Genetic Single Nucleotide Polymorphisms Research Articles

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.

Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer. A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death. Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancer‒specific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancer‒specific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancer‒specific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001). Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancer‒specific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.

Several genetic SNPs identified in acute appendicitis patients including the HLA-C known to be related to coeliac disease in a Genome-Wide Association Study

Acute Appendicitis (AA) is an inflammatory condition of the vermiform appendix in the caecum of the colon. Genetic polymorphisms have been suggested as risk factors predisposing to AA susceptibility but have remained relatively unknown, due to insufficient sample size in previous analyses. Therefore, the primary research aim was to identify genetic variants associated with AA. It was hypothesised that gene polymorphisms associated with AA will provide a connection to other diet-related inflammatory diseases. Genetic variants associated with AA were studied via a Genome-Wide Association Scan (GWAS) using the Global Biobank Meta-Analysis Initiative (GBMI). The GBMI is a collaborative consortium of 23 biobanks with a publicly released repository of de-identified genetic data linked with digital health records spanning 4 continents with a study population size of over 2.2 million consented individuals of multiple ancestral backgrounds1. A linear regression model was used to estimate the association between single nucleotide polymorphisms (SNPs), across the human genome, and AA by each contributing biobank. The results were then meta-analysed with a total of 32,706 cases and 1,075,763 controls. In the present study, the free open-source Complex Traits Genetic Virtual Lab (CTG-VL) platform was used to access, analyse, and visualise the GWAS summary statistics of AA2. Genome-wide significantly associated SNPs (p-value < 5 x 10-8) were further searched for their associations with health-related traits in publicly available GWAS summary statistics. Upon analysis, significantly associated SNPs for AA were identified within or nearby nine genes. HLX, NKX2-3, LTBR, and DLEU1 are genes involved in immune responses; IRF8 associated with maturation of myeloid cells; OSR-1 responsible for transmembrane ion transporter activity; NCALD a regulator of G protein-coupled signal transduction. In addition, based on the hypothesis, the SNP of key clinical importance was the HLA-C rs2524046 (p-value = 2.38 x 10-8), with the AA risk-increasing allele C being also strongly associated with a higher risk of coeliac disease (CD). The CD is an autoimmune condition where gluten, a protein present in grains such as barley, rye, and wheat, elicits an inflammatory response that results in damage to the small intestine lining. Considering how both AA and CD share the same SNP, it is possible to speculate whether gluten initiates a similar pathophysiological mechanism that exacerbates inflammation in the vermiform appendix in AA. In conclusion, the top AA associated SNPs suggests its development could be due to immunological responses influenced by dietary nutrient intake. The HLA-C SNP is common to AA and CD, suggesting that the gluten protein found in certain cereal grains possibly contributes to the pathophysiology of AA like CD. This warrants further investigations into whether dietary gluten could play a key role in AA development.

Dopamine and Norepinephrine Tissue Levels in the Developing Limbic Brain Are Impacted by the Human CHRNA6 3'-UTR Single-Nucleotide Polymorphism (rs2304297) in Rats.

We previously demonstrated that a genetic single-nucleotide polymorphism (SNP, rs2304297) in the 3' untranslated region (UTR) of the human CHRNA6 gene has sex- and genotype-dependent effects on nicotine-induced locomotion, anxiety, and nicotine + cue-induced reinstatement in adolescent rats. This study aims to investigate how the CHRNA6 3'-UTR SNP influences dopaminergic and noradrenergic tissue levels in brain reward regions during baseline and after the reinstatement of drug-seeking behavior. Naïve adolescent and adult rats, along with those undergoing nicotine + cue reinstatement and carrying the CHRNA6 3'-UTR SNP, were assessed for dopamine (DA), norepinephrine (NE), and metabolites in reward pathway regions. The results reveal age-, sex-, and genotype-dependent baseline DA, NE, and DA turnover levels. Post-reinstatement, male α6GG rats show suppressed DA levels in the Nucleus Accumbens (NAc) Shell compared to the baseline, while nicotine+ cue-induced reinstatement behavior correlates with neurotransmitter levels in specific brain regions. This study emphasizes the role of CHRNA6 3'-UTR SNP in the developmental maturation of the dopaminergic and noradrenergic system in the adolescent rat brain, with tissue levels acting as predictors of nicotine + cue-induced reinstatement.

