Effects Of Single Nucleotide Polymorphisms Research Articles

Single nucleotide polymorphisms (SNPs) in circadian genes: Impact on gene function and phenotype.

Circadian rhythm is an endogenous timing system that allows an organism to anticipate and adapt to daily changes and regulate various physiological variables such as the sleep-wake cycle. This rhythm is governed by a molecular circadian clock mechanism, generated by a transcriptional and translational feedback loop (TTFL) mechanism. In mammals, TTFL is determined by the interaction of four main clock proteins: BMAL1, CLOCK, Cryptochromes (CRY), and Periods (PER). BMAL1 and CLOCK form dimers and initiate the transcription of clock-controlled genes (CCG) by binding an E-box element with the promotor genes. Among CCGs, PERs and CRYs accumulate in the cytosol and translocate into the nucleus, where they interact with the BMAL1/CLOCK dimer and inhibit its activity. Several epidemiological and genetic studies have revealed that circadian rhythm disruption causes various types of disease. In this chapter, we summarize the effect of core clock gene SNPs on circadian rhythm and diseases in humans.

Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism – A Randomized, Crossover Study

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

PS-P02-8: HOST GENOMIC INFLUENCE ON THE GUT MICROBIAL METABOLITE-BLOOD PRESSURE RELATIONSHIP

Objective: The human metabolic profile is affected by host genetic, microbiome, environmental/lifestyle, and dietary factors which may all influence human raised blood pressure (BP). We aim to delineate metabolite-BP relationships by evaluating the effect of single-nucleotide polymorphisms (SNPs) mapped to enzyme-coding genes involved in metabolic pathways on this association. We specifically focus on human commensal urinary gut microbial co-metabolites. Design and Method: Two cross-sectional datasets of over 4,000 individuals in total were used in a two-stage design. The first cohort uses two timed 24-hr urine samples for the discovery and replication of urinary metabolites associated with BP. The second cohort uses spot urine samples to validate the associations and subsequently investigates the influence of BP and other metabolic syndrome-related SNPs on these associations. Urine samples from both cohorts were measured with 600 MHz 1H Nuclear Magnetic Resonance spectroscopy. The SNPs were mapped to metabolites using a bioinformatic approach, which also incorporates the microbiome in establishing the metabolic distance between SNPs and metabolites through biochemical reactions and pathways. Results: 11 urinary metabolites, replicated within the first cohort and validated in the second cohort (adjusted P-values 1.68 × 10–15 to 1.08 × 10–4) were associated with systolic BP (SBP); 9 of these were also associated with diastolic BP (DBP) in both cohorts as well as 2 further metabolites with DBP only (adjusted P-values 9.18 × 10–13 to 1.23 × 10–4). The analysis of the host-genomic (SNPs linked to GLYAT, KYAT3 and SULT13A genes) effect on gut microbial co-metabolites phenylacetylglutamine, hippurate and 4-cresylsulfate and their association with BP revealed a significant contribution of SNPs on the metabolite-BP association (P-values 1.08 × 10–133 to 2.87 × 10–29). Other metabolite-BP associations, such as for amino acids tyrosine, glycine, lysine, and leucine, also demonstrated a significant effect of individual SNPs (P-values 1.54 × 10–303 to 2.04 × 10–8) on the relationship. These associations were validated with null models of random SNPs with the same minor allele frequency also mapping to enzyme-coding genes, as well as a null model demonstrating that these metabolites have more SNPs linked to them than other metabolites with similar network topologies in other metabolic pathways. Conclusions: We have shown that human commensal urinary gut microbial co-metabolites are reliably associated with BP differences in two cohorts, and we demonstrated a significant host-genetic component that contributes to these associations. These relationships indicate potential complex mechanisms involving host genetics, the gut microbiome, and metabolic changes associated with BP that may lead to new ways to prevent high BP.

Pleiotropy Structures Plant Height and Seed Weight Scaling in Barley despite Long History of Domestication and Breeding Selection.

