significant results of other SNPs in sleep bruxers compared to controls. We found no positive association concerning the SNPs and groups of awake bruxism and sleep and awake bruxism. CONCLUSION: The different results regarding the SNPs in sleep bruxers could be explained by the genetic distinction between Chilean, Mexican, Japanese, and Polish population. More clinical trials and prospective studies must be conducted with larger sample size and in different ethnicities to confirm the results of this review.

Sleep Bruxism , Case-Control Studies , Cross-Sectional Studies , Humans , Polymorphism, Single Nucleotide , Receptors, Serotonin/genetics , Sleep Bruxism/genetics
Genet Sel Evol ; 54(1): 1, 2022 Jan 03.
Article En | MEDLINE | ID: mdl-34979897

BACKGROUND: The genetic background of trait variability has captured the interest of ecologists and animal breeders because the genes that control it could be involved in buffering various environmental effects. Phenotypic variability of a given trait can be assessed by studying the heterogeneity of the residual variance, and the quantitative trait loci (QTL) that are involved in the control of this variability are described as variance QTL (vQTL). This study focuses on litter size (total number born, TNB) and its variability in a Large White pig population. The variability of TNB was evaluated either using a simple method, i.e. analysis of the log-transformed variance of residuals (LnVar), or the more complex double hierarchical generalized linear model (DHGLM). We also performed a single-SNP (single nucleotide polymorphism) genome-wide association study (GWAS). To our knowledge, this is only the second study that reports vQTL for litter size in pigs and the first one that shows GWAS results when using two methods to evaluate variability of TNB: LnVar and DHGLM. RESULTS: Based on LnVar, three candidate vQTL regions were detected, on Sus scrofa chromosomes (SSC) 1, 7, and 18, which comprised 18 SNPs. Based on the DHGLM, three candidate vQTL regions were detected, i.e. two on SSC7 and one on SSC11, which comprised 32 SNPs. Only one candidate vQTL region overlapped between the two methods, on SSC7, which also contained the most significant SNP. Within this vQTL region, two candidate genes were identified, ADGRF1, which is involved in neurodevelopment of the brain, and ADGRF5, which is involved in the function of the respiratory system and in vascularization. The correlation between estimated breeding values based on the two methods was 0.86. Three-fold cross-validation indicated that DHGLM yielded EBV that were much more accurate and had better prediction of missing observations than LnVar. CONCLUSIONS: The results indicated that the LnVar and DHGLM methods resulted in genetically different traits. Based on their validation, we recommend the use of DHGLM over the simpler method of log-transformed variance of residuals. These conclusions can be useful for future studies on the evaluation of the variability of any trait in any species.

Genome-Wide Association Study , Quantitative Trait Loci , Animals , Female , Genomics , Litter Size/genetics , Phenotype , Polymorphism, Single Nucleotide , Pregnancy , Sus scrofa/genetics , Swine/genetics
Genet Sel Evol ; 54(1): 2, 2022 Jan 03.
Article En | MEDLINE | ID: mdl-34979909

BACKGROUND: Gastroinestinal nematodes (GIN) are one of the major health problem in grazing sheep. Although genetic variability of the resistance to GIN has been documented, traditional selection is hampered by the difficulty of recording phenotypes, usually fecal egg count (FEC). To identify causative mutations or markers in linkage disequilibrium (LD) to be used for selection, the detection of quantitative trait loci (QTL) for FEC based on linkage disequilibrium-linkage analysis (LDLA) was performed on 4097 ewes (from 181 sires) all genotyped with the OvineSNP50 Beadchip. Identified QTL regions (QTLR) were imputed from whole-genome sequences of 56 target animals of the population. An association analysis and a functional annotation of imputed polymorphisms in the identified QTLR were performed to pinpoint functional variants with potential impact on candidate genes identified from ontological classification or differentially expressed in previous studies. RESULTS: After clustering close significant locations, ten QTLR were defined on nine Ovis aries chromosomes (OAR) by LDLA. The ratio between the ANOVA estimators of the QTL variance and the total phenotypic variance ranged from 0.0087 to 0.0176. QTL on OAR4, 12, 19, and 20 were the most significant. The combination of association analysis and functional annotation of sequence data did not highlight any putative causative mutations. None of the most significant SNPs showed a functional effect on genes' transcript. However, in the most significant QTLR, we identified genes that contained polymorphisms with a high or moderate impact, were differentially expressed in previous studies, contributed to enrich the most represented GO process (regulation of immune system process, defense response). Among these, the most likely candidate genes were: TNFRSF1B and SELE on OAR12, IL5RA on OAR19, IL17A, IL17F, TRIM26, TRIM38, TNFRSF21, LOC101118999, VEGFA, and TNF on OAR20. CONCLUSIONS: This study performed on a large experimental population provides a list of candidate genes and polymorphisms which could be used in further validation studies. The expected advancements in the quality of the annotation of the ovine genome and the use of experimental designs based on sequence data and phenotypes from multiple breeds that show different LD extents and gametic phases may help to identify causative mutations.

