Selected Single Nucleotide Polymorphisms Research Articles

STAT3 gain-of-function is not responsible for low total IgE levels in patients with autoimmune chronic spontaneous urticaria.

BackgroundThe pathogenesis of chronic spontaneous urticaria (CSU) has not been clarified entirely. Type IIb autoimmune chronic spontaneous urticaria (CSUaiTIIb) is a distinct subtype of CSU that is often difficult to treat and is connected to low levels of total IgE. Previous findings indicate that an enhanced signal transducer and activator of transcription 3 (STAT3) may be responsible for reduced IgE serum levels.ObjectiveOur aim was to investigate a possible underlying gain-of-function mutation or activating polymorphism in STAT3 that could be responsible for the low levels of IgE in patients with CSUaiTIIb.MethodsWe included 10 patients with CSUaiTIIb and low levels of IgE and sequenced selected single nucleotide polymorphisms (SNP) in STAT3 associated with common autoimmune diseases. Exon sequencing was performed for the most relevant exons of STAT3. To test for a gain-of-function of STAT3, we performed a phospho-specific flow cytometry analysis of STAT3 in peripheral blood mononuclear cells before and after stimulation with interleukin-6.ResultsNo differences were found in the prevalence of the tested SNPs between our patients and a control population. Moreover, we could not find any mutations or variants on the tested exons of STAT3. The function of STAT3 was also not altered in our patients.ConclusionIn total, we could not find any evidence for our hypothesis that low IgE in patients with CSUaiTIIb is linked to mutations in STAT3 or altered activity of STAT3. Thus, it remains to be discovered what causes the low serum levels of IgE in patients with CSUaiTIIb.

LmTag: functional-enrichment and imputation-aware tag SNP selection for population-specific genotyping arrays.

Despite the rapid development of sequencing technology, single-nucleotide polymorphism (SNP) arrays are still the most cost-effective genotyping solutions for large-scale genomic research and applications. Recent years have witnessed the rapid development of numerous genotyping platforms of different sizes and designs, but population-specific platforms are still lacking, especially for those in developing countries. SNP arrays designed for these countries should be cost-effective (small size), yet incorporate key information needed to associate genotypes with traits. A key design principle for most current platforms is to improve genome-wide imputation so that more SNPs not included in the array (imputed SNPs) can be predicted. However, current tag SNP selection methods mostly focus on imputation accuracy and coverage, but not the functional content of the array. It is those functional SNPs that are most likely associated with traits. Here, we propose LmTag, a novel method for tag SNP selection that not only improves imputation performance but also prioritizes highly functional SNP markers. We apply LmTag on a wide range of populations using both public and in-house whole-genome sequencing databases. Our results show that LmTag improved both functional marker prioritization and genome-wide imputation accuracy compared to existing methods. This novel approach could contribute to the next generation genotyping arrays that provide excellent imputation capability as well as facilitate array-based functional genetic studies. Such arrays are particularly suitable for under-represented populations in developing countries or non-model species, where little genomics data are available while investment in genome sequencing or high-density SNP arrays is limited. $\textrm{LmTag}$ is available at: https://github.com/datngu/LmTag.

Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study

Multiple sclerosis (MS) is a neurodegenerative disease characterized by a variable clinical course and diverse pathophysiology, including nitrative and oxidative stresses as well as inflammation. We aimed to detect the potential association between five selected single-nucleotide polymorphisms (SNPs) in genes encoding nitric oxide synthetases as well as antioxidant enzymes and the development of MS in a Polish population. Genomic DNA was isolated from peripheral blood collected from 142 MS patients and 140 controls. Using Taq-Man® probes, we genotyped the following SNPs: rs1879417 in NOS1, and rs2297518 in NOS2 as well as rs4880 in SOD2, rs7943316 in CAT, rs713041 in GPX4. In the case of rs2297518, the C/C genotype and C allele SNP were associated with an enhanced occurrence of MS, while the C/T, T/T genotypes, and T allele of the same polymorphism reduced this risk. Moreover, the C/C homozygote and C allele of the rs4880 SNP reduced MS risk, while the T allele increased the risk. In addition, the A/T heterozygote of rs7943316 polymorphism was associated with an increased risk of MS occurrence. We also detected that the C/C genotype and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased this risk. In conclusion, the results of our study suggest some links between polymorphic variability in the nitrative/oxidative stress-related genes and the risk of MS development in the Polish population.