Size scaling describes the relative growth rates of different body parts of an organism following a positive correlation. Domestication and crop breeding often target the scaling traits in the opposite directions. The genetic mechanism of the size scaling influencing the pattern of size scaling remains unexplored. Here, we revisited a diverse barley (Hordeum vulgare L.) panel with genome-wide single-nucleotide polymorphisms (SNPs) profile and the measurement of their plant height and seed weight to explore the possible genetic mechanisms that may lead to a correlation of the two traits and the influence of domestication and breeding selection on the size scaling. Plant height and seed weight are heritable and remain positively correlated in domesticated barley regardless of growth type and habit. Genomic structural equation modeling systematically evaluated the pleiotropic effect of individual SNP on the plant height and seed weight within a trait correlation network. We discovered seventeen novel SNPs (quantitative trait locus) conferring pleiotropic effect on plant height and seed weight, involving genes with function in diverse traits related to plant growth and development. Linkage disequilibrium decay analysis revealed that a considerable proportion of genetic markers associated with either plant height or seed weight are closely linked in the chromosome. We conclude that pleiotropy and genetic linkage likely form the genetic bases of plant height and seed weight scaling in barley. Our findings contribute to understanding the heritability and genetic basis of size scaling and open a new venue for seeking the underlying mechanism of allometric scaling in plants.

Polygenic risk scores for complex diseases: Where are we now?

Polygenic risk scores for complex diseases: Where are we now?

Structural systems biology approach delineate the functional implications of SNPs in exon junction complex interaction network

In eukaryotes, transcripts that carry premature termination codons (PTC) leading to truncated proteins are degraded by the Nonsense Mediated Decay (NMD) machinery. Missense and nonsense Single Nucleotide Polymorphisms (SNPs) in proteins belonging to Exon junction complex (EJC) and up-frameshift protein (UPF) will compromise NMD leading to the accumulation of truncated proteins in various diseases. The EJC and UPF which are involved in NMD is a good model system to study the effect of SNPs at a system level. Despite the availability of crystal structures, computational tools, and data on mutational and deletion studies, with functional implications, an integrated effort to understand the impact of SNPs at the systems level is lacking. To study the functional consequences of missense SNPs, sequence-based techniques like SIFT and PolyPhen which classify SNPs as deleterious or non-deleterious and structure-based methods like FoldX which calculate the Delta Delta G, (ddGs, ∆∆G) are used. Using FoldX, the ddG for mutations with experimentally validated functional effects is calculated and compared with those calculated for SNPs in the same protein–protein interaction interface. Further, a model is conceived to explain the functional implications of SNPs based on the effects observed for known mutants. The results are visualized in a network format. The effects of nonsense mutations are discerned by comparing with deletion mutation studies and loss of interaction in the crystal structure. The present work not only integrates genomics, proteomics, and classical genetics with ‘Structural Biology’ but also helps to integrate it into a ‘systems-level functional network’. Communicated by Ramaswamy H. Sarma

Fitting Genomic Prediction Models with Different Marker Effects among Prefectures to Carcass Traits in Japanese Black Cattle.

We fitted statistical models, which assumed single-nucleotide polymorphism (SNP) marker effects differing across the fattened steers marketed into different prefectures, to the records for cold carcass weight (CW) and marbling score (MS) of 1036, 733, and 279 Japanese Black fattened steers marketed into Tottori, Hiroshima, and Hyogo prefectures in Japan, respectively. Genotype data on 33,059 SNPs was used. Five models that assume only common SNP effects to all the steers (model 1), common effects plus SNP effects differing between the steers marketed into Hyogo prefecture and others (model 2), only the SNP effects differing between Hyogo steers and others (model 3), common effects plus SNP effects specific to each prefecture (model 4), and only the effects specific to each prefecture (model 5) were exploited. For both traits, slightly lower values of residual variance than that of model 1 were estimated when fitting all other models. Estimated genetic correlation among the prefectures in models 2 and 4 ranged to 0.53 to 0.71, all &lt;0.8. These results might support that the SNP effects differ among the prefectures to some degree, although we discussed the necessity of careful consideration to interpret the current results.

The CCL2 rs4586 SNP Is Associated with Slower Amyloid-β Deposition and Faster Tau Accumulation of Alzheimer's Disease.

