Allele Of SNP Research Articles

Genetic and Anthropometric Interplay: How Waist-to-Hip Ratio Modulates LDL-c Levels in Mexican Population.

Genetic factors contribute to the physiopathology of obesity and its comorbidities. This study aimed to investigate the association of the SNPs ABCA1 (rs9282541), ADIPOQ (rs2241766), FTO (rs9939609), GRB14 (rs10195252), and LEPR (rs1805134) with various clinical, anthropometric, and biochemical variables. The study included 396 Mexican mestizo individuals with obesity and 142 individuals with normal weight. Biochemical markers were evaluated from peripheral blood samples, and SNP genotyping was performed using PCR with TaqMan probes. A genetic risk score (GRS) was computed using an additive model. No significant associations were found between the SNPs ABCA1, ADIPOQ, FTO, and LEPR with obesity. However, the T allele of the GRB14 SNP was significantly associated with obesity (χ2 = 5.93, p = 0.01; OR = 1.52; 95% CI: 1.08-2.12). A multivariate linear regression model (adjusted R-squared: 0.1253; p < 0.001) predicting LDL-c levels among all participants (n = 538) identified significant (p < 0.05) beta coefficients for several anthropometric and biochemical variables, as well as for the GRS. Additionally, the interaction between the GRS and the waist-to-hip ratio (WHR) showed a negative beta coefficient (BC = -26.5307; p = 0.014). Participants with a WHR < 0.839 showed no effect of GRS on LDL-c concentration, while those with a WHR > 0.839 exhibited a greater effect of GRS (~9) at lower LDL-c concentrations (~50 mg/dL) and a lesser effect of GRS (~7) at higher LDL-c concentrations (~250 mg/dL). A significant interaction between genetics and WHR influences LDL-c in Mexicans, which may contribute to the prevention and clinical management of dyslipidemia and cardiovascular disease.

Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions.

Variation of the 3'RR1 HS1.2 Enhancer and Its Genomic Context.

In humans, the HS1.2 enhancer in the Ig heavy-chain locus is modular, with length polymorphism. Previous studies have shown the following features for this variation: (i) strong population structuring; (ii) association with autoimmune diseases; and (iii) association with developmental changes in Ig expression. The HS1.2 region could then be considered as a contributor to inter-individual diversity in humoral response in adaptive immunity. We experimentally determined the HS1.2-length class genotype in 72 of the 1000 Genomes CEU cell lines and assigned the HS1.2 alleles to haplotypes defined by 18 landmark SNPs. We also sequenced the variable portion and ~200 bp of the flanking DNA of 34 HS1.2 alleles. Furthermore, we computationally explored the ability of different allelic arrangements to bind transcription factors. Non-random association between HS1.2 and Gm allotypes in the European population clearly emerged. We show a wealth of variation in the modular composition of HS1.2, with five SNPs further contributing to diversity. Longer alleles offer more potential sites for binding but, for same-length alleles, SNP variation creates/destroys potential binding sites. Altogether, the arrangements of modules and SNP alleles both inside and outside HS1.2 denote an organization of diversity far from randomness. In the context of the strong divergence of human populations for this genomic region and the reported disease associations, our results suggest that selective forces shaped the pattern of its diversity.

Whole-genome SNP allele frequency differences between Tibetan and Large white pigs reveal genes associated with skeletal muscle growth

