Genome-wide DNA methylation and transcriptome expression profiles of peripheral blood mononuclear cells in patients with systemic sclerosis with interstitial lung disease / 中南大学学报(医学版)

OBJECTIVES@#This study aims to investigate the genome-wide DNA methylation and transcriptome expression profiles of peripheral blood mononuclear cells (PBMCs) in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD), and to analyze the effects of DNA methylation on Wnt/β-catenin and chemokine signaling pathways.@*METHODS@#PBMCs were collected from 19 patients with SSc (SSc group) and 18 healthy persons (control group). Among SSc patients, there were 10 patients with ILD (SSc with ILD subgroup) and 9 patients without ILD (SSc without ILD subgroup). The genome-wide DNA methylation and gene expression level were analyzed by using Illumina 450K methylation chip and Illumina HT-12 v4.0 gene expression profiling chip. The effect of DNA methylation on Wnt/β-catenin and chemokine signal pathways was investigated.@*RESULTS@#Genome-wide DNA methylation analysis identified 71 hypermethylated CpG sites and 98 hypomethylated CpG sites in the SSc with ILD subgroup compared with the SSc without ILD subgroup. Transcriptome analysis distinguished 164 upregulated genes and 191 downregulated genes in the SSc with ILD subgroup as compared with the SSc without ILD subgroup. In PBMCs of the SSc group, 35 genes in Wnt/β-catenin signaling pathway were hypomethylated, while frizzled-1 (FZD1), mitogen-activated protein kinase 9 (MAPK9), mothers against DPP homolog 2 (SMAD2), transcription factor 7-like 2 (TCF7L2), and wingless-type MMTV integration site family, member 5B (WNT5B) mRNA expressions were upregulated as compared with the control group (all P<0.05). Compared with the SSc without ILD subgroup, the mRNA expressions of dickkopf homolog 2 (DKK2), FZD1, MAPK9 were upregulated in the SSc with ILD subgroup, but the differences were not statistically significant (all P>0.05). In PBMCs of the SSc group, 38 genes in chemokine signaling pathway were hypomethylated, while β-arrestin 1 (ARRB1), C-X-C motif chemokine ligand 10 (CXCL10), C-X-C motif chemokine ligand 16 (CXCL16), FGR, and neutrophil cytosolic factor 1C (NCF1C) mRNA expressions were upregulated as compared with the control group (all P<0.05). Compared with the SSc without ILD subgroup, the mRNA expressions of ARRB1, CXCL10, CXCL16 were upregulated in the SSc with ILD subgroup, but the differences were not statistically significant (all P>0.05).@*CONCLUSIONS@#There are differences in DNA methylation and transcriptome profiles between SSc with ILD and SSc without ILD. The expression levels of multiple genes in Wnt/β- catenin and chemokine signaling pathways are upregulated, which might be associatea with the pathogenesis of SSc.

How data science and AI-based technologies impact genomics

Advancements in high-throughput sequencing have yielded vast amounts of genomic data, which are studied using genome-wide association study (GWAS)/phenome-wide association study (PheWAS) methods to identify associations between the genotype and phenotype. The associated findings have contributed to pharmacogenomics and improved clinical decision support at the point of care in many healthcare systems. However, the accumulation of genomic data from sequencing and clinical data from electronic health records (EHRs) poses significant challenges for data scientists. Following the rise of artificial intelligence (AI) technology such as machine learning and deep learning, an increasing number of GWAS/PheWAS studies have successfully leveraged this technology to overcome the aforementioned challenges. In this review, we focus on the application of data science and AI technology in three areas, including risk prediction and identification of causal single-nucleotide polymorphisms, EHR-based phenotyping and CRISPR guide RNA design. Additionally, we highlight a few emerging AI technologies, such as transfer learning and multi-view learning, which will or have started to benefit genomic studies.