Genotyping by sequencing for the construction of oil palm (Elaeis guineensis Jacq.) genetic linkage map and mapping of yield related quantitative trait loci.

Oil palm (Elaeis guineensis Jacq.) is one of the major oil-producing crops. Improving the quality and increasing the production yield of oil palm have been the primary focuses of both conventional and modern breeding approaches. However, the conventional breeding approach for oil palm is very challenging due to its longevity, which results in a long breeding cycle. Thus, the establishment of marker assisted selection (MAS) for oil palm breeding programs would speed up the breeding pipeline by generating new oil palm varieties that possess high commercial traits. With the decreasing cost of sequencing, Genotyping-by-sequencing (GBS) is currently feasible to many researchers and it provides a platform to accelerate the discovery of single nucleotide polymorphism (SNP) as well as insertion and deletion (InDel) markers for the construction of a genetic linkage map. A genetic linkage map facilitates the identification of significant DNA regions associated with the trait of interest via quantitative trait loci (QTL) analysis. A mapping population of 112 F1 individuals from a cross of Deli dura and Serdang pisifera was used in this study. GBS libraries were constructed using the double digestion method with HindIII and TaqI enzymes. Reduced representation libraries (RRL) of 112 F1 progeny and their parents were sequenced and the reads were mapped against the E. guineensis reference genome. To construct the oil palm genetic linkage map, informative SNP and InDel markers were used to discover significant DNA regions associated with the traits of interest. The nine traits of interest in this study were fresh fruit bunch (FFB) yield, oil yield (OY), oil to bunch ratio (O/B), oil to dry mesocarp ratio (O/DM) ratio, oil to wet mesocarp ratio (O/WM), mesocarp to fruit ratio (M/F), kernel to fruit ratio (K/F), shell to fruit ratio (S/F), and fruit to bunch ratio (F/B). A total of 2.5 million SNP and 153,547 InDel markers were identified. However, only a subset of 5,278 markers comprising of 4,838 SNPs and 440 InDels were informative for the construction of a genetic linkage map. Sixteen linkage groups were produced, spanning 2,737.6 cM for the maternal map and 4,571.6 cM for the paternal map, with average marker densities of one marker per 2.9 cM and one per 2.0 cM respectively, were produced. A QTL analysis was performed on nine traits; however, only QTL regions linked to M/F, K/F and S/F were declared to be significant. Of those QTLs were detected: two for M/F, four for K/F and one for S/F. These QTLs explained 18.1-25.6% of the phenotypic variance and were located near putative genes, such as casein kinase II and the zinc finger CCCH domain, which are involved in seed germination and growth. The identified QTL regions for M/F, K/F and S/F from this study could be applied in an oil palm breeding program and used to screen palms with desired traits via marker assisted selection (MAS).

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.

Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis. Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed. Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed. Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.

Identification of genetic associations and functional SNPs of bovine KLF6 gene on milk production traits in Chinese holstein

BackgroundOur previous research identified the Kruppel like factor 6 (KLF6) gene as a prospective candidate for milk production traits in dairy cattle. The expression of KLF6 in the livers of Holstein cows during the peak of lactation was significantly higher than that during the dry and early lactation periods. Notably, it plays an essential role in activating peroxisome proliferator-activated receptor α (PPARα) signaling pathways. The primary aim of this study was to further substantiate whether the KLF6 gene has significant genetic effects on milk traits in dairy cattle.ResultsThrough direct sequencing of PCR products with pooled DNA, we totally identified 12 single nucleotide polymorphisms (SNPs) within the KLF6 gene. The set of SNPs encompasses 7 located in 5′ flanking region, 2 located in exon 2 and 3 located in 3′ untranslated region (UTR). Of these, the g.44601035G > A is a missense mutation that resulting in the replacement of arginine (CGG) with glutamine (CAG), consequently leading to alterations in the secondary structure of the KLF6 protein, as predicted by SOPMA. The remaining 7 regulatory SNPs significantly impacted the transcriptional activity of KLF6 following mutation (P < 0.005), manifesting as changes in transcription factor binding sites. Additionally, 4 SNPs located in both the UTR and exons were predicted to influence the secondary structure of KLF6 mRNA using the RNAfold web server. Furthermore, we performed the genotype-phenotype association analysis using SAS 9.2 which found all the 12 SNPs were significantly correlated to milk yield, fat yield, fat percentage, protein yield and protein percentage within both the first and second lactations (P < 0.0001 ~ 0.0441). Also, with Haploview 4.2 software, we found the 12 SNPs linked closely and formed a haplotype block, which was strongly associated with five milk traits (P < 0.0001 ~ 0.0203).ConclusionsIn summary, our study represented the KLF6 gene has significant impacts on milk yield and composition traits in dairy cattle. Among the identified SNPs, 7 were implicated in modulating milk traits by impacting transcriptional activity, 4 by altering mRNA secondary structure, and 1 by affecting the protein secondary structure of KLF6. These findings provided valuable molecular insights for genomic selection program of dairy cattle.