BackgroundThe skeletal muscle growth rate and body size of Tibetan pigs (TIB) are lower than Large white pigs (LW). However, the underlying genetic basis attributing to these differences remains uncertain. To address this knowledge gap, the present study employed whole-genome sequencing of TIB (slow growth) and LW (fast growth) individuals, and integrated with existing NCBI sequencing datasets of TIB and LW individuals, enabling the identification of a comprehensive set of genetic variations for each breed. The specific and predominant SNPs in the TIB and LW populations were detected by using a cutoff value of 0.50 for SNP allele frequency and absolute allele frequency differences (△AF) between the TIB and LW populations.ResultsA total of 21,767,938 SNPs were retrieved from 44 TIB and 29 LW genomes. The analysis detected 2,893,106 (13.29%) and 813,310 (3.74%) specific and predominant SNPs in the TIB and LW populations, and annotated to 24,560 genes. Further GO analysis revealed 291 genes involved in biological processes related to striated and/or skeletal muscle differentiation, proliferation, hypertrophy, regulation of striated muscle cell differentiation and proliferation, and myoblast differentiation and fusion. These 291 genes included crucial regulators of muscle cell determination, proliferation, differentiation, and hypertrophy, such as members of the Myogenic regulatory factors (MRF) (MYOD, MYF5, MYOG, MYF6) and Myocyte enhancer factor 2 (MEF2) (MEF2A, MEF2C, MEF2D) families, as well as muscle growth inhibitors (MSTN, ACVR1, and SMAD1); KEGG pathway analysis revealed 106 and 20 genes were found in muscle growth related positive and negative regulatory signaling pathways. Notably, genes critical for protein synthesis, such as MTOR, IGF1, IGF1R, IRS1, INSR, and RPS6KA6, were implicated in these pathways.ConclusionThis study employed an effective methodology to rigorously identify the potential genes associated with skeletal muscle development. A substantial number of SNPs and genes that potentially play roles in the divergence observed in skeletal muscle growth between the TIB and LW breeds were identified. These findings offer valuable insights into the genetic underpinnings of skeletal muscle development and present opportunities for enhancing meat production through pig breeding.

Environmental variation predicts patterns of genomic variation in an African tropical forest frog

Central African rainforests are predicted to be disproportionately affected by future climate change. How species will cope with these changes is unclear, but rapid environmental changes will likely impose strong selection pressures. Here we examined environmental drivers of genomic variation in the central African puddle frog (Phrynobatrachus auritus) to identify areas of elevated environmentally-associated turnover. We also compared current and future climate models to pinpoint areas of high genomic vulnerability where allele frequencies will have to shift the most in order to keep pace with future climate change. Neither physical landscape barriers nor the effects of past Pleistocene refugia influenced genomic differentiation. Alternatively, geographic distance and seasonal aspects of precipitation are the most important drivers of SNP allele frequency variation. Patterns of genomic differentiation coincided with key ecological gradients across the forest-savanna ecotone, montane areas, and a coastal to interior rainfall gradient. Areas of greatest vulnerability were found in the lower Sanaga basin, the southeastern region of Cameroon, and southwest Gabon. In contrast with past conservation efforts that have focused on hotspots of species richness or endemism, our findings highlight the importance of maintaining environmentally heterogeneous landscapes to preserve genomic variation and ongoing evolutionary processes in the face of climate change.

Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. A total of 50 640 participants were included with a mean age of 49.5years (SD: 1.67years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

