Distinct Single Nucleotide Polymorphisms Research Articles

Uncovering the genetic diversity and adaptability of Butuo Black Sheep through whole-genome re-sequencing.

The Butuo Black Sheep (BBS) is well-known for its ability to thrive at high altitudes, resist diseases, and produce premium-quality meat. Nonetheless, there is insufficient data regarding its genetic diversity and population-specific Single nucleotide polymorphisms (SNPs). This paper centers on the genetic diversity of (BBS). The investigation conducted a whole-genome resequencing of 33 BBS individuals to recognize distinct SNPs exclusive to BBS. The inquiry utilized bioinformatic analysis to identify and explain SNPs and pinpoint crucial mutation sites. The findings reveal that reproductive-related genes (GHR, FSHR, PGR, BMPR1B, FST, ESR1), lipid-related genes (PPARGC1A, STAT6, DGAT1, ACACA, LPL), and protein-related genes (CSN2, LALBA, CSN1S1, CSN1S2) were identified as hub genes. Functional enrichment analysis showed that genes associated with reproduction, immunity, inflammation, hypoxia, PI3K-Akt, and AMPK signaling pathways were present. This research suggests that the unique ability of BBS to adapt to low oxygen levels in the plateau environment may be owing to mutations in a variety of genes. This study provides valuable insights into the genetic makeup of BBS and its potential implications for breeding and conservation efforts. The genes and SPNs identified in this study could serve as molecular markers for BBS.

Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline.

Cognitive abilities tend to decline with aging, with variation between individuals, and many studies seek to identify genetic biomarkers that more accurately anticipate risks related to pathological aging. We investigated the influence of BDNF, NTRK2, and FNDC5 single nucleotide polymorphisms (SNPs) on the cognitive performance of young and older adults with contrasting educational backgrounds. We addressed three questions: (1) Is education associated with reduced age-related cognitive decline? (2) Does the presence of SNPs explain the variation in cognitive performance observed late in life? (3) Is education differentially associated with cognition based on the presence of BDNF, NTRK2, or FNDC5 polymorphisms? We measured the cognitive functions of young and older participants, with lower and higher education, using specific and sensitive tests of the Cambridge Automated Neuropsychological Test Assessment Battery. A three-way ANOVA revealed that SNPs were associated with differential performances in executive functions, episodic memory, sustained attention, mental and motor response speed, and visual recognition memory and that higher educational levels improved the affected cognitive functions. The results revealed that distinct SNPs affect cognition late in life differentially, suggesting their utility as potential biomarkers and emphasizing the importance of cognitive stimulation that advanced education early in life provides.

Fatal hepatic sarcocystosis in three captive and one free-ranging pinniped

Fatal hepatic sarcocystosis was diagnosed as the cause of death in four pinnipeds: two captive Hawaiian monk seals (Monachus schauinslandi), a captive, and a free-ranging California sea lion (Zalophus californianus). Based on necropsy, histopathology, electron microscopy and DNA sequencing, intralesional protozoal schizonts were determined to have caused the necrotizing hepatitis observed. Transmission Electron Microscopy (TEM) revealed schizonts similar to Sarcocystis canis in hepatocytes. PCR-DNA sequencing and phylogenetic analysis at the conserved 18S rRNA and variable ITS1 gene markers within the nuclear rRNA gene array from schizont-laden tissue established that the parasites were indistinguishable from Sarcocystis canis at the 18S rRNA locus. However, six distinct single nucleotide polymorphisms (SNPs) were resolved at ITS1 suggesting that the parasites infecting pinnipeds were distinct from S. canis, which commonly infects bears and dogs. We hypothesize that the parasite represents a novel Sarcocystis variant that we refer to as S. canis-like that infects pinnipeds. The definitive host of S. canis is enigmatic and its life cycle incomplete. These findings document a critical need to identify the life cycle(s), definitive host(s), and all susceptible marine and terrestrial intermediate hosts of S. canis and the S. canis-like variant infecting pinnipeds.

Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study.

The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk. Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.

Using Mendelian randomization analysis to determine the causal connection between unpleasant emotions and coronary atherosclerosis.

