Association Of Single Nucleotide Polymorphisms Research Articles

Association of TP53 Single Nucleotide Polymorphisms with Prostate Cancer in a Racially Diverse Cohort of Men.

Growing evidence indicates the involvement of a genetic component in prostate cancer (CaP) susceptibility and clinical severity. Studies have reported the role of germline mutations and single nucleotide polymorphisms (SNPs) of TP53 as possible risk factors for cancer development. In this single institutional retrospective study, we identified common SNPs in the TP53 gene in AA and CA men and performed association analyses for functional TP53 SNPs with the clinico-pathological features of CaP. The SNP genotyping analysis of the final cohort of 308 men (212 AA; 95 CA) identified 74 SNPs in the TP53 region, with a minor allele frequency (MAF) of at least 1%. Two SNPs were non-synonymous in the exonic region of TP53: rs1800371 (Pro47Ser) and rs1042522 (Arg72Pro). The Pro47Ser variant had an MAF of 0.01 in AA but was not detected in CA. Arg72Pro was the most common SNP, with an MAF of 0.50 (0.41 in AA; 0.68 in CA). Arg72Pro was associated with a shorter time to biochemical recurrence (BCR) (p = 0.046; HR = 1.52). The study demonstrated ancestral differences in the allele frequencies of the TP53 Arg72Pro and Pro47Ser SNPs, providing a valuable framework for evaluating CaP disparities among AA and CA men.

Integrin Subunit Alpha M, ITGAM Nonsynonymous SNP Is Associated with Knee Osteoarthritis among Thais: A Case-Control Study

Knee osteoarthritis (OA), which is one of the most common degenerative joint diseases, presents a multifactorial etiology, involving multiple causative factors including genetic and environmental determinants. Four human neutrophil antigen (HNA) systems can be determined using each HNA allele by single-nucleotide polymorphisms (SNPs). However, there are no data on HNA polymorphisms and knee OA in Thailand, so we investigated the association of HNA SNPs and knee OA in the Thai population. In a case-control study, detection of HNA-1, -3, -4, and -5 alleles by polymerase chain reaction with sequence-specific priming (PCR-SSP) was performed in participants with and without symptomatic knee OA. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence interval (CI) between cases and controls. Among 200 participants, 117 (58.5%) had knee OA; 83 (41.5%) did not and were included as controls in this study. An integrin subunit alpha M (ITGAM) nonsynonymous SNP, rs1143679, was markedly associated with symptomatic knee OA. The ITGAM*01*01 genotype was identified as an important increased risk factor for knee OA (adjusted OR = 5.645, 95% CI = 1.799-17.711, p = 0.003). These findings may contribute to our understanding of the application prospects for therapeutic approaches to knee OA.

Association of single nucleotide polymorphisms with dyslipidemia and risk of metabolic disorders in the State of Qatar.

Dyslipidemia is recognized as one of the risk factors of cardiovascular diseases (CVDs), type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD). The study aimed to investigate the association between selected single nucleotide polymorphisms (SNPs) with dyslipidemia and increased susceptibility risks of CVD, NAFLD, and/or T2DM in dyslipidemia patients in comparison with healthy control individuals from the Qatar genome project. A community-based cross-sectional study was conducted among 2933 adults (859 dyslipidemia patients and 2074 healthy control individuals) from April to December 2021 to investigate the association between 331 selected SNPs with dyslipidemia and increased susceptibility risks of CVD, NAFLD and/or T2DM, and covariates. The genotypic frequencies of six SNPs were found to be significantly different in dyslipidemia patients subjects compared to the control group among males and females. In males, three SNPs were found to be significant, the rs11172113 in over-dominant model, the rs646776 in recessive and over-dominant models, and the rs1111875 in dominant model. On the other hand, two SNPs were found to be significant in females, including rs2954029 in recessive model, and rs1801251 in dominant and recessive models. The rs17514846 SNP was found for dominant and over-dominant models among males and only the dominant model for females. We found that the six SNPs linked to gender type had an influence in relation to disease susceptibility. When controlling for the four covariates (gender, obesity, hypertension, and diabetes), the difference between dyslipidemia and the control group remained significant for the six variants. Finally, males were three times more likely to have dyslipidemia in comparison with females, hypertension was two times more likely to be present in the dyslipidemia group, and diabetes was six times more likely to be in the dyslipidemia group. The current investigation provides evidence of association for a common SNP to coronary heart disease and suggests a sex-dependent effect and encourage potential therapeutic applications.