Parasites , Animals , Female , Genetic Linkage , Genomics , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Sheep/genetics
BMC Neurol ; 22(1): 8, 2022 Jan 03.
Article En | MEDLINE | ID: mdl-34979977

BACKGROUND: Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. OBJECTIVES: To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. RESULTS: Using the inverse variance-weighted method, OTU10032 unclassified Enterobacteriaceae species-level OTU and unclassified Acidaminococcaceae were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01-1.07; P = 0.011 and OR, 1.02; 95% CI, 1.01-1.04; P = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50-2.55; P = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of OTU4607_Sutterella (per 1-unit higher log odds: ß, 2.23; 95% CI, 1.27-3.18; P = 0.020) and Lactobacillales_ORDER (per 1-unit higher log odds: ß, 0.51; 95% CI, 0.09-0.94; P = 0.019). CONCLUSIONS: Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials.

Amyotrophic Lateral Sclerosis , Gastrointestinal Microbiome , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/genetics , Causality , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide
Int J Immunogenet ; 49(1): 1-7, 2022 Feb.
Article En | MEDLINE | ID: mdl-34958529

Haplotyping or determination of genetic phase has always played a pivotal role in MHC (HLA studies) both in helping to understand inheritance patterns in diseases such as type 1 diabetes (T1D) and in ensuring better matching in transplantation scenarios such as haematopoietic stem cell transplantation (HSCT), using donors genetically related to the patient. In recent years the need to establish genetic phase in a number of clinical scenarios has become apparent. These include: Genetic phasing for hematopoietic stem cell transplants using unrelated donors, where the HLA haplotypes are not known but where haplotype-matched recipients fare better clinically than allele matched, but haplotype mismatched patients. The use of checkpoint inhibitors is one of the most innovative and exciting developments in cancer treatment in years. An example is the use of the monoclonal ipilimumab to block the CTLA-4 receptor which is known to contain polymorphic sites. Until the phase of these polymorphisms is known it will not be possible to determine how effectively this monoclonal will perform in individual patients. The role of miRNA single strand molecules and their effect on gene expression. Thousands of non-coding genes have been identified and have been shown to be polymorphic, as have their target genes. Genetic phasing of polymorphism both in the miRNA source genes and their targets is clearly a fertile area of research In areas such a drug metabolism where the polymorphic family of CYP genes is responsible for the metabolism of the majority of prescription drugs, determining phase of SNPs is critical to understanding drug metabolism and efficacy. In multigenic disease studies combinations of single nucleotide polymorphisms (SNPs) in participating genes require accurate phasing in order to fully appreciate their role in the disease process. In addition, the level of expression of genes (point 3) is also important in understanding disease processes at the functional level. This review outlines the techniques that are currently available for approximating phase and discusses the clinical relevance of establishing genetic phase in areas of clinical medicine outlined in points 1-3.

Clinical Medicine , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Haplotypes , Histocompatibility Testing , Humans , Polymorphism, Single Nucleotide , Unrelated Donors
Anticancer Res ; 42(1): 385-395, 2022 Jan.
Article En | MEDLINE | ID: mdl-34969749

BACKGROUND: It has been reported that expression of OCT3 enhanced the sensitivity to melphalan in cells, indicative of potential roles of OCT3 in melphalan transport. Herein we investigated the association of select single nucleotide polymorphisms in SLC22A3 (gene encoding OCT3) with clinical outcomes in multiple myeloma (MM) patients with hematopoietic autologous stem cell transplants followed by high-dose melphalan therapy. MATERIALS AND METHODS: Melphlan concentrations in blood samples from 108 MM patients were measured using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS); genotypes of rs2048327, rs1810126, and rs3088442 in these patients were determined using quatitive RT-PCR assays. RESULTS: Rs3088442 A variant-carriers had a significantly increased risk of severe oral mucositis in comparison with homozygous rs3088442 G-carriers with adjusted odds ratio of 4.00 (95% CI=1.25-14.7; p=0.027). Rs3088442 A carriers tended to have lower creatinine clearance (p=0.10) and higher maximum plasma concentration of melphalan (p=0.07). CONCLUSION: OCT3 might be involved in melphalan transport in MM patients.