Observational studies have shown a correlation between unpleasant emotions and coronary atherosclerosis, but the underlying causal linkages are still uncertain. We conducted a Mendelian randomization (MR) investigation on two samples for this purpose. In genome-wide association studies in the UK Biobank (total = 459,561), we selected 40 distinct single-nucleotide polymorphisms (SNPs) related to unpleasant emotions as genome-wide statistically significant instrumental variables. FinnGen consortium provided summary-level data on coronary atherosclerosis for 211,203 individuals of Finnish descent. MR-Egger regression, the inverse variance weighted technique (IVW), and the weighted median method were used in the process of conducting data analysis. There was sufficient evidence to establish a causal connection between unpleasant emotions and coronary atherosclerosis risk. For each unit increase in the log-odds ratio of unpleasant feelings, the odds ratios were 3.61 (95% CI: 1.64-7.95; P = 0.001). The outcomes of sensitivity analyses were comparable. There was no indication of heterogeneity or directional pleiotropy. Our findings provide causal evidence for the effects of unpleasant emotions on coronary atherosclerosis.

Polymorphisms of Placental Iodothyronine Deiodinase Genes in a Rural Area of Northern China with High Prevalence of Neural Tube Defects

Introduction: We have reported that high total homocysteine and the coexistence of inadequate thyroid hormones in maternal serum increase the risk of fetal neural tube defects (NTDs). Placental iodothyronine deiodinases (DIOs: DIO1, DIO2, and DIO3) play a role in regulating the conversions between different forms of maternal thyroid hormones. This study hypothesized that single nucleotide polymorphisms (SNPs) in placental DIOs genes could be related to NTDs. Methods: We performed a case-control study from 2007 to 2009 that included pregnant women from Lüliang, Shanxi Province, China. Nine distinct SNPs in DIOs genes were analyzed, and placental samples were obtained from 83 pregnant women with NTD fetuses and 90 pregnant women with normal fetuses. The nine SNPs were analyzed using the Cochran-Armitage test and the Fisher’s exact test. Results: There were no statistically significant differences between case and control in the nine SNPs of DIOs (p > 0.05). Conclusions: The results of this study suggested that SNPs of DIO genes in the placenta among pregnant women have no statistically significant difference between the two groups, suggesting that other factors might be involved in metabolism of maternal thyroid hormone provided to fetuses, such as epigenetic modification of methylation and homocysteinylation and genomic imprinting in the placenta. Further functional studies on placenta samples are necessary.

Association of three single nucleotide polymorphisms of interleukin -35 for detection and prediction of women with breast cancer in Erbil city

Association of three single nucleotide polymorphisms of interleukin -35 for detection and prediction of women with breast cancer in Erbil city

Circulating fatty acids and risk of primary open-angle glaucoma: A mendelian randomization study.

The relationship between fatty acids (FAs) and glaucoma remains controversial despite several observational studies. We organized a mendelian randomization (MR) study to determine the genetic causal association between circulating FAs and primary open-angle glaucoma (POAG). The two-sample MR method was used to acquire causal estimates. Fourteen distinct single nucleotide polymorphisms (SNPs) of ten FAs were chosen as instrumental variables (IVs) at a genome-wide significance level (p < 5 × 10-8). Summary statistics for POAG were available from a genome-wide association meta-analysis of 216,257 individuals of European ancestry (16,677 cases, 199,580 controls). The inverse-variance weighted (IVW) method was adopted to evaluate the causality of FAs and POAG. Multiple sensitivity analyses were applied to avoid pleiotropy. The IVW method suggested no evidence to support causal effects of ten FAs on POAG. The odds ratio (OR) per one SD increment of each FA was ORALA = 1.64 (95% CI, 0.441-6.098, p = 0.46), OREPA = 0.815 (95% CI, 0.604-1.101, p = 0.182), ORDPA = 0.896 (95% CI, 0.669-1.198, p = 0.458), ORDHA = 1.014 (95% CI, 0.801-1.283, p = 0.91), ORLA = 1.008 (95% CI, 0.971-1.045, p = 0.683), ORAA = 0.993 (95% CI, 0.973-1.013, p = 0.483), ORPOA = 0.731 (95% CI, 0.261-2.048, p = 0.551), OROA = 1.048 (95% CI, 0.934-1.175, p = 0.425), ORPA = 1.039 (95% CI, 0.903-1.196, p = 0.593), ORSA = 0.967 (95% CI, 0.879-1.062, p = 0.477). Moreover, Sensitivity analysis indicated no pleiotropy. This MR study does not support causal associations between ten FAs and POAG.