Association of Single-Nucleotide Polymorphisms in the VDR Gene with Tuberculosis and Infection of Beijing Genotype Mycobacterium tuberculosis.

The aim of the present study was to investigate the association between vitamin D receptor (VDR) gene polymorphism and tuberculosis susceptibility, as well as the potential interaction of host genetic factors with the heterogeneity of Mycobacterium tuberculosis in the population from Xinjiang, China. From January 2019 to January 2020, we enrolled 221 tuberculosis patients as the case group and 363 staff with no clinical symptoms as the control group from four designated tuberculosis hospitals in southern Xinjiang, China. The polymorphisms of Fok I, Taq I, Apa I, Bsm I, rs3847987 and rs739837 in the VDR were detected by sequencing. M. tuberculosis isolates were collected from the case group and identified as Beijing or non-Beijing lineage by multiplex PCR. Propensity score (PS), univariate analysis and multivariable logistic regression models were used to perform the analysis. Our results showed that the allele and genotype frequencies of Fok I, Taq I, Apa I, Bsm I, rs3847987 and rs739837 in VDR were not correlated with tuberculosis susceptibility or lineages of M. tuberculosis. Two out of six loci of the VDR gene formed one haplotype block, and none of the haplotypes was found to correlate with tuberculosis susceptibility or lineages of M. tuberculosis infected. Polymorphisms in the VDR gene may not indicate susceptibility to tuberculosis. There was also no evidence on the interaction between the VDR gene of host and the lineages of M. tuberculosis in the population from Xinjiang, China. Further studies are nonetheless required to prove our conclusions.

Demographic, clinical and genetic factors associated with COVID-19 disease susceptibility and mortality in a Kurdish population.

Coronavirus disease 2019 (COVID-19) is a devastating pandemic that causes disease with a variability in susceptibility and mortality based on variants of various clinical and demographic factors, including particular genes among populations. Determine associations of demographic, clinical, laboratory, and single nucleotide polymorphisms in the ACE2, TMPRSS2, TNF-α, and IFN-γ genes to the incidence of infection and mortality in COVID-19 patients. Prospective cohort study SETTINGS: Various cities in the Kurdistan Region of Iraq. This prospective cohort study compared laboratory markers (D-dimer, tumor necrosis factor-alpha [TNF-α], interferon-gamma [IFN-γ], C-reactive protein [CRP], lymphocyte and neutrophil counts) between COVID-19 patients and healthy controls. DNA was extracted from blood, and genotypes were done by Sanger sequencing. Single nucleotide polymorphisms of the ACE2, TMPRSS2, TNF-α, and IFN-γ genes and demographic characteristics and laboratory markers for predicting mortality in COVID-19. 203 (153 COVID-19 patients, 50 health control subjects). Forty-eight (31.4%) of the COVID-19 patients died. Age over 40 and comorbidities were risk factors for mortality, but the strongest associations were with serum IFN-γ, the neutrophil-to-lymphocyte ratio (NLR), and serum TNF-α. The AA genotype and A allele of TMPRSS2 rs2070788 decreased while the GA genotype and A allele of TNF-α increased susceptibility to COVID-19. Patients with the GA genotype of TNF-α rs1800629 had shorter survival times (9.9 days) than those carrying the GG genotype (18.3 days) (P<.0001 by log-rank test). The GA genotype versus the GG genotype was associated with higher levels of serum TNF-α. The GA genotype increased mortality rates by up to 3.8 fold. The survival rate for COVID-19 patients carrying the IFN-γ rs2430561 TT genotype (58.5%) was lower than in patients with the TA and AA genotypes (80.3%). The TT genotype increased the risk of death (HR=3.664, P<.0001) and was linked to high serum IFN-γ production. Olfactory dysfunction was a predictor of survival among COVID-19 patients. Age older than 40, comorbidities, the NLR and particular genotypes for and the IFN-γ and TNF-α genes were risk factors for death. Larger studies in different populations must be conducted to validate the possible role of particular SNPs as genetic markers for disease severity and mortality in COVID-19 disease. Small sample size. None.