CC-chemokine ligand 2 (CCL2), the key immunomodulatory chemokine for microglial activation, has been implicated in the pathogenesis of Alzheimer's disease (AD). Whether the association of CCL2 single nucleotide polymorphisms (SNPs) and the risk of AD is still controversial. We aimed to investigate whether CCL2 rs4586 SNP is associated with the pathological changes and cognitive decline of AD. A total of 486 participants with longitudinal cerebrospinal fluid (CSF) amyloid-β (Aβ) and phospho-tau (P-tau) biomarkers, 18F-Florbetapir and 18F-flortaucipir-positron emission tomography (PET), and cognitive assessments from the Alzheimer's disease Neuroimaging Initiative were included in the study. The effects of CCL2 rs4586 SNP on the pathological changes and cognitive decline of AD were assessed with linear mixed-effects models and evaluated according to the Aβ-status so as to identify whether the effects were independent of Aβ status. CCL2 rs4586-CC carriers exhibited a slower global Aβ-PET accumulation, particularly within stage I and stage II. However, they exhibited a faster accumulation of CSF P-tau and global tau-PET standard uptake value ratios, especially in Braak I and Braak III/IV and the inferior temporal gyrus. The congruent effects of CCL2 rs4586 on tau accumulation existed only in the Aβ-group, as is shown in global tau-PET and Braak I. However, CCL2 rs4586 was not associated with the cognitive decline. Our findings showed that the CCL2 rs4586-CC (versus TT/TC) genotype was associated with slower Aβ deposition and faster tau accumulation, and the latter of which was independent of Aβ status.

Examination of a novel expression-based gene-SNP annotation strategy to identify tissue-specific contributions to heritability in multiple traits.

Complex traits show clear patterns of tissue-specific expression influenced by single nucleotide polymorphisms (SNPs), yet current strategies aggregate SNP effects to genes by employing simple physical proximity-based windows. Here, we examined whether incorporating SNPs with effects on tissue-specific cis-expression would improve our ability to detect trait-relevant tissues across 31 complex traits using stratified linkage disequilibrium score regression (S-LDSC). We found that a physical proximity annotation produced more significant tissue enrichments and larger S-LDSC regression coefficients, as compared to an expression-based annotation. Furthermore, we showed that our expression-based annotation did not outperform an annotation strategy in which an equal number of randomly chosen SNPs were annotated to genes within the same genomic window, suggesting extensive redundancy among SNP effect estimates due to linkage disequilibrium. That said, current sample sizes limit estimation of cis-genetic SNP effects; therefore, we recommend reexamination of the expression-based annotation when larger tissue-specific expression datasets become available. To examine the influence of sample size, we used a large whole blood eQTL reference panel (N = 31,684) applying a similar expression-based annotation strategy. We found that significant cis-expression QTLs in whole blood did not outperform the physical proximity annotation when estimating tissue-specific SNP heritability enrichment for either high- or low-density lipoprotein phenotypes but performed similarly for inflammatory bowel disease. Finally, we report new and updated tissue enrichment estimates across 31 complex traits, such as significant heritability enrichment of the frontal cortex for cognitive performance, educational attainment, and intelligence, providing further evidence of this structure's importance in higher cognitive function.

The effect of SNPs in lncRNA as ceRNA on the risk and prognosis of hepatocellular carcinoma

BackgroundMost susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies (GWAS) are located in non-coding regions, and the mechanism of action remains unclear. The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) on long non-coding RNAs (lncRNAs) that affect competing endogenous RNAs (ceRNA) regulation mechanism with the risk and prognosis of HCC.MethodsBased on a set of bioinformatics strategies, eight lncRNA genes that affect HCC through the mechanism of lncRNA-mediated ceRNA were systematically screened, and 15 SNPs that affect microRNA (miRNA) binding in these lncRNA genes were annotated. Genotyping was performed in 800 HCC cases and 801 healthy controls to examine associations of these SNPs with HCC in a northeastern Chinese Han population.ResultsThe GG, GC and GG + GC genotypes of HOTAIR rs7958904 were associated with a 0.65, 0.59 and 0.63-fold decreased HCC risk, respectively. In addition, HCC patients with PVT1 rs3931282 AA + GA genotypes were less prone to develop late-stage cancers in a stratified analysis of clinical characteristics. When stratified by clinical biochemical indexes, rs1134492 and rs10589312 in PVT1 and rs84557 in EGFR-AS1 showed significant associations with aspartate aminotransferase (AST), alanine aminotransferase (ALT) or AST/ALT ratio in HCC patients. Furthermore, we constructed potential ceRNA regulatory axes that might be affected by five positive SNPs to explain the causes of these genetic associations.ConclusionsHOTAIR rs7958904, PVT1 rs3931282, rs1134492 and rs10589312, and EGFR-AS1 rs84557 might be predictors for HCC risk or prognosis. Our results provide new insights into how SNPs on lncRNA-mediated ceRNAs confer interindividual differences to occurrence and progression of HCC.