PREDICTING THE PROBABILITY OF DEVELOPING OBESITY DEPENDING ON LEPTIN AND LEPTIN RECEPTOR POLYMORPHISMS

Introduction. Metabolic syndrome is a heterogeneous pathological condition that combines different stages of obesity, impaired glucose tolerance, atherogenic dyslipidemia and arterial hypertension. Obesity itself is a key element of this syndrome. Hormonal disorders, the central one of which is insulin resistance, trigger a cascade of neuroendocrine changes that lead to the progression of MetS. Monogenic mutations are often detected in patients with severe obesity, as well as with early (up to 10 years) its debut. In recent years, it has been increasingly investigated for a genetically determined breakdown in the mechanism of leptin's influence on the development of obesity. The aim of this study – to evaluate the probability of obesity development in patients with LEP and LEPR polymorphisms in Ukrainian population. Research Methods. 53 obesity and 43 non-obesity patients underwent genotyping of the LEP and LEPR genes (K109R (rs1137100), Q223R (rs1137101), K656N (rs1805094), G2548A (rs7799039)) polymorphism was performed using TaqMan™ SNP Genotyping Human Assays (Thermo Fisher Scientific, USA). Results and Discussion. Comparing rs1137101 Allele A, rs1137101 Allele G statistically significant differences were revealed, while comparing rs1805094 Allele C, rs1805094 Allele G, rs7799039 Allele A, rs7799039 Allele G, rs1137100 Allele A, rs1137100 Allele G depending on group indicated no statistically significant differences. SNP (rs1137101) Allele A statistically significant differences depending on obesity degree (p &lt; 0.001). Comparing the rest of SNP`s Allele`s (rs1805094 Allele C, rs1805094 Allele G, rs7799039 Allele A, rs7799039 Allele G, rs1137101 Allele G, rs1137100 Allele A, rs1137100 Allele G, rs696217 Allele G) no statistically significant differences was noted. Prediction of the probability of developing obesity depending on the polymorphism of leptin and leptin receptors revealed the dependence of only mutations in LEPR (Q223R (rs1137101)) in the Ukrainian population. According to the results of the ROC analysis sensitivity and specificity of the method were 65.5 % and 67.8 %, respectively. Conclusions. Our analysis showed that LEPR Q223R (rs1137101) polymorphism could be a potential genetic risk factor for obesity in Ukrainian population regardless of the homozygous or heterozygous genotype (genotypes AA, AG, GG). At the same time, allele A was found in 70.83 % of cases of patients with 2nd and 3rd degree obesity. And homozygous AA and GG genotypes in 24.5 % and 28.3 %, respectively. The results obtained can be used in the practice for early diagnosis of different types of obesity and for prognosing of results of bariatric surgery.

Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients.

The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens. A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000). Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue. Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.

Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes

BackgroundAnalysing genomes of animal model organisms is widely used for understanding the genetic basis of complex traits and diseases, such as obesity, for which only a few mouse models exist, however, without their lean counterparts.ObjectiveTo analyse genetic differences in the unique mouse models of polygenic obesity (Fat line) and leanness (Lean line) originating from the same base population and established by divergent selection over more than 60 generations.MethodsGenetic variability was analysed using WGS. Variants were identified with GATK and annotated with Ensembl VEP. g.Profiler, WebGestalt, and KEGG were used for GO and pathway enrichment analysis. miRNA seed regions were obtained with miRPathDB 2.0, LncRRIsearch was used to predict targets of identified lncRNAs, and genes influencing adipose tissue amount were searched using the IMPC database.ResultsWGS analysis revealed 6.3 million SNPs, 1.3 million were new. Thousands of potentially impactful SNPs were identified, including within 24 genes related to adipose tissue amount. SNP density was highest in pseudogenes and regulatory RNAs. The Lean line carries SNP rs248726381 in the seed region of mmu-miR-3086-3p, which may affect fatty acid metabolism. KEGG analysis showed deleterious missense variants in immune response and diabetes genes, with food perception pathways being most enriched. Gene prioritisation considering SNP GERP scores, variant consequences, and allele comparison with other mouse lines identified seven novel obesity candidate genes: 4930441H08Rik, Aff3, Fam237b, Gm36633, Pced1a, Tecrl, and Zfp536.ConclusionWGS revealed many genetic differences between the lines that accumulated over the selection period, including variants with potential negative impacts on gene function. Given the increasing availability of mouse strains and genetic polymorphism catalogues, the study is a valuable resource for researchers to study obesity.

The Association of Leptin Receptor Gene Q223R Polymorphism with Obesity in the Yakut Population