Genetic diversity, population structure, and genome-wide association study for the flowering trait in a diverse panel of 428 moth bean (Vigna aconitifolia) accessions using genotyping by sequencing

BackgroundMoth bean (Vigna aconitifolia) is an underutilized, protein-rich legume that is grown in arid and semi-arid areas of south Asia and is highly resistant to abiotic stresses such as heat and drought. Despite its economic importance, the crop remains unexplored at the genomic level for genetic diversity and trait mapping studies. To date, there is no report of SNP marker discovery and association mapping of any trait in this crop. Therefore, this study aimed to dissect the genetic diversity, population structure and marker-trait association for the flowering trait in a diversity panel of 428 moth bean accessions using genotyping by sequencing (GBS) approach.ResultsA total of 9078 high-quality single nucleotide polymorphisms (SNPs) were discovered by genotyping of 428 moth bean accessions. Model-based structure analysis and PCA grouped the moth bean accessions into two subpopulations. Cluster analysis revealed accessions belonging to the Northwestern region of India had higher variability than accessions from the other regions suggesting that this region represents its center of diversity. AMOVA revealed more variations within individuals (74%) and among the individuals (24%) than among the populations (2%). Marker-trait association analysis using seven multi-locus models including mrMLM, FASTmrEMMA FASTmrEMMA, ISIS EM-BLASSO, MLMM, BLINK and FarmCPU revealed 29 potential genomic regions for the trait days to 50% flowering, which were consistently detected in three or more models. Analysis of the allelic effect of the major genomic regions explaining phenotypic variance of more than 10% and those detected in at least 2 environments showed 4 genomic regions with significant phenotypic effect on this trait. Further, we also analyzed genetic relationships among the Vigna species using SNP markers. The genomic localization of moth bean SNPs on genomes of closely related Vigna species demonstrated that maximum numbers of SNPs were getting localized on Vigna mungo. This suggested that the moth bean is most closely related to V. mungo.ConclusionOur study shows that the north-western regions of India represent the center of diversity of the moth bean. Further, the study revealed flowering-related genomic regions/candidate genes which can be potentially exploited in breeding programs to develop early-maturity moth bean varieties.

Correlation between Toll-like Receptor Gene Polymorphisms and Idiopathic Nephrotic Syndrome in Chinese Children.

Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. Toll-like receptors (TLRs) have been reported to be associated with response to steroid treatment in children with INS. Nevertheless, the correlation between TLR genes and the progression of INS has not yet been clarified. The present study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) in TLR2, TLR4, and TLR9 with susceptibility to INS as well as the clinical phenotyping of steroid responsiveness in Chinese children with INS. A total of 183 pediatric inpatients with INS were included and given standard steroid therapy. Based on their clinical response to steroids, the patients were classified into three groups: steroid-sensitive nephrotic syndrome (SSNS), steroid-dependent nephrotic syndrome (SDNS), and steroid-resistant nephrotic syndrome (SRNS). A total of 100 healthy children were employed as controls. The blood genome DNA was extracted from each participant. Six SNPs (rs11536889, rs1927914, rs7869402, rs11536891, rs352140, and rs3804099) in TLR2, TLR4, and TLR9 were selected and detected by multiplex polymerase chain reaction with next-generation sequencing to assess TLR gene polymorphisms. Among the 183 patients with INS, 89 (48.6%) had SSNS, 73 (39.9%) had SDNS, and 21 (11.5%) had SRNS. No significant difference was found in the genotype distribution between healthy children and patients with INS. However, the genotype and allele frequencies of TLR4 rs7869402 were significantly different between SRNS and SSNS. Compared with patients with the C allele and CC genotype, patients with the T allele and CT genotype had an increased risk of SRNS. TLR4 rs7869402 affected the steroid response in Chinese children with INS. It might be a predictor for the early detection of SRNS in this population.