Single nucleotide polymorphisms of PCP pathway related genes participate in the occurrence and development of neural tube defect.

To screen the single nucleotide polymorphisms (SNPs) in the coding regions of VANGL and FZD family members related to the plane cell polarity (PCP) signaling pathway in neural tube defects (NTDs) patients, so as to provide theoretical and experimental basis for the prevention and treatment of NTDs by intervening PCP signal transduction. 112 NTDs patients were collected as the case group and 112 craniocerebral trauma patients as control. Afterwards, blood genomic DNA was extracted and sequenced. The distribution of SNP alleles and genotypes between case and control groups was analyzed. Finally, the NTD rat model was constructed, and the effect of SNPs on the expression level of VANGL and FZD genes was verified by qRT-PCR. GC genotype was newly found at VANGL1 c.346G>A, as well as AT genotype in FZD6 c.97A>G. The distribution of VANGL1 c.346g>A allele and genotype was statistically different between the case and control groups (p < 0.05). The newly found genotype GC increased the risk of NTDs (OR=9.918, 95% CI: 1.234%-79.709%). The results of qRT-PCR showed that the expression level of FZD6 in E11 NTD fetuses were significantly increased (p < 0.05), but there was no obvious difference in the expression of VANGL1. We found a new variant of VANGL1 c.346G>A, whose GC genotype might play an important role in the pathogenesis of NTDs. The SNPs of VANGL1 had no significant effect on its expression level, indicating that it may induce NTDs through other ways. FZD6 was significantly overexpressed in NTDs fetuses.

Genomic Variation Underlying the Breeding Selection of Quinoa Varieties Longli-4 and CA3-1 in China.

Quinoa (Chenopodium quinoa) is a well-known climate-resilient crop and has been introduced into multiple marginal lands across the world, including China, to improve food security and/or balanced nutrient supplies. Conventional breeding has been widely applied in the selection and breeding of quinoa varieties in China since 1980s; however, few studies have been implemented on the genetic variances among different varieties developed by diversity breeding objectives. In this study, the phenotypic and genetic differences between two varieties (Longli-4 and CA3-1) from China were systematically analyzed. A total of 407,651 and 2,731,411 single nucleotide polymorphisms (SNPs) and 212,724 and 587,935 small insertion and deletion (INDELs) were detected for Longli-4 and CA3-1, respectively, when compared with the reference genome of PI614886. The SNPs/INDELs were unevenly distributed across each chromosome for both varieties. There were 143,996 SNPs and 83,410 INDELs shared between Longli-4 and CA3-1, accounting for 4% of the total variances. The variation was then screened based on the SNP effects. There were 818 and 73 genes with the variety-specific non-synonymous and stop-gain variation in Longli-4, whereas there were 13,701 and 733 genes in CA3-1. Specifically, 3501 genes with the non-synonymous variation and 74 genes with the stop-gain variation were found in both Longli-4 and CA3-1. These results suggest that convergent selection occurred during the different breeding processes. A set of candidate genes related to agronomic traits and domestication were further selected to detect the genetic divergence in detail in the two varieties. Only one domestication gene was identified having Longli-4-specific stop-gain variation. Twelve candidate genes related to betalain (1), flowering (4), seed size (2), domestication (1), and saponin (4) were identified having CA3-1-specific stop-gain variation. Interestingly, one seed size gene homologous of CKX1 (cytokinin oxidase/dehydrogenase 1) had the stop-gain variation in both varieties. This research will therefore provide guidance for the molecular-assisted breeding in quinoa.

Protective Role of IL7A-197 A/G Heterozygosity in the Development and Severity of Colorectal Cancer in the Bulgarian Population.