Background: This study aimed to compare the frequencies of alleles and genotypes of the LEPR Q223R SNP in the Yakut population in samples with normal BMI and obesity and compare the data obtained with other populations worldwide. Methods and Results: The study included 336 DNA samples from volunteers of Yakut nationality (117 women and 219 men) without chronic diseases, whose average age was 47.4±0.06 years. All volunteers were divided into two groups: Group 1 (n=151) with normal BMI and Group 2 (n=185) with obesity. Group 2 was divided into two subgroups: Group 2A (n=156) with BMI ≥30 kg/m2 plus OA and Group 2B (n=29) with BMI ≥30 kg/m2 and without abdominal obesity.The study of the LEPR Q223R SNP was performed using the PCR-RFLP method. The frequency of the G allele of the LEPR Q223R SNP was 79.5% in Group 1 and 82.7% in Group 2. Analysis showed a high frequency of genotype GG: 64.2% and 69.7% in Group 1 and Group 2, respectively. The frequency of the GA genotype was 30.5% in Group 1 and 25.9% in Group 2.The frequency of alleles and genotypes does not differ in the sample of Yakuts with normal BMI and those with obesity. There are also no differences in the frequency of alleles and genotypes based on gender and the presence of abdominal obesity.The high frequency of the G allele in the Yakut population is close to that observed in East Asian populations (86.9%). There was no statistical difference in allele frequencies in comparison with the populations of Han Chinese from Beijing, Japanese from Tokyo, and Vietnamese from Ho Chi Minh City. In European, African, American, and South Asian populations, the G allele occurs with a frequency of 43.7% to 59.2%. Conclusion: The LEPR Q223R SNP does not affect BMI in the Yakut population. In this study, Q223R allele frequencies were like allele frequencies in East Asian populations but not in Caucasians, reflecting racial diversity in the allele distribution of this polymorphism.

The Effects of -806 T/C and -857 T/C Single Nucleotide Polymorphisms in the TNF-α Gene on Rheumatoid Arthritis Severity and Inflammatory Markers

Background: Polymorphisms in the TNF-α gene affect the development and progression of rheumatoid arthritis. Objective: To investigate the associations between (-806 T/C) and (-857 T/C) SNPs with rheumatoid arthritis severity and susceptibility in a sample of Iraqi patients. Methods: A case-control study was conducted in Baghdad, Iraq. Twenty healthy controls and 63 patients confirmed to be newly diagnosed with rheumatoid arthritis were included. Those are divided into two groups (patients and controls), and the patients were further subdivided into severe and mild-moderate groups. Samples from those participants were analyzed for clinical and inflammatory parameter measurements. Genotyping by the Sanger method was performed to study the SNPs. Results: No associations were demonstrated between rheumatoid arthritis and polymorphisms at positions -806 and -857. Additionally, there were no differences in the distribution of those SNP genotypes and alleles among the severe and mild-moderate groups. Also, the (-806 C/T) SNP was found to be correlated with DAS 28 in all patients and with hs-CRP in the mild-moderate group. Finally, the -857 C/T SNP was found to be correlated with TNF-α within the mild-moderate group. Conclusions: Polymorphisms at positions -806 and -857 were not associated with rheumatoid arthritis susceptibility, and the CT genotype of -806 C/T SNP was associated with disease activity.

Target enrichment sequencing coupled with GWAS identifies MdPRX10 as a candidate gene in the control of budbreak in apple.

The timing of floral budbreak in apple has a significant effect on fruit production and quality. Budbreak occurs as a result of a complex molecular mechanism that relies on accurate integration of external environmental cues, principally temperature. In the pursuit of understanding this mechanism, especially with respect to aiding adaptation to climate change, a QTL at the top of linkage group (LG) 9 has been identified by many studies on budbreak, but the genes underlying it remain elusive. Here, together with a dessert apple core collection of 239 cultivars, we used a targeted capture sequencing approach to increase SNP resolution in apple orthologues of known or suspected A. thaliana flowering time-related genes, as well as approximately 200 genes within the LG9 QTL interval. This increased the 275 223 SNP Axiom® Apple 480K array dataset by an additional 40 857 markers. Robust GWAS analyses identified MdPRX10, a peroxidase superfamily gene, as a strong candidate that demonstrated a dormancy-related expression pattern and down-regulation in response to chilling. In-silico analyses also predicted the residue change resulting from the SNP allele associated with late budbreak could alter protein conformation and likely function. Late budbreak cultivars homozygous for this SNP allele also showed significantly up-regulated expression of C-REPEAT BINDING FACTOR (CBF) genes, which are involved in cold tolerance and perception, compared to reference cultivars, such as Gala. Taken together, these results indicate a role for MdPRX10 in budbreak, potentially via redox-mediated signaling and CBF gene regulation. Moving forward, this provides a focus for developing our understanding of the effects of temperature on flowering time and how redox processes may influence integration of external cues in dormancy pathways.