Protection against Ischemic Heart Disease: A Joint Role for eNOS and the KATP Channel.

Genetic susceptibility may influence ischemic heart disease (IHD) predisposition and affect coronary blood flow (CBF) regulation mechanisms. The aim of this study was to investigate the association among single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in CBF regulation and IHD. A total of 468 consecutive patients were enrolled and divided into three groups according to coronary angiography and intracoronary functional tests results: G1, patients with coronary artery disease (CAD); G2, patients with coronary microvascular dysfunction (CMD); and G3, patients with angiographic and functionally normal coronary arteries. A genetic analysis of the SNPs rs5215 of the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene and rs1799983 of the nitric oxide synthase 3 (NOS3) gene, respectively encoding for the Kir6.2 subunit of ATP sensitive potassium (KATP) channels and nitric oxide synthase (eNOS), was performed on peripheral whole blood samples. A significant association of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 genes was detected in healthy controls compared with CAD and CMD patients. Based on univariable and multivariable analyses, the co-presence of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 may represent an independent protective factor against IHD, regardless of cardiovascular risk factors. This study supports the hypothesis that SNP association may influence the crosstalk between eNOS and the KATP channel that provides a potential protective effect against IHD.

Association of maternal hypertension and diabetes with variants of the NKX2-5, LEFTY1 and LEFTY2 genes in children with congenital heart defects: a case-control study from Pakistani Population.

Globally, congenital heart defect (CHD) is the most common congenital malformation, responsible for higher morbidity and mortality in the pediatric population. It is a complex multifactorial disease influenced by gene-environment and gene-gene interactions. The current study was the first attempt to study these polymorphisms in common clinical phenotypes of CHD in Pakistan and the association between maternal hypertension and diabetes with single nucleotide polymorphisms (SNPs) in children. A total of 376 subjects were recruited in this current case-control study. Six variants from three genes were analyzed by cost-effective multiplex PCR and genotyped by minisequencing. Statistical analysis was done by GraphPad prism and Haploview. The association of SNPs and CHD was determined using logistic regression. The risk allele frequency was higher in cases as compared to healthy subjects, but the results were not significant for rs703752. However, stratification analysis suggested that rs703752 was significantly associated with the tetralogy of Fallot. The rs2295418 was significantly associated with maternal hypertension (OR = 16.41, p = 0.003), while a weak association was present between maternal diabetes and rs360057 (p = 0.08). In conclusion, variants in transcriptional and signaling genes were associated with Pakistani pediatric CHD patients that showed varied susceptibility between different clinical phenotypes of CHD. In addition, this study was the first report regarding the significant association between maternal hypertension and the LEFTY2 gene variant.

Association of Methylenetetrahydrofolate Reductase Gene Polymorphism in Mothers With Adverse Clinical Outcomes in Neonates.