Genetically Predicted Milk Intake Increased Femoral Neck Bone Mineral Density in Women But Not in Men.

BackgroundCow milk contains more calcium, magnesium, potassium, zinc, and phosphorus minerals. For a long time, people have believed that increasing milk intake is beneficial to increasing bone density. Many confounding factors can affect milk consumption, and thus the association described to date may not be causal. We explored the causal relationship between genetically predicted milk consumption and Bone Mineral Density (BMD) of the femoral neck and lumbar spine based on 53,236 individuals from 27 studies of European ancestry using the Mendelian randomization (MR) study. 32,961 individuals of European and East Asian ancestry were used for sensitivity analysis.MethodsA genetic instrument used for evaluating milk consumption is rs4988235, a locus located at 13,910 base pairs upstream of the LCT gene. A Mendelian randomization (MR) analysis was conducted to study the effect of selected single nucleotide polymorphisms (SNPs) and BMD. The summary-level data for BMD of the femoral neck and lumbar spine were obtained from two GWAS meta-analyses [‘Data Release 2012’ and ‘Data Release 2015’ in the GEnetic Factors for OSteoporosis Consortium (GEFOS)].Resultswe found that genetically predicted milk consumption was not associated with FN-BMD(OR 1.007; 95% CI 0.991–1.023; P = 0.385), LS-BMD(OR 1.003; 95% CI 0.983–1.024; P = 0.743) by performing a meta-analysis of several different cohort studies. High levels of genetically predicted milk intake were positively associated with increased FN-BMD in Women. The OR for each additional milk intake increasing allele was 1.032 (95%CI 1.005–1.059; P = 0.014). However, no causal relationship was found between milk consumption and FN-BMD in men (OR 0.996; 95% CI 0.964–1.029; P = 0.839). Genetically predicted milk consumption was not significantly associated with LS-BMD in women (OR 1.017; 95% CI 0.991–1.043; P = 0.198) and men (OR 1.011; 95% CI 0.978–1.045; P = 0.523).ConclusionOur study found that women who consume more milk have a higher FN-BMD. When studying the effect of milk consumption on bone density in further studies, we need to pay more attention to women.

Informative SNP Selection Based on a Fuzzy Clustering and Improved Binary Particle Swarm Optimization Algorithm.

Single-nucleotide polymorphism (SNP) involves the replacement of a single nucleotide in a deoxyribonucleic acid (DNA) sequence and is often linked to the development of specific diseases. Although current genotyping methods can tag SNP loci within biological samples to provide accurate genetic information for a disease associated, they have limited prediction accuracy. Furthermore, they are complex to perform and may result in the prediction of an excessive number of tag SNP loci, which may not always be associated with the disease. Therefore in this manuscript, we aimed to evaluate the impact of a newly optimized fuzzy clustering and binary particle swarm optimization algorithm (FCBPSO) on the accuracy and running time of informative SNP selection. Fuzzy clustering and FCBPSO were first applied to identify the equivalence relation and the candidate tag SNP set to reduce the redundancy between loci. The FCBPSO algorithm was then optimized and used to obtain the final tag SNP set. The prediction performance and running time of the newly developed model were compared with other traditional methods, including NMC, SPSO, and MCMR. The prediction accuracy of the FCBPSO algorithm was always higher than that of the other algorithms especially as the number of tag SNPs increased. However, when the number of tag SNPs was low, the prediction accuracy of FCBPSO was slightly lower than that of MCMR (add prediction accuracy values for each algorithm). However, the running time of the FCBPSO algorithm was always lower than that of MCMR. FCBPSO not only reduced the size and dimension of the optimization problem but also simplified the training of the prediction model. This improved the prediction accuracy of the model and reduced the running time when compared with other traditional methods.

Polymorphisms in lncRNA CCAT1 on the susceptibility of lung cancer in a Chinese northeast population: A case-control study.