SNPs as Stochastic Oscillators in Inheritance of Human Diseases.

Genetic variants contribute to differences in disease susceptibility. The aim of the study was to elucidate if variants can affect human disease inheritance. Recently, a list of germline hotspot genetic variants across human autosomal chromosomes was published. Recording the genetic variant hotspots across autosomal chromosomes, their frequency was calculated for each distinct type of genetic variant hotspot and for each autosomal chromosome. Then, OMIM autosomal dominant (AD) and recessive diseases (AR) were counted across each chromosome having maximum and minimum coverage of each type of genetic variant hotspot and the data were compared. Subsequently, the study focused on chromosome 16 with the maximum and chromosome 13 with the minimum number of SNP hotspots. AD and AR diseases were recorded, inside or near the reported SNP variant hotspots of chromosome 16 and 13, and the data were compared. The SPSS software was used for statistical analyses. Autosomal dominant diseases were mainly found in low SNP hotspot chromosomal regions compared to recessive ones, underlying SNPs' possible regulatory role in allelic imbalance. The haplotypic background may be the key factor for variant classification, which could explain the current inconsistencies among scientists with the same genetic variant to be classified as pathogenic, likely pathogenic, or of unknown significance. Which came first: the SNPs or the type of inheritance? Third next-generation sequencing with long reads could answer by phasing SNP alleles' haplotypes and tracing their in-cis and in-trans modulator function in human Mendelian and Complex inheritance.

A CLU/APOJ GWAS AD risk variant suppresses the astrocytic response to plaques and reduces axonal and neuritic damage in 5xFAD mice

AbstractBackgroundGenome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer’s disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The region surrounding the SNP risk allele rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.MethodCRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 and 12. Coronal brain sections were immunolabeled to visualize dense‐core plaques (ThioS), microglia (IBA1), astrocytes (S100β and GFAP), axonal (NfL) and neuritic (LAMP1) damage, confocal images of subiculum and cortical regions were taken and analyzed using Imaris software. In addition, brain Aβ and plasma NfL levels were quantified using meso scale discovery technology.Result5xFAD;Clu‐rs2279590_h2kb showed significantly reduced microglial density compared to 5xFAD mice in both brain areas at 4 months. By 12 months of age, microglial density was comparable between genotypes in cortex while in subiculum, elevated IBA1 cell density was observed in 5xFAD;Clu‐rs2279590_h2kb mice. Clu‐rs2279590_h2kb variant in 5xFAD background increased the density of S100β astrocytes in subiculum at 4 months and decreased the total S100β volume at 12 months. Reduced GFAP (reactive astrocytes) levels were found in cortex but not subiculum at 12 months. Despite comparable plaque load and insoluble Aβ42 levels, neuritic and axonal damage was decreased in the brain of 5xFAD;Clu‐rs2279590_h2kb compared to 5xFAD mice at 12 months. Plasma NfL was also significantly decreased.ConclusionDespite the minimal impact on Aβ plaque deposition, humanization of 2kb of Clu allele and introduction of rs2279590 risk SNP suppresses astrocytic response to plaques and is protective against axonal and neuritic damage which is mirrored by the reduced levels of plasma NfL.

Effect of disease‐associated variants in TREM2 on splicing and gene dosage

AbstractBackgroundLoss‐of‐function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu‐Hakola disease (NHD) and behavioral variants of frontotemporal dementia (FTD), while heterozygous variants increase risk of late onset Alzheimer’s disease (AD) and FTD. In over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level, via premature termination codons or via aberrant splicing. The remaining ones are missense variants thought to inactivate the protein; however, the underlying pathogenic mechanism is less clear. In this work we tested whether disease‐associated TREM2 variants may contribute to the pathology via altered splicingMethodSpliceAI prediction algorithm was used to screen 56 disease‐associated/risk‐modifying variants for potential effect on splicing. Variants scored by SpliceAI were tested in the splicing reporter assay with full‐length TREM2. Constructs with the common TREM2 variant or the spliceogenic SNP allele were nucleofected into THP‐1, HMC3 and BV2 cell lines. qRT‐/RT‐PCR and western blots were used to quantify the effect of variants at the transcript and protein levels. Nanostring nCounter analysis was used to measure TREM2 RNA in brains of NHD patients who carried spliceogenic variants.ResultWe demonstrated that multiple variants causative for NHD or associated with AD/FTD affect gene splicing reduced dosage of functional transcript and protein.ConclusionOur findings point to the complex character of pathogenicity of TREM2 variants, in which effects on post‐transcriptional gene regulation and protein function are often combined. This hidden layer of complexity necessitates inclusion of computational and experimental analyses of splicing and mRNA processing for better understanding of genetic variation in disease.