Background: Interleukin (IL)-17A and IL-17F, expressed mainly by a novel subset of CD-positive (+) T-helper (Th) cells of the immune system, has been closely related to inflammatory conditions underlying colorectal cancer pathogenesis. Accordingly, we conducted a case-control study to investigate the association of common single nucleotide polymorphisms (SNP) in the IL17A and IL17F genes (rs2275913 and rs763780, respectively) with the susceptibility and severity of CRC patients from the Bulgarian population. Methods and Materials: 136 patients with histologically confirmed CRC diagnosis and 116 healthy individuals were recruited in the present study. Genotypes were determined by the restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) technique. Results: The IL17A heterozygous A/G-genotype was overrepresented among the control group (p = 0.003). Additionally, the carriers of the heterozygous A/G-genotype had a 2.39-fold lower risk for CRC compared to the G/G-genotype (OR = 0.418, p = 0.006). Our results also indicated that in the advanced CRC stages (III + IV) the heterozygous genotype (A/G) appeared to be less frequent (p = 0.024, χ2-test). Among the patients with detected distant metastases, the A/G-carriers were the smallest part (14.3%) compared to the homozygous genotypes A/A (42.9%) and G/G (42.8%), p = 0.006. There was no association of the studied IL17F rs763780 SNP with susceptibility and severity of CRC among the studied subjects, although the heterozygous C/T-carriers had shorter median survival compared to the T/T-carriers (p = 0.129). Conclusions: Our study finds a protective role of heterozygosity for the IL17A-197A/G SNP and negative effects of the A-allele on CRC progression.

Pharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolism

Introduction. Identification of pharmacogenetic effects on antiretroviral therapy (ART) has become an important milestone to reach in the advancement of personalised treatment for HIV-positive patients. The therapy schemes are accompanied by multiple side effects. Therapy effectiveness and adverse reactions can be dictated by individual genetic predisposition factors, which should be taken into account for an optimal prescription. Some genetic markers (HLA-B*57:01 and UGT1A1*28), were already proven to improve discontinuation rates, and efforts are allocated to expand the range of clinically-relevant genetic tests.Objective. In this review, an updated summary of genetic polymorphisms and their effects defining patients’ tolerability to ART is presented. The aim of this research is to assess single nucleotide polymorphisms (SNPs) present in the genes that encode proteins involved in ART metabolism and transport. This review will be used to develop a PCR-based testing methodology for the detection and confirmation of risk alleles in the Caucasian population.Materials and methods. Data from 46 original research papers and reviews was analysed. Allele frequencies of the most relevant polymorphisms were checked against the data for European population.Results. As an outcome of this review, a few most promising SNPs were selected for future research. Firstly, ABCC4 rs1751034 and rs3742106 and ABCC10 rs9349256 and rs2125739 were associated with an increased risk of renal impairment, higher plasma concentration, and toxicity when treated with tenofovir. Parallel analysis of ABCC4 and ABCC10 SNP effects on renal impairment together with CYP24A1 rs2248359 that was recently reported as a potential renal toxicity marker might be more informative. Secondly, CYP2B6 rs3745274 that was associated with an increased efavirenz plasma concentration, and increased risk of liver and CNS toxicity should be evaluated. SNPs in CYP2B6, CYP2A6 (rs28399433), and CYP3A4 (rs4646437) should be evaluated in parallel since possession of all three variants might put patients at a much higher risk.Conclusion. Identified alleles could become new markers used in drug prescription protocols if significant effect in Caucasian population will be found. The most relevant SNPs should be tested in in supporting future studies to evaluate the significance for patients with HIV in Russia.

LncRNASNP v3: an updated database for functional variants in long non-coding RNAs.

Long non-coding RNAs (lncRNAs) act as versatile regulators of many biological processes and play vital roles in various diseases. lncRNASNP is dedicated to providing a comprehensive repository of single nucleotide polymorphisms (SNPs) and somatic mutations in lncRNAs and their impacts on lncRNA structure and function. Since the last release in 2018, there has been a huge increase in the number of variants and lncRNAs. Thus, we updated the lncRNASNP to version 3 by expanding the species to eight eukaryotic species (human, chimpanzee, pig, mouse, rat, chicken, zebrafish, and fruitfly), updating the dataand adding several new features. SNPs in lncRNASNP have increased from 11 181 387 to 67 513 785. The human mutations have increased from 1 174 768 to 2 387 685, including 1 031 639 TCGA mutations and 1 356 046 CosmicNCVs. Compared with the last release, updated and new features in lncRNASNP v3 include (i) SNPs in lncRNAs and their impacts on lncRNAs for eight species, (ii) SNP effects on miRNA-lncRNA interactions for eight species, (iii) lncRNA expression profiles for six species, (iv) disease & GWAS-associated lncRNAs and variants, (v) experimental & predicted lncRNAs and drug target associations and (vi) SNP effects on lncRNA expression (eQTL) across tumor & normal tissues. The lncRNASNP v3 is freely available at http://gong_lab.hzau.edu.cn/lncRNASNP3/.