To explore the association of rs1948915, rs7013433 in long noncoding RNA (lncRNA) CCAT1 and rs6983267 in MYC enhancer region with the risk of lung cancer in a Chinese northeast population, a case-control study was conducted. The hospital-based case-control study contained 669 lung cancer patients and 697 healthy controls. Taqman® Probe allele resolution was used for genotyping. The differences between the case-control groups were analyzed using Student t-test and chi-square test. Logistic regression analysis was used to assess the relationship between the genotypes and the risk of lung cancer. Cross-generation analysis was used to explore the relationship between gene-environment interaction and lung cancer. There was no association between the three selected single-nucleotide polymorphisms (SNPs) and the susceptibility of lung cancer. Rs1948915 CT was correlated with lung adenocarcinoma. In female stratification, rs1948915 CT/CC was associated with a decreased susceptibility of lung cancer significantly. Additionally, the additive and multiplicative interaction models showed that there was no interaction between the three selected SNPs and smoking status in lung cancer. There may be an association between lung adenocarcinoma and rs1948915 polymorphism in the Chinese northeast population, while rs7013433 and rs6983267 might have no association. There was no interaction between the three selected SNPs and smoking status.

Analysis of selected polymorphisms in FOXP3 gene in a cohort of Egyptian patients with schizophrenia

BackgroundSchizophrenia is a chronic mental disorder with different symptoms. The environmental and genetic factors are suggested to be the etiology of schizophrenia. However, the exact cause and pathogenesis of schizophrenia are still unclear. Different studies suggested that the immune system may have a role in schizophrenia. A genetic study found a relation between the disease and the HLA region on the sixth chromosome. Regulatory T cells (Treg) have a role in the regulation of immune response, especially the balance between TH1 and TH2 cells. The FOXP3 protein is a key regulator for Treg cell’s functions. FOXP3 is a transcriptional factor, and its gene is present on the short arm of the X chromosome. The selected SNPs present in the promoter region which act as binding sites for transcriptional factors. This study investigated FOXP3 gene polymorphisms (rs3761548, rs3761549, and rs2232365) in Egyptian patients with schizophrenia. There are no previous studies about the association of FOXP3 gene polymorphisms with schizophrenia. The three selected single-nucleotide polymorphisms (SNPs) were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 125 schizophrenia patients and 160 healthy controls. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate patients with schizophrenia. ResultsNo significant associations were found between schizophrenia patients and healthy controls for the alleles and genotypes of the selected SNPs (P-value > 0.05). However, a significant association with ACC and ATC haplotypes was detected (P-value 0.001). No significant association was detected between the PANSS score and any of the studied SNPs. ConclusionThe ATC haplotype of rs2232365, rs3761549, and rs3761548 could be considered a risk factor for schizophrenia in Egyptian patients.

Type 2 Diabetes-Related Variants Influence the Risk of Developing Prostate Cancer: A Population-Based Case-Control Study and Meta-Analysis.

Simple SummaryWe investigated the influence of GWAS-identified variants for T2D in modulating prostate cancer (PCa) risk through a meta-analysis of our data with those from the UKBiobank and FinnGEn cohorts and four large European cohorts. We found that genetic variants within the FTO, HNF1B, and JAZF1 loci were associated with PCa risk. Our results also suggested, for the first time, a potentially interesting association of SNPs within NOTCH2 and RBMS1 genes that need to be further explored and validated. This study also shed some light onto the functional mechanisms behind the observed associations, and demonstrated that the HNF1Brs7501939 polymorphism correlated with lower levels of SULT1A1, an enzyme responsible for the sulfate conjugation of multiple endogenous and exogenous compounds. Furthermore, we found that SNPs within the HFN1B, NOTCH2, and RBMS1 genes impacted PCa risk through the modulation of mRNA gene expression levels of their respective genes. However, given the healthy nature of the subjects included in the cohort used for functional experiments, the link between the HNF1B locus and SULT1A1 should be considered still speculative and, therefore, requires further validation. In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10−5, p = 9.39 × 10−54, p = 5.04 × 10−54, p = 1.19 × 10−71, and p = 1.66 × 10−18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10−4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.

Causal Association Between Tea Consumption and Bone Health: A Mendelian Randomization Study.