Dietary Behavior of Spanish Schoolchildren in Relation to the Polygenic Risk of Obesity

Several precedents support an association between single nucleotide genetic polymorphisms (SNPs), the obese phenotype, and eating behavior in the infant-juvenile population. This study aims to study this aspect in depth, analyzing the eating behavior of a sample of schoolchildren from Madrid in regard to their genetic predisposition to obesity. A total of 258 schoolchildren, aged 6 to 16 years, were evaluated through the Children’s Eating Behaviour Questionnaire (CEBQ) and the genotyping of 32 SNPs. Associations were observed between the total genetic risk score and eating behaviors related to emotional eating and food responsiveness. Individually, different SNPs were associated with eating behaviors, primarily those related to pro-eating behaviors or increased risk of developing obesity. However, diverse results are obtained, depending on the SNP. These results highlighted the strongest associations between the rs1801725 SNP risk allele (CASR) and increased enjoyment of food by 1846-fold. Likewise, the satiety response was associated with SNP rs11676272 (ADCY3) 2.39 and SNP rs7566605 (INSIG2), increasing this response by 2.39 and 1.63 times, respectively. Emotional anti-ingesting behaviors were inversely associated with SNP rs1421085 (FTO) and SNP rs987237 (TFAP2B). In contrast, SNP rs55915917 (CRHR1) increased the risk of these behaviors. SNPs rs4788099 (SH2B1), rs6857 (NECTIN2), and rs180172 (ADCY3) were associated with slow feeding. In conclusion, associations were found between most of the analyzed SNPs and the CEBQ items. This suggests that feeding behavior exists as a mediator between genotype and obesity phenotype, beginning in childhood.

Allelic variants of CYP2B6 gene expression and its implication on the pathogenesis of malaria among a cohort of outpatients in North-Central Nigeria

Abstract Background Human cytochrome P450 2B6 (CYP2B6) is fortified with the biotransformation of the antimalarial, artemisinin combination therapy (ACT). Owing to emerging reports of Plasmodium species resistance to ACT in other climes, CYP2B6*6 genotype significantly alters ACT metabolism. In North-Central Nigeria, the distribution of the CYP2B6*6 variant is poorly documented. This study investigated the distribution of CYP2B6 c.516G&gt;T variants and its relationship with certain malaria pathogenesis among a cohort of clinical-malaria outpatients in Ilorin, Nigeria. Methods A total of 50 symptomatic P. falciparum malaria-positive samples were genotyped for CYP2B6 c.516G&gt;T using restriction fragment length polymorphism and a specific haplotype population was established. The allele frequencies and genotype distributions were analyzed. Haplotypes were clustered using Ward’s method. Correlations determined include defective CYP2B6 versus parasitemia densities and thrombocytopenia, respectively. Results Forty-five samples show genotypic ratios and nine CYP2B6 genetic single nucleotide polymorphisms were identified. The following haplotypes (64C&gt;T = *1/*2, 785A&gt;G = *1/*4, and 1459C&gt;T = *1/*5) occurred and *2, *3, and *18 alleles harbor 64C&gt;T, 777C&gt;A, −82T&gt;C, and 499C&gt;G. The codon 64CT, 516GT, and 785AG; −82TC and 777CA; and 499CG, 516GT, and 785AG were identified as *2/*6 heterozygotes. Samples with 516GT and 785GG genotypes occurred with *4/*6 heterozygotes. Mutant trait alleles recorded high parasitemia 72 h post-ACT regimen. Only individuals with CYP2B6*6 alleles had severe malaria and thrombocytopenia. Conclusion This report contributes to the growing knowledge of CYP2B6*6 genotype frequency and its relationship with malaria pathogenesis among a Nigerian population.