The presence of polymorphic methylenetetrahydrofolate reductase(MTHFR) in mothers poses a risk for numerous detrimental outcomes in neonates. The present study investigated the association of maternal MTHFR A1298C and C677T single nucleotide polymorphisms (SNPs) with the clinical outcomes in their neonates. The cross-sectional study included 60 mothers and their neonates. Blood samples from mothers were analyzed for MTHFR A1298C and C677T SNP genotyping by real-time polymerase chain reaction. Clinical details of mothers and neonates were documented. Study groups were stratified based on wild, heterozygous, and mutant genotypes for the respective polymorphisms observed in mothers. Multinomial regression was applied for the association, followed by gene model formulation to estimate the impact of the genetic variants on the outcomes. The frequency percentages of mutant CC1298 and TT677 genotypes were 25% and 8.06%, respectively, and the mutant allele frequencies (MAF) were 42.5% and 22.5%. Percentages of adverse outcomes such as intrauterine growth restriction, sepsis, anomalies, and mortality were higher in neonates born to mothers with homozygous mutant genotypes. Maternal C677T MTHFR SNPs revealed a significant association with neonatal anomalies (p = 0.001). The multiplicative risk model depicted OR (95% CI) for CT vs. CC+TT as 3.0 (95% CI: 0.66-13.7), and for TT vs. CT+CC was 15 (95% CI: 2.01-112.12). The C677T SNP in mothers predicted a dominant model for neonatal death (OR (95% CI): 5.84 (0.57-60.03), p = 0.15), whereas the A1298C reported recessive model for 1298CC mothers (OR (95% CI): 11 (1.05-115.5), p = 0.02). Both the genotypes assumed a recessive model for adverse neonatal outcomes: OR (95%CI) for CC vs. AA+ACwas 3.2 (0.79-12.9, p = 0.1), and for TT vs. CC+CT was 5.48 (0.57-175.7, p = 0.2). The risk for sepsis in neonates was nearly six times higher in those born from mothers with homozygous CC1298 and TT677 than in the wild and heterozygous variants. Mothers with C677T and A1298C SNPs are highly susceptible to adverse outcomes in their neonates. Hence, screening the SNPs during the antenatal period can purposefully serve as a better predictive marker, following which proper clinical management could be planned.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS

BackgroundThe study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. MethodsWe analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. ResultsNo SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LimitationsOur main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. ConclusionsOur results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Exogenous exposures shape genetic predisposition to lipids, Alzheimer's, and coronary heart disease in the MLXIPL gene locus.

Associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer's (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were examined in two samples of European ancestry from the US (22,712 individuals 587/2,608 AD/CHD cases) and the UK Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures. Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (βIE = 0.015, pIE = 1.9 × 10-3), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (βIE = 0.019, pIE = 8.6 × 10-4). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD.

Association of interleukin 33 gene polymorphisms with susceptibility and regulation of inflammatory mediators in Systemic lupus erythematosus patients.

Studies have indicated the involvement of interleukin (IL)-33 in the pathogenesis of Systemic lupus erythematosus (SLE). This research intended to evaluate the association of IL33 gene rs1929992 and rs7044343 Single nucleotide polymorphisms (SNPs) with risk of SLE. In addition, the association between these SNPs and inflammatory cytokines was determined. In this study, 200 SLE cases and 200 healthy subjects were recruited. Using allelic discrimination Real-time PCR, IL33 gene rs1929992 and rs7044343 SNPs were genotyped. The mRNA expression levels of IL-1β, IL-6, IL-33, TNF-α were determined in the peripheral blood mononuclear cells (PBMCs). The serum levels of cytokines were also measured. The G allele (OR = 1.57, CI: 1.18-2.08, P = 0.0017), GG genotype (OR = 2.52, CI: 1.33-4.77, P = 0.0043), and GA genotype (OR = 2.12, CI: 1.34-3.34, P = 0.0011) of rs1929992 SNP was significantly associated with an increased SLE risk. The C allele (OR = 1.44, CI: 1.08-1.90; P = 0.0105), CC genotype (OR = 2.07, CI: 1.15-3.71; P = 0.0146), and CT genotype (OR = 1.61, CI: 1.02-2.53, P = 0.0395) of rs7044343 was significantly associated with increased SLE risk. The PBMC mRNA expression and serum levels of IL-1β, IL-6, IL-33, TNF-α were significantly increased in the SLE patients compared to controls. However, there was no significant difference in the mRNA expression and serum levels of IL-1β, IL-6, IL-33, and TNF-α among the SLE patients with three genotypes for both rs1929992 and rs7044343 polymorphisms. IL33 gene rs1929992 and rs7044343 SNPs are involved in SLE pathogenesis but they might not influence on the inflammatory pathway.