BackgroundMuch observational research reported that tea consumption decreases the risk of osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis (OP) which are the three major bone disorders. However, the observed correlation is inconclusive. To determine the causal relationship between genetically predicted tea intake and OA, RA, and OP, we performed a two-sample Mendelian randomization (MR) study based on large samples.MethodsThe European population’s genome-wide association meta-analysis (GWAS) dataset identified SNPs associated with tea consumption was obtained from Neale Lab’s analysis of UK Biobank data that comprised 349,376 participants of European ancestry. We extracted genetic data for knee OA (17,885 controls and 4,462 cases), hip OA (50,898 controls and 12,625 cases), and RA (43,923 controls and 14,361 cases) from the UK Biobank and OP cases (93083 controls and 1,175 cases) from FinnGen Data Freeze 2. A MR study was conducted to examine the effect of selected single nucleotide polymorphisms (SNPs) and OA, RA, and OP risk. Several sensitivity analyses were performed with weighted median and inverse-variance weighted methods for estimating the causal effects.ResultsIn this MR study, the genetically predicted per one cup increase of tea consumption was not associated with knee OA (OR 1.11,95% CI: 0.79–1.55) using IVW with random effect. Genetic predisposition to tea consumption was not associated with hip OA (OR: 1.20, 95% CI: 0.84–1.71), RA (OR: 1.24 95% CI: 0.81–1.91), and OP (OR: 1.11, 95% CI: 0.89, 1.39). Following the sensitivity analysis, there was no potential pleiotropy.ConclusionAccording to our study, According to our study, there was no statistical power to confirm a causal relationship between tea consumption and the risk of knee OA, hip OA, RA, and OP.

The Pharmacogenetics of Opiates and Its Impact on Delirium in Mechanically Ventilated Adults: A Pilot Study.

Background: Pharmacogenetics may explain a substantial proportion of the variation seen in the efficacy and risk profile of analgesosedative drugs and the incidence of delirium in critically ill adults. Objectives: Conduct a feasibility study to demonstrate the reliability of collecting and analyzing pharmacogenetic information from critically ill patients and to assess the impact of pharmacogenetics on intensive care unit (ICU) outcomes. Methods: We prospectively enrolled subjects from the Medical ICU at the University of North Carolina (UNC). DNA was obtained via a buccal swab and evaluated using the DNA2Rx assay. We collected data on demographics, daily cumulative psychoactive medication exposure, and severity of illness. We performed daily delirium assessments via the CAM-ICU. We analyzed associations between select single nucleotide polymorphisms (SNPs) and delirium. Results: From June, 2018 through January, 2019, we screened 244 patients and enrolled 50. The median age was 62.0 years old (range: 28-82 years old), and 27 (54%) of the subjects were female. In all, 49 (98%) samples were both high quality and sufficient quantity. In secondary analyses, we found that 80% (12/15) of patients with two 2 copies of a G allele at rs4680 on COMT experienced delirium, whereas 44% (4/9) of patients with 2 copies of an A allele at this location had delirium. In all, 44% (4/9) of patients with 2 T allele copies at rs7439366 on UGT2B7 experienced delirium compared to 73% (11/15) of patients with 2 C allele copies at this location. Conclusions: We can feasibly collect genetic information from critically ill adults. We were able to efficiently collect high quality DNA of sufficient quantity to conduct pharmacogenetic analysis in this critically ill population. Although the sample size of our current study is too small to conduct robust inferential analyses, it suggests potential SNP targets for a future larger study.

Development and validation of polygenic risk scores for prediction of breast cancer and breast cancer subtypes in Chinese women