Molecular characterization of mutations associated with resistance among 72 multidrug-resistant strains of Mycobacterium tuberculosis by whole genome sequencing / 中国热带医学

@#Abstract: Objective　To understand the characteristics of mutations associated with resistance among 72 multidrug-resistant tuberculosis (MDR-TB) strains using whole genome sequencing (WGS) and to evaluate the performance of WGS for predicting MDR-TB drug resistance. Methods　The clinical strains isolated from patients who visited the outpatient department of Tianjin Center for Tuberculosis Control from January to September in 2020 were collected. Identification tests using p-nitrobenzoic acid (PNB) medium were performed. Drug susceptibility tests (proportion method) on L-J medium were performed. After excluding duplicate strains, 72 MDR-TB strains were selected for WGS. Data were analyzed by using online databases and the phenotypic drug susceptibility test results were compared with resistance profiles predicted by WGS. Results　All of 72 MDR-TB strains belonged to linage 2, and there was no significant difference in rate of pre-extensive drug-resistant tuberculosis (pre-XDR-TB) between modern type and ancestral type (χ2=0.287, P=0.592). A total of 81 mutation types were found from resistance-related genes for 12 anti-tuberculosis drugs, and the common mutation types in different drug-resistant strains were: streptomycin (SM): rpsL Lys43Arg; isoniazid (INH): katG Ser315Thr; rifampicin (RIF): rpoB Ser450Leu; ethambutol (EMB): embB Met306Val; ofloxacin (OFX), levofloxacin (LFX), moxifloxacin (MFX): gyrA Asp94Gly; kanamycin (KAM), capreomycin (CAP), amikacin (AMK): rrs 1401a>g; para-aminosalicylic acid (PAS): folC Ile43Thr. Nine mutation types were found in 9 prothionamide (PTO)-resistant strains, one type for each strain. The sensitivity and specificity of WGS for predicting resistance to different drugs were SM: 98.15% and 88.89%, INH: 90.28% and -, RIF: 98.62% and -, EMB: 79.49% and75.76%, OFX: 97.30% and 85.71%, KAM: 85.71% and 98.46%, PAS: 27.27% and 95.08%, PTO: 81.82% and 60.66%, CAP: 60.00% and 98.51%, LFX: 97.22% and 83.33%, MFX: 97.30% and 85.71%, AMK:100.00% and 100.00%, respectively. Conclusion　WGS is a rapid and promising method which has high consistency with the phenotypic drug sensitivity test. Therefore, it has good application prospects in predicting drug resistance in MDR-TB.

Association of ticagrelor with risk of infection：a two-sample Mendelian randomization study based on the GWAS database / 中国药房

OBJECTIVE To investigate the causal association between ticagrelor and risk of infection METHODS Two-sample Mendelian randomization was adopted. Genetic instrumental variables were selected based on the results of the largest genome-wide association analysis to in vivo exposure of ticagrelor and its major active metabolite AR-C124910XX. The causal associations of ticagrelor and its major active metabolite AR-C124910XX with drug indications （coronary artery disease， unstable angina pectoris， myocardial infarction， stroke and ischemic stroke）were analyzed by inverse variance weighted Mendelian randomization model as a positive control for genetic instrumental variables. The causal relationship between ticagrelor and bacterial infection， acute lower respiratory infection， bacterial pneumoniae， pneumoniae，acute upper respiratory infection and sepsis were furtheranalyzed by using this method， and the robustness of the results was assessed by using heterogeneity tests and horizontal 202002030415） pleiotropy tests. RESULTS The increase of area under the curve at steady state （AUCss） of the genetic surrogated ticagrelor significantly reduced the risk of coronary artery disease， myocardial infarction and unstable angina pectoris （P＜0.001）. AUCss genetic instrument variables of its main active metabolite AR-C124910XX failed to pass positive control. Further analysis showed that the increase of the genetic surrogated ticagrelor exposure suggestively reduced the risk of bacterial infection [OR（95%CI）＝0.80（0.65，0.99），P＝0.040] and sepsis [OR （95%CI）＝0.84（0.73， 0.98）， P＝0.023]. The results of the heterogeneity tests showed that there was no heterogeneity in the causal association of the genetic surrogated ticagrelor AUCss with bacterial infection and sepsis （P＞0.05）. The results of horizontal pleiotropy tests showed that the causal association of genetic surrogated ticagrelor AUCss with bacterial infection and sepsis had no effects on horizontal pleiotropy （P＞0.05）. CONCLUSIONS Ticagrelor has a potential role in reducing the risk of sepsis and bacterial infections.

Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population

Background: Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. Objectives: The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. Methods: To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. Results: Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. Limitations: The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. Conclusion: Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.