Association between arsenic (+3 oxidation state) methyltransferase gene polymorphisms and arsenic methylation capacity in rural residents of northern China: a cross-sectional study.

Arsenic is a toxic metal-like element. The toxic reaction of the body to arsenic is related to the ability of arsenic methylation metabolism. As the rate-limiting enzyme of arsenic methylation metabolism, the genetic single nucleotide polymorphisms (SNPs) of arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene are related to capacity of arsenic methylation. In this paper, we investigated the association of five SNPs (rs7085104, rs3740390, 3740393, rs10748835, and rs1046778) in AS3MT with arsenic methylation metabolizing using the data and samples from a cross-sectional case-control study of arsenic and Type 2 diabetes mellitus conducted in Shanxi, China. A total of 340 individuals were included in the study. Urinary total arsenic (tAs, μg/L) was detected by liquid chromatography-atomic fluorescence spectrometry (LC-AFS). According to "safety guidance value of urinary arsenic for population" as specified in WS/T665-2019 (China), participants were divided into the control group (tAs ≤ 32μg/L, n = 172) and arsenic-exposed group (tAs > 32μg/L, n = 168). iAs%, MMA%, and DMA% are as the indicator of arsenic methylation capacity. The genotypes of AS3MT SNPs were examined by Multiple PCR combined sequencing. Linear regression analysis showed that AG + GG genotype in rs7085104 was associated with decreased iAs% and increased DMA%. Moreover, AG + AA genotype in rs10748835 and TC + CC genotype in rs1046778 were associated with decreased iAs% and MMA% and increased DMA%. The interaction between rs7085104 and arsenic is associated with iAs% and DMA%. The interaction of rs3740390 and rs10748835 with arsenic is associated with iAs%. Haplotype CTAC (rs3740393-rs3740390-rs10748835-rs1046778) was associated with lower iAs% and higher DMA%, but this association disappeared after adjusting for age, gender, drink, smoking, BMI and tAs. Haplotype GCAC was associated with decreased MMA%. Our study provides additional support for revealing the factors influencing the metabolic capacity of arsenic methylation and might be helpful to identify the population susceptible to arsenic exposure through individualized screening in the future.

Association between a single nucleotide polymorphism of the ALOX5 gene and susceptibility to multisystem tuberculosis in a Chinese Han population

BackgroundHost genetic single nucleotide polymorphisms can exert an influence susceptibility to tuberculosis infection. Previous investigations have demonstrated an association between the polymorphism in the ALOX5 gene and a range of diseases, encompassing not only noninfectious conditions like asthma, acute myocardial infarction, and cerebral infarction but also infections caused by various pathogens. However, the relationship between ALOX5 gene polymorphism and susceptibility to tuberculosis has received limited research attention. The ALOX5 gene encodes arachidonic acid 5-lipoxygenase(5-LO), which serves as the initiating catalyst in the generation of the inflammatory mediator leukotriene.Leukotrienes, products derived from the 5-LO pathway, are potent proinflammatory lipid mediators that assume a pivotal role in tuberculosis infections.Consequently, ALOX5 gene variants may be intricately associated with the pathogenesis of tuberculosis. In instances where the host exhibits immunocompromisation, infection with Mycobacterium tuberculosis can impact multiple systems. The involvement of multiple systems significantly augments the complexity of treatment and escalates patient mortality rates. Regrettably, the underlying mechanisms driving multisystem tuberculosis pathogenesis remain enigmatic, with clinicians paying scant attention to this aspect. Although the protein encoded by the ALOX5 gene represents a pivotal enzyme that catalyzes the metabolism of arachidonic acid into LXA4, and thereby plays a significant role in the inflammatory response during tuberculosis infection, studies investigating ALOX5 gene polymorphism and its association with susceptibility to multisystem tuberculosis in the Chinese Han population are exceptionally scarce. Therefore, the primary objective of this study is to comprehensively examine the correlation between ALOX5 gene polymorphisms and susceptibility to tuberculosis within the Chinese Han population, with particular emphasis on multisystemic tuberculosis. MethodsA case‒control study design was employed, encompassing 382 individuals with pulmonary tuberculosis and 367 individuals with multisystemic tuberculosis as the case groups, along with 577 healthy controls.Whole blood DNA was extracted from all patients and healthy controls. Subsequently, three tag polymorphisms (rs2029253, rs7896431, rs2115819) within the ALOX5 gene were selectively identified and genotyped. ResultsAfter adjusting for age and sex, the presence of allele A at rs2029253 exhibited a pronounced association with an elevated risk of TB susceptibility when compared to the tuberculosis group and healthy control group. (ORa: 2.174, 95% CI: 1.827–2.587; Pa<0.001, respectively). Notably, the rs2029253 AG genotype and AA genotype displayed a significantly increased susceptibility to tuberculosis (ORa: 2.236, 95% CI: 1.769–2.825; Pa <0.001 and ORa: 4.577, 95% CI: 2.950–7.100; Pa <0.001, respectively) compared to the GG genotype. Moreover, in the analysis utilizing genetic models, rs2029253 also exhibited a markedly heightened susceptibility to tuberculosis in additive models, dominant models, and recessive models (Pa <0.001). Conversely, no significant association was observed between rs7896431, rs2115819, and tuberculosis. In the subgroup analysis, when comparing the pulmonary tuberculosis group with the healthy control group, we observed no significant disparities in the distribution frequencies of alleles, genotypes, and gene models (additive model, dominant model, and recessive model) for the three tag SNPs, with P-values were >0.05 after adjusting for age and sex. Additionally, we noted that the presence of allele A at rs2029253 was linked to an increased susceptibility to tuberculosis in the multisystemic tuberculosis group relative to the healthy control group (ORa: 2.292, 95% CI: 1.870–2.810; Pa<0.001). Similarly, the rs2029253 AG genotype, AA genotype, and gene models, including the additive model, dominant model, and recessive model, demonstrated a significantly elevated risk of tuberculosis susceptibility. ConclusionsThe polymorphism in the ALOX5 gene is associated with susceptibility to multisystemic tuberculosis in the Chinese Han population.