BackgroundStudies investigating breast cancer polygenic risk score (PRS) in Chinese women are scarce. The objectives of this study were to develop and validate PRSs that could be used to stratify risk for overall and subtype-specific breast cancer in Chinese women, and to evaluate the performance of a newly proposed Artificial Neural Network (ANN) based approach for PRS construction.MethodsThe PRSs were constructed using the dataset from a genome-wide association study (GWAS) and validated in an independent case-control study. Three approaches, including repeated logistic regression (RLR), logistic ridge regression (LRR) and ANN based approach, were used to build the PRSs for overall and subtype-specific breast cancer based on 24 selected single nucleotide polymorphisms (SNPs). Predictive performance and calibration of the PRSs were evaluated unadjusted and adjusted for Gail-2 model 5-year risk or classical breast cancer risk factors.ResultsThe primary PRSANN and PRSLRR both showed modest predictive ability for overall breast cancer (odds ratio per interquartile range increase of the PRS in controls [IQ-OR] 1.76 vs 1.58; area under the receiver operator characteristic curve [AUC] 0.601 vs 0.598) and remained to be predictive after adjustment. Although estrogen receptor negative (ER−) breast cancer was poorly predicted by the primary PRSs, the ER− PRSs trained solely on ER− breast cancer cases saw a substantial improvement in predictions of ER− breast cancer.ConclusionsThe 24 SNPs based PRSs can provide additional risk information to help breast cancer risk stratification in the general population of China. The newly proposed ANN approach for PRS construction has potential to replace the traditional approaches, but more studies are needed to validate and investigate its performance.

SNP Discovery Using BSR-Seq Approach for Spot Blotch Resistance in Wheat (Triticum aestivum L.), an Essential Crop for Food Security.

The pathogenic fungus, Bipolaris sorokiniana, that causes spot blotch (SB) disease of wheat, is a major production constraint in the Eastern Gangetic Plains of South Asia and other warm, humid regions of the world. A recombinant inbred line population was developed and phenotyped at three SB-prone locations in India. The single nucleotide polymorphism (SNP) for SB resistance was identified using a bulked segregant RNA-Seq-based approach, referred to as “BSR-Seq.” Transcriptome sequencing of the resistant parent (YS#24), the susceptible parent (YS#58), and their resistant and susceptible bulks yielded a total of 429.67 million raw reads. The bulk frequency ratio (BFR) of SNPs between the resistant and susceptible bulks was estimated, and selection of SNPs linked to resistance was done using sixfold enrichments in the corresponding bulks (BFR >6). With additional filtering criteria, the number of transcripts was further reduced to 506 with 1055 putative polymorphic SNPs distributed on 21 chromosomes of wheat. Based on SNP enrichment on chromosomal loci, five transcripts were found to be associated with SB resistance. Among the five SB resistance-associated transcripts, four were distributed on the 5B chromosome with putative 52 SNPs, whereas one transcript with eight SNPs was present on chromosome 3B. The SNPs linked to the trait were exposed to a tetra-primer ARMS-PCR assay, and an SNP-based allele-specific marker was identified for SB resistance. The in silico study of these five transcripts showed homology with pathogenesis-related genes; the metabolic pathway also exhibits similar results, suggesting their role in the plant defense mechanism.

Genetic variation of six specific SNPs of chronic obstructive pulmonary disease among Chinese population

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic bronchitis (or) emphysema with a high disability and fatality rate. This study aimed to explore the correlation between the six selected single nucleotide polymorphisms (SNPs) and the risk of COPD in the Chinese population. MethodsThe Agena MassARRAY platform was used to select six SNPs from 629 subjects for genotyping. The correlation between SNPs and COPD risk was evaluated using calculated odds ratios (ORs) and 95% confidence intervals (CIs). Multi-factor dimensionality reduction (MDR) was performed to analyze the impact of SNP interactions on COPD risk. Multiple comparisons were performed using Bonferroni- correction. ResultsOur results indicated that rs4719841 and rs7934083 variants were associated with a reduced risk of COPD. The analysis results of age, gender and non-smokers showed that rs4719841 and rs7934083 were associated with reducing the risk of COPD. In addition, the results showed that the genetic models of rs4719841, rs7934083 and rs7780562 were related to the forced vital capacity, respiratory rate per second, and respiratory rate / forced vital capacity of COPD patients, respectively. The results of the MDR analysis showed that the three-locus model (rs4719841, rs7934083, and rs78750958) is the best for COPD risk assessment. ConclusionThis study shows that rs4719841 and rs7934083 are associated with the risk of COPD in the Chinese population, which provides some insights for early screening, prevention, and diagnosis of COPD in high-risk populations.