Single-Cell Transcriptomics for Residual Disease Detection in Acute Myelogenous Leukemia Post Allogeneic Hematopoietic Cell Transplantation

Detection of residual disease is a critical component of modern, risk-adapted therapy for Acute Myeloid Leukemia (AML). However, the genetic and phenotypic diversity of AML has made the development of a universal assay for disease assessment particularly challenging. While purely mutation-based tests promise high sensitivity, they are not broadly applicable given molecular heterogeneity and complex clonal evolution. Single-cell approaches, such as multiparameter flow cytometry (MFC), are more broadly applicable and increasingly accepted as the standard in clinical care. However, the limited number of leukemia-specific cell-surface markers and high numbers of shared markers between malignant myeloid blasts and healthy progenitors make MFC data extremely challenging to interpret. Motivated to develop a broadly applicable assay that can provide a more confident assessment of residual disease, we developed a platform using droplet-partitioned single-cell RNA sequencing accompanied by a computational pipeline specifically tailored to quantify residual disease after allogeneic HCT (alloHCT).With bone marrow samples from an 11-year-old patient with suspected post-alloHCT relapse of AML, we interrogated three methods of sample processing, 1) RBC lysis, 2) Ficoll-centrifugation, and 3) Ficoll-centrifugation combined with CD34+ immunomagnetic selection. The samples were further split to separately capture the 3' or 5' end of polyadenylated transcripts. The six resulting libraries were sequenced using standard short-read sequencing, and reads were demultiplexed and counted using common workflows. Data from the samples were combined, and sub-populations were visualized using UMAP (see Figure).This study demonstrated the feasibility of real-time single-cell sequencing for clinical utility. It is possible to process, capture, and sequence a patient's sample in approximately three working days (A). By integrating our data with single-cell expression profiles from an atlas of healthy human bone marrow, we were able to identify cells with gene-expression programs distinct from those of normal hematopoietic cells (B). With these integrated data, we could clearly identify populations of cells that embed away from healthy atlas cells (yellow circle, B), defining a different than normal single-cell profile. This “malignant” profile also included several genes whose expression is usually restricted to healthy hematopoietic progenitors (Panel C), suggesting these cells had a severely dysregulated transcriptome. As this patient was post-alloHCT, we interrogated the abundance of single-nucleotide-polymorphisms (SNPs) in the sequence data. We quantified these SNPs in single cells to distinguish each cell as either of donor or recipient origin using a method we have previously validated for genotyping RNA sequence in single cells. We clearly demonstrate that those cells identified as “different than normal” have a distinct SNP profile suggesting they are of recipient origin. Further analysis revealed that this malignant population was highly enriched for a population of cells expressing a previously described set of “AML-restricted genes” (Huang, B. et al., ASH 2021). (Panel E). Finally, from the Ficoll-processed sample, we quantified a level of 9.8% residual disease (243 malignant cells from a total of 2487). Notably, the number of abnormal myeloid progenitors determined by MFC was 2.0% which increased to 13% on a subsequent marrow sample drawn one week later. Incidentally, we observed only minimal differences across the two single-cell sequencing chemistries (3' vs. 5').Taken together, our data strongly argue that droplet-based, single-cell RNA sequencing is a feasible and powerful tool for the ascertainment of residual disease in AML. Given the robust nature of the platform and the ability to incorporate SNP integration into the analytic pipeline, it allows confident detection of residual disease in the post-alloHCT setting. By combining genomic quantification of transcripts with the power of SNP-based genotyping all at the level of the single cells, we believe this technology can substantially improve our diagnosis of post-alloHCT AML relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Single-Nucleotide Polymorphism Associates' β-Tubulin Isotype-1 Gene in Onchocerca volvulus Populations in Ivermectin-Treated Communities in Taraba State, Nigeria.