Is Alzheimer's disease a manifestation of brain quantum decoherence resulting from mitochondrial and microtubular deterioration?

The etiology of Alzheimer's dementia is, at best multifactorial. Before the emergence of cognitive impairment, symptoms such as thinning of the cortex, accumulation of β-amyloid, and decreased hippocampal volume are common. Hence, the accumulation of β-amyloid and hyperphosphorylated tau fibrillary tangles are two pathological hallmarks in Alzheimer's disease brains, but antibody therapy aimed to decrease β-amyloid has been a failure and, in most optimistic opinions, may delay somewhat disease progression. However, 31-38 % of subjects develop cerebral micro-hemorrhages in aducanumab therapy, an antibody to the amyloid beta plaque by Biogen. Genetics such as Apo E3/E3 have demonstrated defects in the blood-brain barrier in early-onset dementia. Late Onset Alzheimer’s Dementia, has implicated microbe cerebral infections and numerous genetic single nucleotide polymorphisms. However, several cellular biological signatures of Alzheimer's disease have been identified, such as synaptic dysfunction, β-amyloid plaques, hyperphosphorylated tau, cofilin-actin rods, and Hirano bodies which are related to the actin cytoskeleton. Cofilin is one of the most affluent and common actin-binding proteins and plays a role in cell motility, migration, shape, and metabolism. They also play an important role in severing actin filament, nucleating, depolymerizing, and bundling activities. This review summarizes the structure of cofilins appearing after ATP interruptions and deficits in mitochondrial and microtubules and their functional and regulating roles, focusing on the synaptic dysfunction, β-amyloid plaques, hyperphosphorylated tau, cofilin-actin rods, and Hirano bodies of Alzheimer's disease. These findings strengthen our hypothesis that Alzheimer’s dementia is characterized by “Quantum Decoherence” resulting from mitochondrial and microtubular deterioration and responding to near-infrared transcranial photobiomodulation to support mitochondrial and microtubule repair, regrowth and neuronal synaptic renormalization.

Dissecting the Molecular Role of ADIPOQ SNPs in Saudi Women Diagnosed with Gestational Diabetes Mellitus.