Genome-wide identification and transcriptional profiling analysis of PIN/PILS auxin transporter gene families in Panax ginseng / 中草药·英文版

Objective: Plant hormones act as chemical messengers in the regulation of plant development and metabolism. The production of ginsenosides in Panax hybrid is promoted by auxins that are transported and accumulated by PIN-FORMED (PIN) and PIN-LIKES (PILS) auxin transporters. However, genome-wide studies of PIN/PILS of ginseng are still scarce. In current study, identification and transcriptional profiling of PIN/PILS gene families, as well as their potential relationship with ginsenoside biosynthesis in Panax ginseng were investigated. Methods: PIN/PILS genes in P. ginseng was identified via in silico genome-wide analysis, followed by phylogenetic relationships, gene structure, and protein profiles investigation. Moreover, previously reported RNA-sequence data from various tissues and roots after infection were utilized for PIN/PILS genes expression pattern analysis. The Pearson's correlation analysis of specific PIN/PILS genes expression level and main ginsenoside contents were taken to reveal the potential relationship between auxin transports and ginsenoside biosynthesis in P. ginseng. Results: A genome-wide search of P. ginseng genome for homologous auxin transporter genes identified a total of 17 PIN and 11 PILS genes. Sequence alignment, putative motif organization, and sub-cellular localization indicated redundant and complementary biological functions of these PIN/PILS genes. Most PIN/PILS genes were differentially expressed in a tissue-specific manner, and showed significant correlations with ginsenoside content correspondingly. Eight auxin transporter genes, including both PIN and PILS subfamily members, were positively correlated with ginsenoside content (cor > 0.60; P-value <0.05). The expression levels of eleven auxin transporter genes were increased dramatically in the early stage (0–0.5 DPI) after Cylindrocarpon destructans infection, accompanied with various overall expression patterns, implying the dynamic auxin transport in response to biotic stress. Conclusion: Based on the results, we speculate that the accumulation or depletion in temporal or spatial manner of auxin by PIN/PILS transporters involved in the regulation of HMGR activity and subsequent ginsenoside biosynthesis.

Genetic studies of primary biliary cholangitis in the post-GWAS era / 临床肝胆病杂志

With the constant increase in the awareness of primary biliary cholangitis (PBC) and the continuous improvement in related diagnostic methods in the past two decades, the incidence and prevalence rates of PBC tend to increase and PBC is now the most common autoimmune liver disease worldwide. A series of family-based studies in the early stage have shown that PBC has strong genetic tendency, and subsequent genomic analyses have been performed for PBC in different populations and have obtained a large amount of genetic data. Future genetic studies of PBC will focus on translating these results into clinical practice.

Progress in genetic epidemiology of gestational diabetes mellitus / 中华围产医学杂志

Gestational diabetes mellitus poses a substantial threat to the short- and long-term health of women and their offspring. Previous studies have identified a number of genetic risk factors for gestational diabetes through candidate gene strategy and whole genome studies. Many of these identified genetic variations have also been proved to be associated with type 2 diabetes, abnormal glycometabolism as well as insulin secretion and resistance. This article reviews the recent progress in the genetic epidemiology of gestational diabetes mellitus.

Genetic study of cardiovascular disease subtypes defined by International Classification of Diseases / 北京大学学报(医学版)

OBJECTIVE@#To study the molecular connection among cardiovascular diseases (CVD) subtypes defined by the International Classification of Diseases (ICD) version 10 (ICD-10).@*METHODS@#Both phenotypic data and genotypic data used in this study were obtained from the UK Biobank. A total of 380 083 participants aged between 40 and 69 years were included. Those without any cardiovascular disease (either no ICD-10 code at all or no ICD-10 code containing letter I) were assigned to the control group. The five CVD subtypes were: ischaemic heart diseases (IHD), pulmonary heart disease and diseases of pulmonary circulation (PHD), cerebrovascular diseases (CRB), diseases of arteries, arterioles and capillaries (AAC), diseases of veins, lymphatic vessels and lymph nodes, and diseases not elsewhere classified (VLL). We first performed a genome-wide association study (GWAS) for each of the five subtypes. We summarized novel loci using genome-wide significance threshold P=5×10-8. Next, we used linkage disequilibrium score regression (LDSC) method to assess genetic correlation among the five subtypes. Lastly, we applied mendelian randomization (MR) approach to assess the causal relationship among the subtypes. The particular software that we used was generalised summary-data-based mendelian randomisation (GSMR).@*RESULTS@#Through GWAS, we identified hundreds of genome-wide significant SNPs: 672 for IHD, 241 for PHD, 31 for CRB, 48 for AAC, and 193 for VLL. By comparing with published literature, we found 28 novel loci, for PHD (n=14), CRB (n =7) and AAC (n =7). Eight of these 28 loci were rare, where the lead SNP had minor allele frequency (MAF) less than 1%. LDSC analyses indicated IHD had significant genetic correlation with VLL (P=2.52×10-7), PHD (P=3.77×10-3) and AAC (P=4.90×10-3), respectively. Bidrectional GSMR analyses showed that IHD had a positive causal relationship with VLL (P=7.40×10-5) and AAC (P=1.50×10-3), while reverse causality was not supported.@*CONCLUSION@#This study adopted an innovative approach to study the molecular connection among CVD subtypes that are defined by ICD. We identified potentially positive genetic correlation and causal effects among some of these subtypes. Research along this line will provide scientific insights and serve as a guidance for future ICD standards.