Association of Genetic Variability in Selected Genes with Platelet Hyperaggregability and Arterial Thrombosis

Abstract Introduction: Inherited platelet hyperaggregability, so called “Sticky platelet syndrome” (SPS), is a prothrombotic platelet disorder. The syndrome contributes more often to arterial than venous thrombosis. The most common localization of arterial occlusion involves cerebral or coronary arteries. However, SPS may also lead to thrombosis in the atypical sites of the circulation. This qualitative platelet alteration causes platelet hyperaggregability after a very low concentration of platelet inducers – adenosine diphosphate (ADP) and/or epinephrine (EPI). The precise genetic background of the syndrome has not been defined. In the present study we aimed to determine the association between selected single nucleotide polymorphisms (SNPs) within genes for platelet endothelial aggregation receptor 1 (PEAR1) and murine retrovirus integration site 1 (MRVI1) and the risk for arterial thrombosis in patients with SPS. The products of these selected genes play an important role in platelet aggregation. Patients and methods: We examined 69 patients with SPS and a history of arterial thrombosis and 69 healthy blood donors who served as controls. SPS was confirmed by a light transmission aggregometry (LTA) according to the method and criteria described by Mammen and Bick. We assessed two SNPs within PEAR1 gene (rs12041331, rs1256888) and two SNPs within MRVI1 gene (rs1874445, rs7940646). Results: Selected PEAR1 and MRVI1 polymorphisms seem not to be a risk factor for the development of SPS as the syndrome with an arterial thrombosis phenotype. However, in the subgroup of SPS1 patients there was found a decreased frequency of the minor A allele of SNP rs12041331 in PEAR1 gene (borderline p value, p=0.061) that can be hypothesized as protective against arterial thrombosis. In the same SPS1 subgroup the haplotype TA in PEAR1 gene also showed a decreased frequency with a borderline insignificance (p=0.056). We can theorize also about its protective role in SPS1 patients. We did not confirm the protective effect of polymorphism (T/T of rs 12566888) in PEAR1 against arterial thrombosis in SPS patients and SPS subgroups. Conclusion: Our results support the idea that examined genetic variability of the selected SNPs in PEAR1 and MRVI1 genes is not associated with platelet hyperaggregability manifested as arterial thrombosis. The possible protective role of the minor A allele of SNP rs12041331 as well as a role of haplotype TA in PEAR1 gene related to the arterial thrombosis found in the subgroup of SPS1 patients needs to be verified in further research.

Selection of Genome-Wide SNPs for Pooled Allelotyping Assays Useful for Population Monitoring.

Parasitic worms are serious pests of humans, livestock, and crops worldwide. Multiple management strategies are employed in order to reduce their impact, and some of these may affect their genome and population allelic frequency distribution. The evolution of chemical resistance, ecological changes, and pest dispersal has allowed an increasing number of pests to become difficult to control with current management methods. Their lifestyle limits the use of ecological and individual-based management of populations. There is a need to develop rapid, affordable, and simple diagnostics to assess the efficacy of management strategies and delay the evolution of resistance to these strategies. This study presents a multilocus, equal-representation, whole-genome pooled single nucleotide polymorphisms (SNPs) selection approach as a monitoring tool for the ovine nematode parasite Haemonchus contortus. The SNP selection method used two reference genomes of different quality, then validated these SNPs against a high-quality recent genome assembly. From over 11 million high-quality SNPs identified, 334 SNPs were selected, of which 262 were species-specific, yielded similar allele frequencies when assessed as multiple individuals or as pools of individuals, and suitable to distinguish mixed nematode isolate pools from single isolate pools. As a proof-of-concept, 21 Australian H. contortus populations with various phenotypes and genotypes were screened. This analysis confirmed the overall low level of genetic differentiation between populations collected from the field, but clearly identifying highly inbred populations, and populations showing genetic signatures associated with chemical resistance. The analysis showed that 66% of the SNPs were necessary for stability in assessing population genetic patterns, and SNP pairs did not show linkage according to allelic frequencies across the 21 populations. This method demonstrates that ongoing monitoring of parasite allelic frequencies and genetic changes can be achieved as a management assessment tool to identify drug-treatment failure, population incursions, and inbreeding signatures due to selection. The SNP selection method could also be applied to other parasite species.