Multi-Polymorphism Analysis Reveals Joint Effects in Males With Chronic Central Serous Chorioretinopathy.

Central serous chorioretinopathy (CSCR) is a leading cause of central vision impairment in the working-age population with male predilection. Knowledge about the genetic basis of CSCR and its male predilection remained limited. This study aimed to evaluate the association patterns of multiple gene variants in chronic CSCR (cCSCR) in Chinese patients. This case-control genetic association study included 531 patients with cCSCR and 2383 controls from two independent Chinese cohorts. Nine single-nucleotide polymorphisms (SNPs) of six genes, namely CFH, NR3C2, GATA5, VIPR2, TNFRSF10A, and ARMS2, were genotyped in all subjects. The main outcome measures were the association of individual single-nucleotide polymorphism (SNP) with cCSCR, the sex-stratification effects of individual SNP, and joint effects of different SNPs on cCSCR. Association results in the two cohorts were consistent with low heterogeneities. In the combined analysis, SNPs CFH rs800292 (odds ratio [OR] = 1.25, P = 0.0020), CFH rs1329428 (OR = 1.23, P = 0.0037), and TNFRSF10A rs13278062 (OR = 1.43, P = 0.0014) were significantly associated with cCSCR. In stratification analysis by sex, 3SNPs in CFH, rs3753394, rs800292, and rs1329428, were associated with cCSCR in male patients, but not in female patients. Joint analysis revealed that subjects homozygous for the risk alleles of CFH rs800292 and TNFRSF10A rs13278062 had over 4-fold of increased risk of cCSCR when compared with subjects homozygous for the non-risk alleles (OR = 4.06, P = 2.30 × 10-5). This study revealed main and joint effects of SNPs in CFH and TNFRSF10A on cCSCR, and suggested CFH as a potential genetic factor underlying the male predilection of cCSCR. Further replication in other study populations is needed.

The Associations of Single Nucleotide Polymorphisms of the COL3A1, COL6A5, and COL8A1 Genes with Atopic Dermatitis.

The pathophysiology of atopic dermatitis (AD) is complex, multifactorial, and not fully understood. Genes encoding collagens, the most abundant proteins in the extracellular matrix (ECM), may play a potential role in the pathogenesis of AD. Our study aimed to estimate the associations between Col3A1/rs1800255, Col6A5 /29rs12488457, and Col8A1/rs13081855 polymorphisms and the occurrence, course, and features of AD in the Polish population. Blood samples were collected from 157 patients with AD and 111 healthy volunteers. The genotype distribution of the investigated collagens genes did not differ significantly between the AD and control subjects (p > 0.05). The AA genotype of Col3A1/rs1800255 was significantly associated with the occurrence of mild SCORAD (OR = 0.16; 95% Cl: 0.03-0.78; p = 0.02) and mild pruritus (OR = 18.5; 95% Cl: 3.48-98.40; p = 0.0006), while the GG genotype was significantly associated with severe SCORAD (OR = 6.6; 95% Cl: 1.23-32.35; p = 0.03). Regarding Col6A5/29rs12488457 polymorphism, the average SCORAD score was significantly lower in the group of patients with genotype AA than in patients with the AC genotype (39.8 vs. 53.4; p = 0.04). Nevertheless, both average SCORAD scores were high, and represent the moderate and severe grades of the diseases, respectively. The single nucleotide polymorphisms (SNPs) of COL3A1/ rs1800255 and Col6A5/29rs12488457 seem to be associated with AD courses and symptoms, suggesting new disease biomarkers. The modulation of collagens, the major component of the ECM, may serve as a therapeutic target of AD in the future.

Systematic Review and Meta-Analyses of Aminopeptidases as Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the "C" allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.