A longitudinal study of transcriptional profiling of carbon-ions exposure on the lung / 中华放射肿瘤学杂志

Objective:To investigate the expression changes at the transcriptional level in normal lung tissues of mice after exposure to heavy ion radiation for different durations at different doses, aiming to provide evidence for exploring sensitive genes of heavy ion radiation, heavy ion radiation effect and the damage mechanism.Methods:Experiments on the temporal kinetics: the whole thorax of mice was irradiated with 14.5Gy carbon-ions and the total RNA of lung tissue was extracted at 3days, 7days, 3 weeks and 24 weeks. In dose-dependent experiment, the total RNA of lung tissue was extracted at 1 week after irradiated with a growing thoracic dose of 0, 7.5, 10.5, 12.5, 14.5, 17.5 and 20Gy. Protein-to-protein interaction (PPI) analysis and gene-ontology biological process enrichment analysis were performed on significant differentially expressed genes (DEGs).Results:A clearly differential expression patterns were observed at 3-day (acute stage), 1-week (subacute stage), 3-week (inflammatory stage) and 24-week (fibrosis stage) following 14.5Gy carbon-ions irradiation. Among those, the 3-day time point was found to be the mostly different from the other time points, whereas the 7-day time point had the highest uniformity with the other time points. Cellular apoptosis was the main type of cell death in normal lung tissues following carbon-ions exposure. The interactive genes of Phlda3, GDF15, Mgmt and Bax were identified as the radiosensitive genes, and Phlda3 was the center ( R=0.76, P<0.001). Conclusion:The findings in this study provide transcriptional insights into the biological mechanism underlying normal lung tissue toxicity induced by carbon-ions.

Polymorphism of urate transporter in gout and its correlation with gout treatment / 中国组织工程研究

BACKGROUND: Urate transporters such as GLUT9, URAT1, NPT1 and ABCG2 are directly involved in the regulation of human serum uric acid levels. The gene polymorphism of urate transporter is closely related to the occurrence and development of gout. Therefore, the targeted therapy of urate transporter is a new way to treat gout. OBJECTIVE: To summarize the research progress of polymorphism expression of urate transporter in gout and its correlation with clinical drugs in recent years, therefore providing literature and theoretical basis for further exploration of personalized treatment of gout and hyperuricemia. METHODS: The first author searched CNKI, WanFang database and PubMed database. The key words were “Gout, Urate transporter, Hyperuricemia, Polymorphism, GWAS, Therapy” in Chinese and English, respectively. Totally 131 literatures were retrieved. According to the inclusion and exclusion criteria, 78 articles regarding the genetic polymorphism of urate transporter in gout and the correlation between the mechanism of action of gout drugs and urate transporter were screened out and summarized. RESULTS AND CONCLUSION: A large number of studies have shown that urate transporter polymorphism is closely related to uric acid homeostasis, with GLUT9, URAT1, NPT1 and ABCG2 being the most important. These proteins are differentially expressed in different populations and are closely related to the reaction mechanism of gout drugs. In the future diagnosis and treatment, the results of these studies can help assess the need for treatment in patients with hyperuricemia, and help patients with gout formulate personalized and effective treatment plans. It may be a feasible solution to treat hyperuricemia by activating BCRP to enhance the clearance of uric acid in the intestine.

Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer / 亚洲男科学杂志(英文版)

Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.