Genetic Predisposition to Disease , Multiple Myeloma/therapy , Organic Cation Transport Proteins/genetics , Stomatitis/genetics , Adult , Aged , Genetic Association Studies , Genotype , Humans , Male , Melphalan/adverse effects , Melphalan/therapeutic use , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Polymorphism, Single Nucleotide/genetics , Stem Cell Transplantation/adverse effects , Stomatitis/epidemiology , Stomatitis/pathology , Transplantation, Autologous/adverse effects
Anticancer Res ; 42(1): 419-427, 2022 Jan.
Article En | MEDLINE | ID: mdl-34969752

BACKGROUND/AIM: With the progress in cancer immunotherapy using immune checkpoint blockade (ICB) therapy, histological observations of tumor-infiltrating lymphocyte (TIL) status are needed to evaluate the antitumor effect of ICB using imaging analysis software. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded sections obtained from colorectal cancer and gastric cancer patients with more than 500 single nucleotide variants were stained with anti-CD8 and anti-PD-1 antibodies. Based on our own algorithm and imaging analysis software, an automatic TIL measurement method was established and compared to the manual counting methods. RESULTS: In the CD8+ T cell number measurement, there was a good correlation (r=0.738 by Pearson test) between the manual and automated counting methods. However, in the PD-1+ T cell measurement, there was a large difference in TIL numbers in both groups. After adjustment of the parameter settings, the correlation between the manual and automated methods in the PD-1+ T cell measurements improved (r=0.668 by Pearson test). CONCLUSION: An imaging software-based automatic measurement could be a simple and useful tool for evaluating the therapeutic effect of cancer immunotherapies in terms of TIL status.

CD8 Antigens/genetics , Colorectal Neoplasms/genetics , Programmed Cell Death 1 Receptor/genetics , Stomach Neoplasms/genetics , Antibodies, Anti-Idiotypic/immunology , Antibodies, Anti-Idiotypic/pharmacology , CD8 Antigens/isolation & purification , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Humans , Image Processing, Computer-Assisted , Immune Checkpoint Inhibitors/therapeutic use , Lymphocytes, Tumor-Infiltrating/pathology , Male , Polymorphism, Single Nucleotide/genetics , Programmed Cell Death 1 Receptor/isolation & purification , Software , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy
Gene ; 807: 145933, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-34464678

BACKGROUND: Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-ß), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer. METHODS: A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated. RESULTS: Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-ß, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype. CONCLUSION: We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.

Interleukin-10/genetics , Uterine Cervical Neoplasms/genetics , Adult , Alleles , Alphapapillomavirus/genetics , Alphapapillomavirus/pathogenicity , Cytokines , Female , Gene Frequency/genetics , Genotype , Humans , Inflammation , Interferon-gamma , Interleukin-10/metabolism , Middle Aged , Odds Ratio , Papillomaviridae/genetics , Papillomaviridae/pathogenicity , Polymorphism, Single Nucleotide/genetics , Real-Time Polymerase Chain Reaction , Risk Factors , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolism
Gut ; 71(1): 68-76, 2022 01.
Article En | MEDLINE | ID: mdl-33526437

OBJECTIVES: Coeliac disease (CD) is a complex autoimmune disorder that develops in genetically susceptible individuals. Dietary gluten triggers an immune response for which the only available treatment so far is a strict, lifelong gluten free diet. Human leucocyte antigen (HLA) genes and several non-HLA regions have been associated with the genetic susceptibility to CD, but their role in the pathogenesis of the disease is still essentially unknown, making it complicated to develop much needed non-dietary treatments. Here, we describe the functional involvement of a CD-associated single-nucleotide polymorphism (SNP) located in the 5'UTR of XPO1 in the inflammatory environment characteristic of the coeliac intestinal epithelium. DESIGN: The function of the CD-associated SNP was investigated using an intestinal cell line heterozygous for the SNP, N6-methyladenosine (m6A)-related knock-out and HLA-DQ2 mice, and human samples from patients with CD. RESULTS: Individuals harbouring the risk allele had higher m6A methylation in the 5'UTR of XPO1 RNA, rendering greater XPO1 protein amounts that led to downstream nuclear factor kappa B (NFkB) activity and subsequent inflammation. Furthermore, gluten exposure increased overall m6A methylation in humans as well as in in vitro and in vivo models. CONCLUSION: We identify a novel m6A-XPO1-NFkB pathway that is activated in CD patients. The findings will prompt the development of new therapeutic approaches directed at m6A proteins and XPO1, a target under evaluation for the treatment of intestinal disorders.