The occurrence of Single-Nucleotide Polymorphisms (SNPs) associated with repeated ivermectin treatment and sub-optimal responses reported by previous findings is of great concern in Onchocerciasis endemic areas. This study investigated SNPs' occurrence after 15years of ivermectin intervention in Onchocerciasis endemic communities in two Local Government Areas of Taraba State, Nigeria. Microfilariae samples were collected by skin snip from individuals treated with ivermectin for 10-15years of annual distribution and preserved in RNAlater® in a 1.5ml micro-centrifuge tube. Genomic DNA was extracted from microfilariae and residual skin, amplification in two regions within the β-tubulin gene, sequenced and analyzed for SNPs using Bioinformatics tools. Three distinct SNP positions: 1183 (T/G), 1188 (T/C) and 1308 (C/T) on the β-tubulin gene on the targeted 1083-1568bp fragment, associate's with the ivermectin-treated population. Furthermore, SNPs positions detected in this study are 1730 (A/G) and 1794 (T/G) in the β-tub gene in the 1557-1857 (bp) region. The 1794 (T/G) SNP position (Phe243Val) in the exon within the β-tubulin gene region were observed in this study. The present study indicates that SNPs are observed in Onchocerca volvulus, thus strengthening the warning that genetic changes could occur in some parasite populations in some ivermectin-treated areas.

GENETIC POLYMOPRHISMS MAY DIFFERENTIATE BETWEEN COMPLICATED PEDIATRIC SMALL BOWEL VERSUS COLONIC CROHN’S DISEASE

Abstract Objectives About 9% of pediatric Crohn’s disease (CD) patients experience complications within 3 years from diagnosis in spite of anti-Tumor Necrosis Factor-alpha (anti-TNF) biologic treatment. Within 5 years, such complications may require surgical interventions in up to 20% of cases. Due to the relatively rare nature of these complicated pediatric CD cases within large CD cohorts, traditional genome wide association studies (GWAS) rarely capture this patient population. Our aim was to identify critical genetic associations of anti-TNF refractory complicated pediatric CD subtypes. Methods The study was approved by BCM IRB. Included patients had developed CD between the ages of 6 and 18. The Paris classification was used to place patients in the following categories: 1. Anti-TNF refractory small bowel CD (RSB-CD): L4b; L4b/B2; or L4b/B2B3 who had or were imminent to have small bowel resection. 2.. Anti-TNF refractory colonic CD (RC-CD): L2 requiring ileal diversion; or L2/B2; or L2/B2B3 who had or were considered to receive colectomy or partial colonic resection. Whole-exome sequencing (WES) was performed from peripheral blood derived DNA. PLINK (https://www.cog-genomics.org/plink2/) was used to identify enriched single nucleotide polymorphisms (SNPs). The level of significance for exome wide differentiation was relaxed to p&amp;lt;0.01. The potential deleteriousness of single nucleotide variants was determined by CADD (https://cadd.gs.washington.edu/). Gene Ontology enRIchment anaLysis and visuaLizAtion tool (GORILLA) was used to compare gene lists associated with colonic enriched SNPs versus ileal enriched SNPs (http://geneontology.org/). Results In eight RSB-CD and 11 RC-CD cases, age at presentation, gender, ethnicity, and need for surgery (75% and 55%, respectively) did not significantly differ between the groups. There were 269 genes associated with 277 SNPs that had significantly (p&amp;lt;0.01) different allele variation between colonic vs ileal CD. Of these, 170 genes associated with 116 distinct SNPs had a CADD score of &amp;gt;10. Out of the top five SNP candidate associated genes, four (4/5 = 80%: EFNA3, STEAP1B, DSG1, and CYP4F2) have been already linked with Crohn’s disease and/or colitis. GORILLA based investigation indicated that colonic CD associated genes were enriched (p&amp;lt;0.001) in biologic function relevant for lipid metabolic process (GO:0006629), small molecule metabolic process (GO:0044281), and organic substance metabolic process (GO:0071704) compared to ileal CD associated genes. Conclusions We have uncovered candidate genetic risk loci, which may differentially influence pediatric CD towards developing primarily small intestinal or colonic complications. The discovered loci hold significant potential as novel genetic modifiers, which may set the basis for risk assessment, prevention and personalized treatment against complicated pediatric CD.