Advances in the study of POAG-related genes and central nervous system diseases / 国际眼科杂志(Guoji Yanke Zazhi)

@#In recent years, considerable progress has been made in the study of glaucoma, especially primary open angle glaucoma(POAG). A series of POAG genes has been identified through genetic linkage analysis and genome-wide association studies(GWAS), which significantly advanced the study of glaucoma genetics. The latest perspective suggests that glaucoma is a disease of the central nervous system(CNS). A large number of basic clinical studies have demonstrated the close association between CNS disease and glaucoma. Among these studies, discoveries related to genetics are of prominence.

Identification and functional analysis of a novel phospholipase D2 gene mutation associated with familial systemic lupus erythematosus / 中南大学学报(医学版)

OBJECTIVES@#Systemic lupus erythematosus (SLE) is a kind of autoimmune inflammatory connective tissue disease which seriously endangers human health. Genetic factors play a key role in the pathogenesis of SLE. This study aims to investigate a novel phospholipase D2 (PLD2) mutation associated with familial SLE, and further explore the underlying mechanism of the mutation in SLE.@*METHODS@#The blood samples from a SLE patient, the patient's parents, and 147 normal controls were collected and DNA was extracted. Whole genome high-throughput sequencing was performed in the patient and her parents and the results were further analyzed by various bioinformatics methods. The wild type (wt), mutant type (mu), and negative control PLD2 plasmids were further constructed and transfected into 293 cells. The expression level of HRAS protein in 293 cells was detected by Western blotting.@*RESULTS@#In this SLE family, the female SLE patient and her mother, 1 in generation II and 1 in generation III had typical clinical manifestations of SLE, and all of them had lupus nephritis at early stage. The genetic characteristics are consistent with autosomal dominant inheritance. A novel PLD2 heterozygous mutation (c.2722C>T) was found in the patient and her mother, but not in her father and other normal controls. Compared with wtPLD2 plasmid and negative control PLD2 plasmid, the expression of HRAS in 293 cells transfected with muPLD2 plasmid was significantly up-regulated (both @*CONCLUSIONS@#PLD2 c.2722C>T mutation may be one of the pathogeny of SLE in this family.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma / 医学前沿

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Alelos asociados al índice de severidad de la enfermedad Mal de Río Cuarto en germoplasma exótico de maíz / Alleles associated to disease severity index of Mal de Río Cuarto disease in maize exotic germplasm

RESUMEN El Mal de Río Cuarto (MRC) es una de las enfermedades virales más importantes del maíz en Argentina. El índice de severidad de enfermedad (ISE) permite combinar la incidencia y la severidad de una enfermedad en una métrica única. La reacción genotípica a MRC ha sido muy estudiada en poblaciones biparentales, sin embargo este carácter complejo no se ha analizado mediante estudios de mapeo por asociación. El objetivo del presente trabajo es identificar nuevos alelos de resistencia asociados con el ISE de la enfermedad MRC de maíz en un germoplasma exótico del Centro Internacional de Mejoramiento de Maíz y Trigo (CIMMYT). Una población de líneas de maíz del CIMMYT se evaluó fenotípicamente en ambientes donde la enfermedad es endémica. Los predictores del efecto genotípico (BLUP, best linear unbiased predictor) del ISE de MRC y 78.376 marcadores SNP (Single Nucleotide Polymorphism) se usaron para realizar el mapeo por asociación en 186 líneas de maíz. Los componentes de varianza y los valores de heredabilidad sugieren una amplia variabilidad genotípica en la población de líneas. El mapeo por asociación permitió identificar 11 posibles QTL de resistencia a MRC. La incorporación de germoplasma exótico en los programas de mejoramiento de maíz locales podría contribuir favorablemente a la creación de genotipos híbridos con mayor nivel de resistencia a MRC. La capacidad predictiva de los marcadores asociados con la resistencia a MRC indican que la selección asistida por marcadores es una herramienta recomendable para seleccionar genotipos resistentes a MRC.