The Study of the Association of Polymorphisms in LSP1, GPNMB, PDPN, TAGLN, TSPO, and TUBB6 Genes with the Risk and Outcome of Ischemic Stroke in the Russian Population

To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an analysis of the results obtained from animal models of brain ischemia could be helpful. To this end, we developed a bioinformatic approach for exploring single-nucleotide polymorphisms (SNPs) in human orthologs of rat genes expressed differentially after induced brain ischemia. Using this approach, we identified and analyzed 11 SNPs from 6 genes in 553 Russian individuals (331 patients with IS and 222 controls). We assessed the association of SNPs with the risk of IS and IS outcomes. We found that the SNPs rs858239 (GPNMB), rs907611 (LSP1), and rs494356 (TAGLN) were associated with different parameters of IS functional outcomes. In addition, the SNP rs1261025 (PDPN) was associated significantly with IS itself (p = 0.0188, recessive model). All these associations were demonstrated for the first time. Analysis of the literature suggests that they should be characterized as being inflammation related. This supports the pivotal role of inflammation in both the incidence of stroke and post-stroke outcomes. We believe the findings reported here will help with stroke prognosis in the future.

The association of paraoxonase 1 activities, serum mRNA expression and polymorphisms with in-stent coronary restenosis; a case-control study

BackgroundPON1 polymorphisms and enzyme activity have been reported to be associated with cardiovascular disease (CVD). The aim of current study was to assess the association of these PON1 SNPs and serum enzyme activity and with restenosis following coronary artery stenting. MethodsA total of 306 unrelated Iranian patients with history of coronary stent implantation who underwent elective re-angiography were enrolled in the current study. Three single nucleotide polymorphisms (SNPs) of PON1 gene were genotyped. We used a double ARMS PCR method for genotyping at the Q192R and L55M loci, and PCR-RFLP method for C-108 T. Serum mRNA expression of PON1 was determined using SYBER green method and Roche LightCycler. ResultsThere were 104 patients considered as in-stent restenosis (ISR) (mean age: 60.55 ± 8.60 years), and 202 individuals as non ISR (NISR) (mean age: 61.94 ± 9.18 years). There were no significant difference between paraoxonase and arylestrase actvities of paraoxonase 1 enzyme. Furthermore, there were no significant differences in the distribution of genotypes of PON1 polymorphism with ISR compared to the control group. The AAC haplotype was the most frequent haplotype in our population study, and haplotypes were not associated with ISR occurrence. The difference between serum mRNA expression of PON1 was not significant between ISR and NISR groups. ConclusionsAccording to our finding it seems that paraoxonase 1 activities, the most important polymorphisms of PON1 including Q192R, L55M and C-108 T and serum mRNA expression of PON1 are not beneficial markers for ISR diagnosis.

Abstract 5234: Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea

Abstract Background: One of the major topics about colorectal cancer (CRC) is the core role of various immune cells against cancer cells. To comprehensively understand genetic basis of immune system underlying CRC progression, association of single-nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of immune-related genes were investigated with colorectal cancer survival. Methods: CRC patients enrolled in the Seoul National University Hospital with prospective follow-up were included in the study. From blood-derived DNA from CRC patients, genome-wide SNPs were genotyped by using the Korea Biobank Array (KoreanChip). 2,729 immune-related genes were selected from Ensembl, Gene Ontology (GO), and KEGG database and 37,398 mapped SNPs were extracted. SNP or PRS-based Cox proportional hazard models were fit for events of overall survival (OS) and progression-free survival (PFS) estimating effect sizes with hazard ratios (HRs). PRS was calculated as effect size weighted sum of risk alleles of individual patients and categorized into tertiles. To investigate enriched pathways, protein-protein interaction networks analysis was conducted. Bonferroni-corrected p-value (1.3 × 10−6) was used as statistically significance threshold. Results: Among 960 CRC patients, 154 (16.0%) occurred events of death and 245 (25.5%) of progression during the follow-up (median=1,698 days, range=7-2,563 days). For OS, a statistically significant associations were mapped to ACTR3B, ST6GAL1, COTL1, PRKCZ, and CAMK1D genes with the strongest SNP rs14808985 (HR=3.07, P=1.87 × 10−7). For PFS, marginal association was mapped to MECOM gene with the strongest SNP rs16854234 (HR=1.48, P=6.13 × 10−6). In PRS analysis, the highest tertile group showed the prominently increased risk for OS (HR=25.0, P&amp;lt;2.0 × 10−16 ) and PFS (HR=5.88, P&amp;lt;2.0 × 10−16 ) compared with the lowest group for a reference. In protein-protein interaction networks analysis, the strongest enrichments were shown in Th17 cell differentiation pathway for OS and in adherences junction for PFS. Conclusions: We identified novel predictive biomarker genetic variants in ACTR3B and MECOM genes associated with OS and PFS, respectively, among CRC patients. Additionally, we presented PRS as a useful biomarker for survival outcomes and suggested enriched biological pathways involved in CRC progression. These knowledges can promote the understanding of CRC survival and the development of immune-related therapeutic interventions for CRC patients in the future. Citation Format: Dabin Yun, Nan Song, Jin-Ah Sim, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5234.