The traditional definition of gestational diabetes mellitus (GDM) is the leading cause of carbohydrate intolerance in hyperglycemia of varying severity, with onset or initial detection during pregnancy. Previous studies have reported a relationship among obesity, adiponectin (ADIPOQ), and diabetes in Saudi Arabia. ADIPOQ is an adipokine that is produced and secreted by adipose tissue involved in the regulation of carbohydrate and fatty acid metabolism. This study investigated the molecular association between rs1501299, rs17846866, and rs2241766 single-nucleotide polymorphisms (SNPs) in ADIPOQ and GDM in Saudi Arabia. Patients with GDM and control patients were selected, and serum and molecular analyses were performed. Statistical analyses were performed on clinical data, Hardy Weinberg Equilibrium, genotype and allele frequencies, multiple logistic regression, ANOVA, haplotype, linkage disequilibrium, as well as MDR and GMDR analyses. The clinical data showed significant differences in various parameters between the GDM and non-GDM groups (p < 0.05). In GDM women with alleles, genotypes, and different genetic models, the rs1501299 and rs2241766 SNPs showed a strong association (p < 0.05). Multiple logistic regression analysis revealed a negative correlation (p > 0.05). This study concluded that rs1501299 and rs2241766 SNPs were strongly associated with GDM in women in Saudi Arabia.

Fast and accurate Bayesian polygenic risk modeling with variational inference

The advent of large-scale genome-wide association studies (GWASs) has motivated the development of statistical methods for phenotype prediction with single-nucleotide polymorphism (SNP) array data. These polygenic risk score (PRS) methods use a multiple linear regression framework to infer joint effect sizes of all genetic variants on the trait. Among the subset of PRS methods that operate on GWAS summary statistics, sparse Bayesian methods have shown competitive predictive ability. However, most existing Bayesian approaches employ Markov chain Monte Carlo (MCMC) algorithms, which are computationally inefficient and do not scale favorably to higher dimensions, for posterior inference. Here, we introduce variational inference of polygenic risk scores (VIPRS), a Bayesian summary statistics-based PRS method that utilizes variational inference techniques to approximate the posterior distribution for the effect sizes. Our experiments with 36 simulation configurations and 12 real phenotypes from the UK Biobank dataset demonstrated that VIPRS is consistently competitive with the state-of-the-art in prediction accuracy while being more than twice as fast as popular MCMC-based approaches. This performance advantage is robust across a variety of genetic architectures, SNP heritabilities, and independent GWAS cohorts. In addition to its competitive accuracy on the "White British" samples, VIPRS showed improved transferability when applied to other ethnic groups, with up to 1.7-fold increase in R2 among individuals of Nigerian ancestry for low-density lipoprotein (LDL) cholesterol. To illustrate its scalability, we applied VIPRS to a dataset of 9.6 million genetic markers, which conferred further improvements in prediction accuracy for highly polygenic traits, such as height.

Single Nucleotide Polymorphisms and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis of the Literature.

Meta-analysis. To determine the single nucleotide polymorphisms (SNPs) that are related to adult idiopathic scoliosis. Adolescent idiopathic scoliosis (AIS) is considered one of the most prevalent spinal diseases. Even though the cause of AIS is yet to be determined, family history and sex have shown conclusive associations. Multiple studies have indicated that AIS is more prevalent in families where at least one other first-degree relative is similarly affected, indicating a possible genetic etiology to AIS. Articles were collected from 3 different search engines and then processed in 2 stages for final article selection for quantitative analysis. Five different genetic models were represented to show the association between the different SNPs and AIS. The Hardy-Weinberg equilibrium was examined using Fisher exact test, with significance set at P <0.05. The final analysis paper's quality was evaluated using the Newcastle Ottawa Scale. Kappa interrater agreement was calculated to evaluate the agreement between authors. The final analysis comprised 43 publications, 19412 cases, 22005 controls, and 25 distinct genes. LBX1 rs11190870 T>C and MATN-1 SNPs were associated with an increased risk of AIS in one or all of the 5 genetic models. IGF-1 , estrogen receptor alfa, and MTNR1B , SNPs were not associated with AIS in all 5 genetic models. Newcastle Ottawa Scale showed good quality for the selected articles. Cohen k = 0.741 and Kappa interrater agreement of 84% showed that the writers were in strong agreement. There seem to be associations between AIS and genetic SNP. Further larger studies should be conducted to validate the results.