Case-control study on CYP4B1 gene polymorphism and susceptibility to gastric cancer in the chinese Han population

Background:In China, gastric cancer (GC) is one of the most common malignant tumors. This study aimed to explore the relationship of rs2297810, rs4646491 and rs2297809 polymorphisms of CYP4B1 with susceptibility to GC in the Chinese Han population.Methods:A case-control study including 707 GC cases and 707 normal controls was conducted. Three single nucleotide polymorphisms (SNPs) were genotyped by Agena MassARRAY system. Logistic regression analysis was utilized to assess the effects of SNPs on GC risk. Furthermore, multifactor dimensionality reduction (MDR) approach was used to analyze the SNP-SNP interactions.Results:No significant relationships were found between rs2297810 and rs2297809 and GC risk under all genetic models. For rs4646491, people with TC genotype had a 1.40-fold higher risk of GC than those with CC genotype (OR = 1.40; 95% CI = 1.13–1.74; p = 0.002), and people with TT-TC genotype had a 1.30-fold higher risk of GC than those with CC genotype (OR = 1.30; 95% CI = 1.06–1.61; p = 0.014). Stratification results showed that GC risk in people carrying TC genotype was higher than that in people with CC genotype, males (OR = 1.36; 95% CI = 1.06–1.75; p = 0.015), non-smokers (OR = 1.52; 95% CI = 1.11–2.07; p = 0.009) and non-drinkers (OR = 1.50; 95% CI = 1.10–2.04; p = 0.010). Additionally, the study also revealed that GC risk in people carrying TT-TC genotype was higher than that in people with CC genotype, males (OR = 1.29; 95% CI = 1.01–1.64; p = 0.040), non-smokers (OR = 1.40; 95% CI = 1.04–1.89; p = 0.027) and non-drinkers (OR = 1.39; 95% CI = 1.03–1.87; p = 0.030).Conclusion:This study firstly found that CYP4B1-rs4646491 was significantly correlated with GC risk, and it might be a risk factor for GC.

In silico assessment of missense point mutations on human cathelicidin LL-37

Cathelicidin antimicrobial peptides are a diverse family of cationic amphipathic peptides with multiple activities. In humans, cathelicidin LL-37 is one of the main host defense peptides with a remarkable medical and biotechnological potential. Deregulation of LL-37 expression has been associated with inflammatory diseases. However the effects of point mutations driven by single nucleotide polymorphisms (SNPs) on LL-37 are unknown. Here we applied an array of computational tools to investigate the effects of such mutations on LL-37 structure and activity. Due to the fact that, on cathelicidins, the prodomain is more conserved than the mature peptide, the SNP effect predictions were biased and, overall, resulted in neutral effects; and due to the slight changes in physicochemical properties, the antimicrobial predictions indicated the maintenance of such activity. Nonetheless, R07P, R07W, R29Q, R29W mutations reduced the peptide net charge, which in turn could result in less active LL-37 variants. Molecular dynamics data indicated that R07Q and N30Y mutations altered the LL-37 structure, leading to potential deleterious effects. In addition, the helix dipole is altered in G03A, R07P, R07W and L31P mutations, which could also alter the antimicrobial activity. Our results indicated that despite the mutations did not alter the residues from LL-37 active core, they could influence the antimicrobial activity and consequently, could be involved in inflammatory diseases.

Novel Genome-Wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm.