ABSTRACT Mal de Río Cuarto (MRC) is one of the most important viral diseases of maize in Argentina. The disease severity index (DSI) allows to combine the incidence and severity of a disease in a single metric. The genotypic reaction to MRC has been extensively studied in biparental populations. However, this complex trait has not been analyzed by genome-wide association studies (GWAS). The aim of this work is to identify new resistance alleles associated with DSI of MRC in an exotic germplasm from the International Maize and Wheat Improvement Center (CIMMYT). A population of maize lines from CIMMYT was phenotypically evaluated in environments in the area where the disease is endemic. The predictors of genetic effects (BLUP, best linear unbiased predictor) and 78,376 SNP markers (Single Nucleotide Polymorphism) were used to perform the GWAS in 186 maize lines. The values of variance components and mean-basis heritability suggest a wide genotypic variability in the population. The GWAS allowed to identify 11 putative QTL of resistance to MRC. The incorporation of exotic germplasm into local maize breeding programs could contribute favorably to the creation of hybrids with a higher level of resistance to MRC. The predictive ability of associated markers with MRC resistance indicates that marker-assisted selection is an advisable tool for selecting MRC resistant genotypes.

Obesity subtypes, related biomarkers & heterogeneity

Obesity is a serious medical condition worldwide, which needs new approaches and recognized international consensus in treating diseases leading to morbidity. The aim of this review was to examine heterogeneous links among the various phenotypes of obesity in adults. Proteins and associated genes in each group were analysed to differentiate between biomarkers. A variety of terms for classification and characterization within this pathology are currently in use; however, there is no clear consensus in terminology. The most significant groups reviewed include metabolically healthy obese, metabolically abnormal obese, metabolically abnormal, normal weight and sarcopenic obese. These phenotypes do not define particular genotypes or epigenetic gene regulation, or proteins related to inflammation. There are many other genes linked to obesity, though the value of screening all of those for diagnosis has low predictive results, as there are no significant biomarkers. It is important to establish a consensus in the terminology used and the characteristics attributed to obesity subtypes. The identification of specific molecular biomarkers is also required for better diagnosis in subtypes of obesity.

Evaluating the effect of WNT pathway genes considering interactions on the risk of non-syndromic oral clefts among Chinese populations / 北京大学学报(医学版)

OBJECTIVE@#In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction.@*METHODS@#We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction.@*RESULTS@#A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios.@*CONCLUSION@#Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.

Genome-wide characterization of the abscisic acid-, stress- and ripening-induced (ASR) gene family in wheat (Triticum aestivum L)

BACKGROUND: Abscisic acid-, stress-, and ripening-induced (ASR) genes are a class of plant specific transcription factors (TFs), which play important roles in plant development, growth and abiotic stress responses. The wheat ASRs have not been described in genome-wide yet. METHODS: We predicted the transmembrane regions and subcellular localization using the TMHMM server, and Plant-mPLoc server and CELLO v2.5, respectively. Then the phylogeny tree was built by MEGA7. The exon-intron structures, conserved motifs and TFs binding sites were analyzed by GSDS, MEME program and PlantRegMap, respectively. RESULTS: In wheat, 33ASR genes were identified through a genome-wide survey and classified into six groups. Phylogenetic analyses revealed that the TaASR proteins in the same group tightly clustered together, compared with those from other species. Duplication analysis indicated that the TaASR gene family has expanded mainly through tandem and segmental duplication events. Similar gene structures and conserved protein motifs of TaASRs in wheat were identified in the same groups. ASR genes contained various TF binding cites associated with the stress responses in the promoter region. Gene expression was generally associated with the expected group-specific expression pattern in five tissues, including grain, leaf, root, spike and stem, indicating the broad conservation of ASR genes function during wheat evolution. The qRT-PCR analysis revealed that several ASRs were up-regulated in response to NaCl and PEG stress. CONCLUSION: We identified ASR genes in wheat and found that gene duplication events are the main driving force for ASR gene evolution in wheat. The expression of wheat ASR genes was modulated in responses to multiple abiotic stresses, including drought/osmotic and salt stress. The results provided important information for further identifications of the functions of wheat ASR genes and candidate genes for high abiotic stress tolerant wheat breeding.

Research progress of GWAS in hyperuricemia / 公共卫生与预防医学

Hyperuricemia is a chronic disease caused by the imbalance of uric acid synthesis and excretion, which is influenced by both environmental and genetic factors. The results of genome-wide association analysis related to hyperuricemia in different regions during the past decade have shown that genes related to hyperuricemia may be region- specific. This article summarizes the genes detected by GWAS, and describes some of the involved molecular mechanisms. The genes related to hyperuricemia shared by people in Europe, Asia, Africa and South America, and genes related to hyperuricemia unique to Asian populations are reviewed in this article. In addition, some of the genes’ functions are discussed to enhance the understanding of the pathogenesis of hyperuricemia.