Associations Between Genetic Variants near the CHREBP Locus and Lipoprotein Concentrations May Be Modified by Sugar-Sweetened Beverage Consumption

Abstract Objectives Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Consumption of sugar-sweetened beverages (SSB) and genetic variants at the CHREBP (also known as MLXIPL) locus have separately been linked to dyslipidemia. We hypothesized that SSB intake may modify the associations between CHREBP variants and HDL-C and TG concentrations. Methods We conducted a cross-sectional analysis of data from 11 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium cohorts (N = 63,599). A total of 1606 single-nucleotide polymorphisms (SNPs) were selected within or near the CHREBP locus. SSB intake (sodas, fruit punches, lemonades, or other fruit drinks) was estimated from food-frequency questionnaires. Participants were grouped by five categories of SSB intake (ranging from &amp;lt; 1 serving/month to &amp;gt; 1 serving/day). Inverse-variance weighted fixed- and random-effect meta-analyses were used to quantify the following associations: 1) SSB consumption and HDL-C and TG concentrations; 2) selected SNPs and HDL-C and TG concentrations; and 3) interactions between SSB consumption and selected SNPs, and HDL-C and TG concentrations. Results were corrected for multiple testing to achieve a global p &amp;lt; 0.05. Results SSB intake was inversely associated with HDL-C and positively associated with TG concentrations (ptrend &amp;lt; 0.0001). We replicated previously observed GWAS associations between one distinct SNP on HDL-C (rs71556736) and two distinct SNPs (rs71556736 and rs13225660) on TG concentrations (Bonferroni-corrected P &amp;lt; 0.0001). Additionally, we identified two distinct novel SNP associations with TG concentrations (rs42124 and rs10245965). One distinct SNP displayed a statistically significant difference in effect size by category of SSB intake with HDL-C, where each additional minor allele at rs71556729 was significantly associated with HDL-C concentrations only among the highest SSB consumers [&amp;gt;1 serving/day: β (SE) = 4.47 (1.10) mg/dl, P = 5.0E-05; pinteract = 0.0001]. Additional SNPs displayed a suggestive difference in effect size for both HDL-C and TG concentrations. Conclusions Our results indicate that high SSB consumption may modify the association between genetic variants within or near the CHREBP locus and HDL-C and TG concentrations. Funding Sources NIH, AHA, USDA-ARS.

Genotyping of immune-related loci associated with delayed HBeAg seroconversion in immune-active chronic hepatitis B patients

The progression of chronic hepatitis B (CHB) is associated with single-nucleotide polymorphisms (SNPs). In this study, we demonstrated the association between immune-related SNPs and delayed spontaneous HBeAg seroconversion in immune-active CHB patients. In addition, we investigated the impact of delayed spontaneous HBeAg seroconversion-related SNPs on HBeAg seroconversion within 3 years during antiviral treatment. We enrolled 332 CHB patients and genotyped 124 SNPs associated with HBV-infected clinical outcomes, including 32 interleukin-related genes, 62 HLA genes, 9 CD marker genes, 7 NK cell receptor genes, and 14 other genes, using ABI OpenArray as a platform. Comparing the immune-active CHB patients with delayed spontaneous HBeAg seroconversion (persistent HBeAg seropositivity, older than 40 years) to those with early inefficient HBeAg seroconversion (HBeAg seroconversion with high viremia, younger than 40 years), logistic analysis revealed that rs3820998 (TANK), rs2621377 (HLA-DOB), rs3130215 (HLA-DPB2), rs2255336 (KLRK1), and rs11614913 (MIR-196A2) were significantly associated with delayed spontaneous HBeAg seroconversion. Using multivariate analysis, we determined that high serum HBV DNA levels (OR = 1.66, 95% CI = 1.33–2.08), rs3820998 (CA, OR = 3.37, 95% CI = 1.24–9.12), rs2621377 (TC, OR = 4.96, 95% CI = 1.85–13.3), rs2255336 (TT, OR = 0.09, 95% CI = 0.01–0.86), and rs11614913 (TT, OR = 2.53, 95% CI = 1.05–6.11) were five independent risk factors for delayed spontaneous HBeAg seroconversion. After patients received nucleos(t)ide analogue treatment, rs3820998 heterozygous CA variant conversely became the only independent favorable factor for treatment-induced HBeAg seroconversion within 3 years (OR = 0.21, 95% CI = 0.06–0.78). These results indicate that distinct immune-related SNPs play a vital role in regulating HBeAg status in immune-active CHB patients with or without antiviral treatment.