Abstract P3-05-31: PVT1, CASC16, TNFRSF13B and NAMPT may be the key genes correlated with recurrence and metastasis of breast cancer

Abstract Background: It is vital to find the risk genes and loci related to recurrence and metastasis in breast cancer (BC) patients. The Genome-wide association study (GWAS) can detect the risk of single nucleotide polymorphism (SNP) and help us understand the mechanism of disease progression by analyzing the SNP information of the whole genome. At present, GWAS have identified several genetic susceptibility SNPs for BC, but it is unclear about its significance in the recurrence and metastasis of BC patients. Therefore, in this study we aimed to identify the risk SNPs related to recurrence and metastasis of BC based on GWAS analysis. Methods: This study adopts a two-stage GWAS research strategy. In the first stage, according to propensity score matching, we chose 97 pairs of BC patients with or without recurrence and metastasis who were treated in Shandong Cancer Hospital and Institute from November 2013 to April 2014. Their peripheral blood samples were collected and DNA was extracted for genome-wide detection by Illumina ASA chip. The SNP loci related to recurrence and metastasis of BC were obtained by logistic regression analysis of GWAS. In the second stage, 854 BC patients from the same hospital were verified from May 2014 to June 2015. The SNP genotyping was detected by time-of-flight mass spectrometry to verify its correlation with recurrence and metastasis of BC. The SNP loci and their corresponding genes and pathways were analyzed using DAVID (https://david.ncifcrf.gov/) online enrichment analysis website. Results: In the first stage, 191 SNPs were obtained from GWAS analysis (P&amp;lt; 0.001). Based on these SNPs and their corresponding genes, we further found that glutamatergic synaptic transmission may be related to BC recurrence and metastasis through GO analysis. Similar results were found in calcium signaling pathway and insulin secretion pathway through KEGG enrichment analysis. And 21 SNPs were screened for their association with the tumor evolution process and whether they are located in the gene coding functional region. In the second stage, Cox regression analysis showed that the genotyping of the four SNPs was consistent with the results of GWAS analysis, and these SNPs are located in the intron region of the gene. Specifically, compared with homozygous AA, BC patients carrying TNFRSF13B rs4273077(AG/GG) and PVT1 rs10108514(AG/GG) had a 26% (HR: 0.74, 95%CI: 0.54-1.01) and 27% (HR: 0.73, 95%CI: 0.54-0.98) reduced risk of recurrence and metastasis, respectively; compared with homozygous CC, patients with BC carrying NAMPT rs4730155(CT/TT) had a 35% (HR: 0.65, 95%CI: 0.45-0.93) reduced risk of recurrence and metastasis; while compared with CASC16 rs12920540(CA/AA), BC patients with homozygous CC has a 52% (HR: 1.52, 95%CI: 1.06-2.18) increased risk of recurrence and metastasis. Analysis of TCGA and GTEX databases showed that the expression levels of PVT1 and CASC16 in breast tumors were significantly higher than those in normal tissues and matched para-cancerous tissues (P&amp;lt; 0.001), whereas the expression level of NAMPT in breast tumors was significantly lower than that in normal tissues (P&amp;lt; 0.001). No significant difference was shown about the expression level of TNFRSF13B between breast tumor and normal tissues or matched para-cancerous tissues (P≥0.05). Conclusion: Our study suggested that PVT1, CASC16, TNFRSF13B and NAMPT may be correlated with the risk of recurrence and metastasis of BC. Glutamatergic synaptic transmission, calcium signaling pathway and insulin secretion pathway may be involved in BC recurrence and metastasis. Citation Format: Huihui Li, Sha Yin, Shujuan Sun, Qiaorui Tan, Xiaochu Man, Jie Huang, Xuemei Xie. PVT1, CASC16, TNFRSF13B and NAMPT may be the key genes correlated with recurrence and metastasis of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-31.

Rare genetic variants underlie outlying levels of DNA methylation and gene-expression.

Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared with complex traits. Here, we investigate DNAm in healthy ageing populations-the Lothian Birth Cohorts of 1921 and 1936-and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic single nucleotide polymorphisms (SNPs) within 1kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels toward the tails of the population distribution. This study demonstrates the role of rare SNPs in the phenotypic variation of DNAm and the effect of extreme levels of DNAm on gene expression.