The association between boule (BOLL) and endothelin receptor type A (EDNRA) loci and intracranial aneurysm (IA) formation has been reported via genome-wide association studies. We sought to identify genome-wide interactions involving BOLL and EDNRA loci for IA in a Korean adult cohort. Genome-wide pairwise interaction analyses of BOLL and EDNRA involving 250 patients with IA and 296 controls were performed using the additive effect model after adjusting for confounding factors. Among 512575 single-nucleotide polymorphisms (SNPs), 23 and 11 common SNPs suggested a genome-wide interaction threshold (p<1.25×10-8) involving rs700651 (BOLL) and rs6841581 (EDNRA). Rather than singe SNP effect of BOLL or EDNRA on IA development, they showed a synergistic effect on IA formation via multifactorial pair-wise interactions. The rs1105980 of PTCH1 gene showed the most significant interaction with rs700651 (natural log-transformed odds ratio [lnOR], 1.53; p=6.41×10-11). The rs74585958 of RYK gene interacted strongly with rs6841581 (lnOR, -19.91; p=1.64×10-9). Although, there was no direct interaction between BOLL and EDNRA variants, two EDNRA-interacting gene variants of TNIK (rs11925024 and rs1231) and FTO (rs9302654), and one BOLL-interacting METTL4 gene variant (rs549315) exhibited marginal interaction with BOLL gene. BOLL or EDNRA may have a synergistic effect on IA formation via multifactorial pair-wise interactions.

Systematic analysis of the effects of genetic variants on chromatin accessibility to decipher functional variants in non-coding regions.

Genome-wide association study (GWAS) has identified thousands of single nucleotide polymorphisms (SNPs) associated with complex diseases and traits. However, deciphering the functions of these SNPs still faces challenges. Recent studies have shown that SNPs could alter chromatin accessibility and result in differences in tumor susceptibility between individuals. Therefore, systematically analyzing the effects of SNPs on chromatin accessibility could help decipher the functions of SNPs, especially those in non-coding regions. Using data from The Cancer Genome Atlas (TCGA), chromatin accessibility quantitative trait locus (caQTL) analysis was conducted to estimate the associations between genetic variants and chromatin accessibility. We analyzed caQTLs in 23 human cancer types and identified 9,478 caQTLs in breast carcinoma (BRCA). In BRCA, these caQTLs tend to alter the binding affinity of transcription factors, and open chromatin regions regulated by these caQTLs are enriched in regulatory elements. By integrating with eQTL data, we identified 141 caQTLs showing a strong signal for colocalization with eQTLs. We also identified 173 caQTLs in genome-wide association studies (GWAS) loci and inferred several possible target genes of these caQTLs. By performing survival analysis, we found that ~10% caQTLs potentially influence the prognosis of patients. To facilitate access to relevant data, we developed a user-friendly data portal, BCaQTL (http://gong_lab.hzau.edu.cn/caqtl_database), for data searching and downloading. Our work may facilitate fine-map regulatory mechanisms underlying risk loci of cancer and discover the biomarkers or therapeutic targets for cancer prognosis. The BCaQTL database will be an important resource for genetic and epigenetic studies.

Detection and Discrimination of Single Nucleotide Polymorphisms by Quantification of CRISPR-Cas Catalytic Efficiency.

The specificity of CRISPR-Cas12 assays is attractive for the detection of single nucleotide polymorphisms (SNPs) implicated in, e.g., cancer and SARS-CoV-2 variants. Such assays often employ endpoint measurements of SNP or wild type (WT) activated Cas12 trans-cleavage activity; however, the fundamental kinetic effects of SNP versus WT activation remain unknown. We here show that endpoint-based assays are limited by arbitrary experimental choices (like used reporter concentration and assay duration) and work best for known target concentrations. More importantly, we show that SNP (versus WT) activation results in measurable kinetic shifts in the Cas12 trans-cleavage substrate affinity (KM) and apparent catalytic efficiency (kcat*/KM). To address endpoint-based assay limitations, we then develop an assay based on the quantification of Michaelis-Menten parameters and apply this assay to a 20 base pair WT target of the SARS-CoV-2 E gene. We find that the kcat*/KM measured for WT is 130-fold greater than the lowest kcat*/KM among all 60 measured SNPs (compared to a 4.8-fold for endpoint fluorescence of the same SNP). KM also offers a strong ability to distinguish SNPs, varies 27-fold over all the cases, and, importantly, is insensitive to the target concentration. Last, we point out trends among kinetic rates and SNP base and location within the CRISPR-Cas12 targeted region.