Phylogenomic structure of Bacillus anthracis isolates in the Northern Cape Province, South Africa revealed novel single nucleotide polymorphisms

Bacillus anthracis, the aetiological agent of anthrax, is regarded as a highly monomorphic pathogen that presents a low genetic diversity using standard molecular techniques. Whole genome sequencing and single nucleotide polymorphisms (SNPs) are definitive signatures for subtyping of B. anthracis. Here we employed whole genome single nucleotide polymorphism (wgSNP) analysis to investigate the genetic diversity of B. anthracis in the historically endemic region of Northern Cape Province (NCP), South Africa. Twenty-six isolates from anthrax outbreaks that occurred between 1998 and 2008/9 in NCP as well as from Namibia-South Africa Transfontier Conservation area and Botswana were compared to global B. anthracis genomes. Most NCP B. anthracis strains (n = 22) clustered in the A.Br.003/004 (A.Br.101) branch and are closely related to the Zimbabwe and Mozambique strains (A.Br.102 branch). A total of 4923 parsimony informative-SNPs accurately established the A.Br.003/004 phylogenetic relationships of the NCP isolates into two distinct sub-clades and SNP markers designated as A.Br.172 and A.Br.173 were developed. Other NCP strains (n = 2) grouped in the A.Br.001/002 (Sterne) branch while strains (n = 2) from the Namibia-South Africa Transfontier Conservation area and Botswana clustered in A.Br.005/006 (Ancient A) branch. The sequenced B. anthracis strains (A0094, A0096 and A0097) that clustered in the A.Br.064 (V770) clade were isolated from Vaalbos National Park and similar strains have not been isolated. The B. anthracis A0088 strain cluster with the NCP strains in the A.Br.003/004 (A.Br.172) SNP branch which has been isolated in NCP, South Africa. This study highlights the phylogenetic structure of NCP B. anthracis strains with distinctive SNP branches important for forensic tracing and novel SNP discovery purposes. The sequenced strains will serve as a means to further trace the dissemination of B. anthracis outbreaks in NCP, South Africa, and on the continent, as well as for forensic tracking on a global scale.

Abstract 1370: Germinal immunogenetics predicts treatment outcome for PD1 PD-L1 checkpoint inhibitors