Celiac Disease/genetics , Karyopherins/genetics , Polymorphism, Single Nucleotide , RNA/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Adenosine/analogs & derivatives , Adenosine/genetics , Animals , Cell Line , Disease Models, Animal , Epithelial Cells/pathology , HLA-DQ Antigens/genetics , Humans , Intestinal Mucosa/pathology , Methylation , Mice, Knockout , NF-kappa B/metabolism
Gene ; 808: 145953, 2022 Jan 15.
Article En | MEDLINE | ID: mdl-34500048

BACKGROUND: Previous studies have indicated the connections between autophagy-lysosome pathway genes dysfunction and prostate cancer, but few studies have investigated whether single nucleotide polymorphisms (SNPs) in autophagy-lysosome pathway genes are implicated in prostate cancer risk and survival. MATERIALS AND METHODS: Logistic regression analysis and stepwise Cox regression analysis were conducted in 4,662 cases and 3,114 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The false positive rate probability (FPRP) method was applied to correct for multiple comparisons. Gene-based analysis was calculated by versatile gene-based association study approach. RESULTS: We found that SLC11A1 rs7573065 significantly increased the risk of prostate cancer [adjusted odds ratio (OR) = 1.24, 95% confidence interval (CI) = 1.06-1.46, P = 7.02 × 10-3, FPRP = 0.082]. Furthermore, rs7573065 was confirmed as the independent predicator of overall survival (OS) for prostate cancer patients [Hazard ratio (HR) = 1.30, 95% CI = 1.01-1.66, P = 0.041]. The significant association between SLC11A1 and prostate cancer risk was calculated by gene-based analysis (P = 0.030). We also observed that the mRNA of SLC11A1 in prostate tumor tissues was significantly over-expressed than that in normal tissues. CONCLUSION: This study suggested that rs7573065 in SLC11A1 was associated with an increased risk and poor OS of prostate cancer. Our findings may provide evidence for genetic variants in autophagy-lysosome pathway as the risk and prognostic biomarkers for prostate cancer.

Autophagy/genetics , Cation Transport Proteins/genetics , Prostatic Neoplasms/genetics , Aged , Cation Transport Proteins/metabolism , Genetic Association Studies/methods , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study/methods , Humans , Lysosomes/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Proportional Hazards Models , Prostatic Neoplasms/physiopathology , Quantitative Trait Loci/genetics , Regression Analysis , Signal Transduction/genetics
Gene ; 808: 145962, 2022 Jan 15.
Article En | MEDLINE | ID: mdl-34530082

Japanese encephalitis (JE), an acute encephalitis syndrome disease caused by infection with JE virus (JEV), is an important mosquito borne disease in developing countries. The clinical outcomes of JEV infection show inter individual differences. Only in a minor percent of the infected subjects, the disease progresses into acute encephalitis syndrome. Single nucleotide polymorphisms in the host immune response related genes are known to affect susceptibility to JE. In the present study, 238 JE cases and 405 healthy controls (HCs) without any known history of encephalitis were investigated for SNPs in the CD209 MX1, TLR3, MMP9, TNFA and IFNG genes which are important in the immune response against JEV by PCR based methods. The results revealed higher frequencies of heterozygous genotypes of CD209 rs4804803, MMP9 rs17576, TNFA rs1800629 and IFNG rs2430561 in JE cases compared to HCs. These SNPs were associated with JE in an over-dominant genetic model (Odds ratio with 95% CI 1.51 (1.09-2.10) for CD209 rs4804803, 1.52 (1.09-2.11) for MMP9 rs17576, and 1.55 (1.12-2.15) for IFNG rs2430561). The association of G/A genotype of TNFA rs1800629 with JE was confirmed in a larger sample size. The results suggest the association of CD209 rs4804803, MMP9 rs17576, IFNG rs2430561 and TNFA rs1800629 polymorphisms with susceptibility to JE.

Encephalitis, Japanese/genetics , Cell Adhesion Molecules/genetics , Child , Child, Preschool , Encephalitis Virus, Japanese/pathogenicity , Encephalitis, Japanese/virology , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , India/epidemiology , Interferon-gamma/genetics , Lectins, C-Type/genetics , Male , Matrix Metalloproteinase 9/genetics , Odds Ratio , Polymorphism, Single Nucleotide/genetics , Receptors, Cell Surface/genetics , Tumor Necrosis Factor-alpha/genetics