An early prediction model for chronic kidney disease

Based on the high incidence of chronic kidney disease (CKD) in recent years, a better early prediction model for identifying high-risk individuals before end-stage renal failure (ESRD) occurs is needed. We conducted a nested case–control study in 348 subjects (116 cases and 232 controls) from the “Tianjin Medical University Chronic Diseases Cohort”. All subjects did not have CKD at baseline, and they were followed up for 5 years until August 2018. Using multivariate Cox regression analysis, we found five nongenetic risk factors associated with CKD risks. Logistic regression was performed to select single nucleotide polymorphisms (SNPs) from which we obtained from GWAS analysis of the UK Biobank and other databases. We used a logistic regression model and natural logarithm OR value weighting to establish CKD genetic/nongenetic risk prediction models. In addition, the final comprehensive prediction model is the arithmetic sum of the two optimal models. The AUC of the prediction model reached 0.894, while the sensitivity was 0.827, and the specificity was 0.801. We found that age, diabetes, and normal high values of urea nitrogen, TGF-β, and ADMA were independent risk factors for CKD. A comprehensive prediction model was also established, which may help identify individuals who are most likely to develop CKD early.

Genetic Susceptibility Toward Nausea and Vomiting in Surgical Patients.

Postoperative nausea and vomiting (PONV) are frequently occurring adverse effects following surgical procedures. Despite predictive risk scores and a pallet of prophylactic antiemetic treatments, it is still estimated to affect around 30% of the patients, reducing their well-being and increasing the burden of post-operative care. The aim of the current study was to characterize selected genetic risk factors of PONV to improve the identification of at risk patients. We genotyped 601 patients followed during the first 24 h after surgery for PONV symptoms in the absence of any antiemetic prophylaxis. These patients were recruited in the frame of a randomized, placebo controlled clinical study aiming to test the efficacy of dexamethasone as a treatment of established PONV. We examined the impact of selected single nucleotide polymorphisms (SNPs) located around 13 different genes and the predicted activity of 6 liver drug metabolizing enzymes from the cytochromes P450 family (CYP) on the occurrence and recurrence of PONV. Our genetic study confirms the importance of genetic variations in the type 3B serotonin receptor in the occurrence of PONV. Our modelling shows that integration of rs3782025 genotype in preoperative risk assessments may help improve the targeting of antiemetic prophylaxis towards patients at risk of PONV.

Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC.

In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

Association between SNPs of Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1)and the susceptibility to chronic Hepatitis C infection in virus C-infected patients

BackgroundCytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are immune inhibitory factors that provide inhibitory signals to T cells. MethodsA case-controlled genetic association study was conducted in478 patients (160 patients with chronic Hepatitis C virus (HCV) and diabetes mellitus (DM) and156 patients with chronic HCV without DM) and162healthy controls. We genotyped selected single nucleotide polymorphisms (SNPs) of rs10204525 and rs231775using real-time-polymerase chain reaction (RT-PCR). ResultsOur study revealed thatthers10204525 CT genotype was significantly associated with a high susceptibility to chronic HCV infection and to HCV+DM (adjusted odds ratio (OR)7.531, 95% confidence interval (CI):4.099–13.836, P < 0.0001 and adjusted OR 7.791, 95% CI:4.244–14.303, P < 0.0001, respectively).In addition, the frequency of CT+TT genotypes versus the CC genotype and the T allele versus the C allele were elevated in non-responder patients to antiviral therapy compared with responder patients (P < 0.0001) in HCV group. For rs231775,the AG genotype was significantly associated with a high susceptibility to chronic HCV infection and HCV infection with DM (adjusted OR 5.124,95% CI:3.150–8.334, P < 0.0001 and adjusted OR 20.594, 95% CI:11.026–38.467, P < 0.0001, respectively).Furthermore, the frequency of AG+GG genotypes versus the CC genotype and the G allele versus the A allele was elevated in non-responder patients to antiviral therapy when compared with responder patients in the HCV and HCV+DM groups(P < 0.05). ConclusionsBoth rs10204525 and rs231775 are associated with a risk of chronic HCV, with or without DM.

Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations.

Genome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genomes of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on tag SNPs and to generate an internal population-specific imputation reference panel, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed add-on tags to the base H3Africa array.