Abstract Background Checkpoint inhibitors (CPIs) benefit only a proportion of patients and may be associated with severe adverse events (AEs) which cannot be predicted. We hypothesized that the host genetics could be used as predictive biomarkers for CPI response and AE prediction. Therefore, we conducted a study based on single nucleotide polymorphisms (SNPs) from genes affiliated with immune response and tumor-microenvironment interaction. Methods Germinal DNA was obtained from advanced cancer patients treated with anti PD-1/PD-L1 CPIs in the Centre Antoine Lacassagne (Nice, France) from July 2012 to January 2018. DNA was genotyped on the MassARRAY system (Agena Bioscience®) using a custom panel of 166 SNPs covering 86 preselected immunogenetic-related genes (Minor allele frequency MAF&amp;gt;0.05 in Caucasians). All tested SNPs were in Hardy-Weinberg equilibrium. Univariate analysis was performed to select the significant SNPs (p&amp;lt;0.05) by either Fisher or Ki2 tests. Treatment outcome prediction was based on an elastic-net penalized logistic regression with 5-fold cross validation. The predictive ability model was performed using a concordance (c)-index (c-index &amp;gt; 0.5 being considered as good prediction). Computational analysis using a GTEX portal was used to determine potential eQTL (expression Quantitative Trait Loci) in tissues. Results 94 patients were identified, with median age 68 (32-85), 67% male, with a majority (51%) having advanced non-small cell lung cancer. Median follow-up was 16.3 months (95% CI: 12.5-18.3). Overall response rate (ORR) was observed in 49/94 (54%) of patients, with adverse events (grade 3-4) observed in 15/94 (16%) of patients. ORR was significantly predicted by tumor microenvironment related gene polymorphisms (CCL2, NOS3, IL1RN, IL12B, CXCR3, IL6R). In contrast, grade 3-4 AEs were linked to target-related gene SNPs (UNG, IFNW1, CTLA-4, PD-L1, IFNL4). The predictive (c)-index was 0.81 (95% CI: 0.72-0.9) for response and 0.89 (95% CI: 0.76-1.00) for toxicity. In silico functionality exploring (GTEX portal) pointed IL6R (rs4845618) and CTLA4 (rs3087243) as impacting gene expression. Conclusion Our data strongly support the role of distinct SNPs in immunogenetic related genes to predict efficacy and safety of anti PD1/PD-L1 therapies. These data support the notion that patient-specific, germinal biomarkers may supplement tumor-specific biomarkers in predicting response to CPI therapy, and that additional germinal biomarkers may predict grade 3-4 AEs. Citation Format: Sadal REFAE, Jocelyn GAL, Nathalie EBRAN, Josiane OTTO, Delphine BORCHIELLINI, Frederic Peyrade, Emmanuel CHAMOREY, Patrick Brest, Gerard Alain Milano, Esma SAADA-BOUZID. Germinal immunogenetics predicts treatment outcome for PD1 PD-L1 checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1370.

Genome-wide association study identifies the PLAG1-OXR1 region on BTA14 for carcass meat yield in cattle.

Carcass meat yield is an important carcass trait that contributes to the production efficiency and economic benefits in beef cattle. It is therefore critical to identify quantitative trait loci associated with carcass traits to enable selection. Our previous studies have identified several causal variants within the pleomorphic adenoma gene 1 (PLAG1) and coiled-coil-helix-coiled-coil-helix domain-containing 7 (CHCHD7) genes on BTA14 for carcass traits in Chinese Simmental. In the current study, we carried out a genome-wide association study for carcass meat yield in 472 Wagyu cattle with Bovine HD SNP array. Our results showed that 27 single nucleotide polymorphisms (SNPs) were identified for tenderloin weight (TDW), striploin weight (SPW), chuck roll weight (CRW), bicep weight (BPW), knuckle weight (KCW), and flank steak weight (FSW) in Wagyu cattle. Of these SNPs, 10 distinct SNPs were detected within the oxidation resistance 1 (OXR1), fatty acid binding protein 5 (FABP5), TNF receptor superfamily member 11b (TNFRSF11B), and zinc finger CCCH-type containing 3 (ZC3H3) genes on BTA14. Notably, three significant SNPs, BovineHD1400016738, BovineHD1400016743, and BovineHD1400016665 within OXR1, were shown strong linkage disequilibrium (r2 > 0.8) and significantly associated with CRW (P = 1.37 × 10-8 ~ 1.94 × 10-8). Moreover, Ingenuity Pathway Analysis showed that OXR1, FABP5, and CAP1A genes were involved in a single network and FABP5 may regulate the expression of OXR1 gene via node gene, peroxisome proliferator-activated receptor gamma (PPARG). Overall, this study suggests that OXR1 and FABP5 are candidate genes affecting carcass traits in Wagyu and the PLAG1-OXR1 region on BTA14 as a putative susceptibility locus for carcass meat yield for both Chinese Simmental and Wagyu.

Albendazole resistance induced in Ancylostoma ceylanicum is not due to single-nucleotide polymorphisms (SNPs) at codons 167, 198, or 200 of the beta-tubulin gene, indicating another resistance mechanism.