Влияние однонуклеотидных полиморфизмов генов свертывающей системы крови и фолатного цикла на тяжесть течения и исходы COVID-19

Objective. To characterize the relationship of alleles of single nucleotide genetic polymorphisms in the genes of the hemostasis system and folate cycle with the severity of the course and outcomes of the COVID-19 coronavirus infection. Patients and methods. The study conducted on the basis of the Republican Clinical Infectious Diseases Hospital of Izhevsk in 2020–2021 included 40 patients with COVID-19. The study of alleles of single nucleotide polymorphisms (SNP) of 12 genes encoding factors of the blood coagulation system was performed in patients. Biological analysis of genomic DNA was performed using a set of reagents "Real-Best-Genetics Hemostasis (12)". A CFX96 amplifier (Bio-Rad, USA) was used to carry out the polymerase chain reaction. The significance level of differences between the groups was determined using the criteria χ2, Mann–Whitney and Fisher's exact criterion. Results. The C allele of SNP of ITGB3:1565 β3 integrin gene (T/C) tends to be associated with a more severe course of the disease (p = 0.048). The C allele of SNP of β3 integrin gene ITGB3:1565 (T/C), the T allele of SNP of α2 integrin gene ITGA2:807 (C/T), and the T allele of SNP of methylenetetrahydrofolate reductase gene MTHFR:677 (C/T) tend to be associated with higher mortality with COVID-19 (p &lt; 0.05). Conclusion. The minor allele of SNP of ITGB3:1565 (T/C) gene can be considered as a predictor of the severe course of COVID-19, minor alleles of SNP of ITGB3:1565 (T/C), ITGA2:807 (C/T), and MTHFR:677 (C/T) genes can be considered as predictors of a higher risk of a lethal outcome. Key words: COVID-19, single nucleotide gene polymorphisms, blood coagulation system, folate cycle

Genetic Single Nucleotide Polymorphisms of IL-16 and its Concentration of Patients Infected with Alopecia Areata in Diyala Province, Iraq

Genetic Single Nucleotide Polymorphisms of IL-16 and its Concentration of Patients Infected with Alopecia Areata in Diyala Province, Iraq

ACE2 polymorphisms impact COVID-19 severity in obese patients

A strong association between obesity and COVID-19 complications and a lack of prognostic factors that explain the unpredictable severity among these patients still exist despite the various vaccination programs. The expression of angiotensin converting enzyme 2 (ACE2), the main receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is enhanced in obese individuals. The occurrence of frequent genetic single nucleotide polymorphisms (SNPs) in ACE2 is suggested to increase COVID-19 severity. Accordingly, we hypothesize that obesity-associated ACE2 polymorphisms increase the severity of COVID-19. In this study, we profiled eight frequently reported ACE2 SNPs in a cohort of lean and obese COVID-19 patients (n = 82). We highlight the significant association of rs2285666, rs2048683, rs879922, and rs4240157 with increased severity in obese COVID-19 patients as compared to lean counterparts. These co-morbid-associated SNPs tend to positively correlate, hence proposing possible functional cooperation to ACE2 regulation. In obese COVID-19 patients, rs2285666, rs879922, and rs4240157 are significantly associated with increased blood nitrogen urea and creatinine levels. In conclusion, we highlight the contribution of ACE2 SNPs in enhancing COVID-19 severity in obese individuals. The results from this study provide a basis for further investigations required to shed light on the underlying mechanisms of COVID-19 associated SNPs in COVID-19 obese patients.

A Review of Genetic Polymorphisms and Susceptibilities to Complications after Aneurysmal Subarachnoid Hemorrhage

Delayed cerebral ischemia (DCI) and vasospasm are two complications of subarachnoid hemorrhages (SAHs) which entail high risks of morbidity and mortality. However, it is unknown why only some patients who suffer SAHs will experience DCI and vasospasm. The purpose of this review is to describe the main genetic single nucleotide polymorphisms (SNPs) that have demonstrated a relationship with these complications. The SNP of the nitric oxide endothelial synthase (eNOS) has been related to the size and rupture of an aneurysm, as well as to DCI, vasospasm, and poor neurological outcome. The SNPs responsible for the asymmetric dimetilarginine and the high-mobility group box 1 have also been associated with DCI. An association between vasospasm and the SNPs of the eNOS, the haptoglobin, and the endothelin-1 receptor has been found. The SNPs of the angiotensin-converting enzyme have been related to DCI and poor neurological outcome. Studies on the SNPs of the Ryanodine Receptor yielded varying results regarding their association with vasospasm.