Abstract 2247: Evaluation of multidrug resistant genes among breast cancer patients in Ghana

Abstract Background: Breast cancer (BC) is a leading cause of cancer death in Ghana and around the world. Ghanaian women are diagnosed at younger ages with the more aggressive Triple Negative BC (TNBC) subtype where West African ancestry is associated with advanced BC diagnosis and higher mortality rates compared to age-matched women of European ancestry. Genomic comparisons of BC tumors from women of African and European ancestry show differences in frequencies of single nucleotide polymorphisms (SNP) and copy number variations. These differences may contribute to disparities in disease and treatment outcomes observed in women of African ancestry. Chemotherapy plays a major role in treatment of recurrent and metastatic BC. Long-term BC survival remains poor especially in Africa due to multidrug resistance (MDR). MDR has been associated with binding cassette (ABC) protein transporters. ABCB1, ABCC1 and ABCG2 are ABC transporter genes that code for proteins involved in drug efflux. We hypothesize that SNPs in ABC transporter genes may alter their physiological protective role and increase risk of MDR, treatment failure and death among BC patients. Preliminary dataWe explored gene expression profiles of ABCB1, ABCC1 and ABCG2 in an African ancestry-enriched subset of women with TNBC (ICSBCS cohort: Ghanaian n = 6, African American (AA) n = 9, Ethiopian n = 11). Preliminary data showed significantly higher expression of ABCC1 among Ghanaian and AA patients compared to Ethiopians, and a significant positive correlation with African ancestry. ABCB1 and ABCG2 showed lower expression in all three groups (ns).To study the relationship between ABC transporter gene SNPs and MDR, we have collected data over a 3-year period (2019-2021) from the Oncology Department of the Komfo Anokye Teaching Hospital in Ghana. The overall prevalence of BC recurrence was 3.4% (CI = 2.5 - 4.7%), and prevalence of metastatic BC was 47.6% (CI = 44.6 - 50.6%). Methodology: SNPs in ABC transporter genes will be obtained from 150 consented female BC patients who have undergone chemotherapy. We will compare genotype frequencies among patients with disease recurrence and/or metastasis (n = 100) to those with no disease recurrence or metastasis (n = 50). Single-plex genotyping of the ABC gene SNPs will be completed using a real-time PCR allelic discrimination assay. Conclusion: ABCC1 has been established to be associated with African ancestry. Determining the association of ABC gene SNPs and MDR among Ghanaian BC patients will provide further information on allelic variants and their effects on BC treatment outcomes. Citation Format: Gloria Agyekum Boaitey, Rachel Martini, Melissa B. Davis, Lisa Newman, Brian Stonaker, Linda Ahenkorah Fondjo, Christian Obirikorang, Ernest Osei Bonsu, Ernest Adjei, Ishmael Kyei, Mavis Bobie Ansah, Mahteme Bekele, Timothy Chu, Nicolas Robine. Evaluation of multidrug resistant genes among breast cancer patients in Ghana [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2247.