Mass drug administration has been implicated as the major cause of drug resistance in nematodes of ruminants. Single-nucleotide polymorphisms (SNPs) at codons 167, 198, and 200 of the beta-tubulin isotype 1 gene are associated with albendazole resistance mechanisms. Although drug resistance is suspected to occur in nematodes of the same order, at present, there is no evidence of a strong correlation between these canonical SNPs and albendazole resistancein hookworms. In the absence of a hookworm strain that is naturally resistant to albendazole, we produced an albendazole-resistant Ancylostoma ceylanicum strain by selective drug pressure. Restriction fragment length polymorphism-PCR (RFLP-PCR) was employed to identify the presence of SNPs previously associated with drug resistance in other nematodes. However, none of the benzimidazole resistance-associated SNPs known in other nematodes were found. A beta-tubulin isotype 1 gene mini-cDNA library was constructed to obtain the complete cDNA gene sequence for the analysis of the entire gene to identify distinct SNPs associated with resistance. Some SNPs were found, but the resulting sequences were not reproducibly detected among the different clones, preventing their association with the resistance mechanism. The parasitological and hematological parameters of the albendazole-resistant strain were characterized and compared to those of the sensitive strain. Although the albendazole-resistant strain was less adapted to its host, with fewer worms recovered, all other parameters analyzed were similar between both strains. The results of the present study indicate that the mechanism of albendazole resistance of the resistant strain described herein must differ from those that have previously been characterized. Thus, new mechanistic studies are needed in the future.

Genetic Determinants and Prediction of Antibiotic Resistance Phenotypes in Helicobacter pylori.

Helicobacter pylori is a major human pathogen. Diagnosis of H. pylori infection and determination of its antibiotic susceptibility still mainly rely on culture and phenotypic drug susceptibility testing (DST) that is time-consuming and laborious. Whole genome sequencing (WGS) has recently emerged in medical microbiology as a diagnostic tool for reliable drug resistance prediction in bacterial pathogens. The aim of this study was to compare phenotypic DST results with the predictions based on the presence of genetic determinants identified in the H. pylori genome using WGS. Phenotypic resistance to clarithromycin, metronidazole, tetracycline, levofloxacin, and rifampicin was determined in 140 clinical H. pylori isolates by E-Test®, and the occurrence of certain single nucleotide polymorphisms (SNPs) in target genes was determined by WGS. Overall, there was a high congruence of >99% between phenotypic DST results for clarithromycin, levofloxacin, and rifampicin and SNPs identified in the 23S rRNA, gyrA, and rpoB gene. However, it was not possible to infer a resistance phenotype for metronidazole based on the occurrence of distinct SNPs in frxA and rdxA. All 140 H. pylori isolates analysed in this study were susceptible to tetracycline, which was in accordance with the absence of double or triple nucleotide substitutions in the 16S rRNA gene.

Genotyping-by-Sequencing of Gossypium hirsutum Races and Cultivars Uncovers Novel Patterns of Genetic Relationships and Domestication Footprints.

Determining the genetic rearrangement and domestication footprints in Gossypium hirsutum cultivars and primitive race genotypes are essential for effective gene conservation efforts and the development of advanced breeding molecular markers for marker-assisted breeding. In this study, 94 accessions representing the 7 primitive races of G hirsutum, along with 9 G hirsutum and 12 Gossypium barbadense cultivated accessions were evaluated. The genotyping-by-sequencing (GBS) approach was employed and 146 558 single nucleotide polymorphisms (SNP) were generated. Distinct SNP signatures were identified through the combination of selection scans and association analyses. Phylogenetic analyses were also conducted, and we concluded that the Latifolium, Richmondi, and Marie-Galante race accessions were more genetically related to the G hirsutum cultivars and tend to cluster together. Fifty-four outlier SNP loci were identified by selection-scan analysis, and 3 SNPs were located in genes related to the processes of plant responding to stress conditions and confirmed through further genome-wide signals of marker-phenotype association analysis, which indicate a clear selection signature for such trait. These results identified useful candidate gene locus for cotton breeding programs.

102 Genome-Wide Analysis in Inbred Mice Identifies Distinct Single Nucleotide Polymorphisms Associated With Cerebral Vasospasm and Neurological Outcome Following Subarachnoid Hemorrhage

102 Genome-Wide Analysis in Inbred Mice Identifies Distinct Single Nucleotide Polymorphisms Associated With Cerebral Vasospasm and Neurological Outcome Following Subarachnoid Hemorrhage