Biotechnological Strategies Adopted for Sugarcane Disease Management in Tucumán, Argentina

Sugarcane diseases can be controlled by an integrated management approach where biotechnological tools can successfully contribute. The Obispo Colombres Agroindustrial Experimental Station (EEAOC) in Tucumán (Argentina’s main sugarcane producer) has successfully implemented multiple strategies that greatly enhance the productivity of sugarcane fields. The local breeding program develops resistant varieties by applying molecular markers to reveal the presence of Bru1 gene for brown rust resistance throughout the EEAOC germplasm collection. In addition, SNP alleles linked to novel sources of resistance were identified following a selective genotyping strategy. Another strategy is the implementation of a seed cane sanitation project using hydrothermal therapy, an in vitro culture technique, molecular diagnosis of diseases, and bionanoparticles. As a result, the incidence of systemic diseases has significantly decreased in the production fields. More recently, the use of biological products has shown to be effective for disease control in EEAOC varieties. In summary, several biotechnological strategies including molecular markers associated with resistant sources, in vitro culture of apical meristems, molecular diagnostic techniques, and the use of bioproducts are being successfully used for the sustainable management of sugarcane diseases in Tucumán, Argentina.

Distribution of human gene polymorphisms allele frequencies associated with viral infections.

The design of studies aimed at finding the association between the genetic factor and the studied feature (disease) involves a comparison of the ratio of genotypes or allelic proportions in the study group with those in the control group. At the stage of determining the ratio of genotypes of the studied polymorphisms in the reference group, researchers meet a number of problems, which are the subject of the present work. Aim of the work is to provide scientific rationale for the feasibility of creating a national information system comprising genetic data of the relatively healthy population of Russia, incorporating its ethnic diversity. The study group, total 1020 people, was genotyped for a number of single nucleotide polymorphisms of human genes. A comparative characteristic of the frequency distribution of the studied polymorphisms with those presented in international databases as reference data was carried out using χ2 index. The frequency of SNP rs4986790 of the TLR4 gene significantly differs from the EUR population (p = 0.032) and the CEU subpopulation (p = 0.047). The allele frequencies of the rs1800795 (IL6) and rs1800896 (IL10) polymorphisms in the study population differ from the CEU subgroup (p = 0.030 and 0.012, respectively). The frequency of SNP rs2295119 (HLA-DPA2) in the study group is significantly different from the EUR population (p = 0.034). The analysis carried out in this work confirms the need to create a domestic information system containing data on the occurrence of SNP alleles and genotypes for a conditionally healthy population and in subgroups with various pathological conditions.

Association of ADAM33 gene with COPD pathophysiology: a case–control study

BackgroundWorldwide, Chronic Obstructive pulmonary disease (COPD) is a main cause of morbidity and mortality. Considering the global increase in the prevalence of COPD, research on the genetic factors that predispose to COPD is reviving. Recently, ADAM 33 has been found to be related to severe lung function decline and COPD.Aim and objectiveThe present study is carried out with the main aim of determining the association of SNP, i.e., S2 (rs528557), with COPD.MethodA case–control methodology is used to recruit participants. 50 COPD patients over 40 years of age and with a history of more than 20 pack years of cigarette smoking were enlisted. The same number of age and gender-matched controls with no COPD history were involved. PCR sequencing was used to analyze the genetic polymorphism of the ADAM 33 gene (SNP, i.e., S2 (rs528557). Statistical analysis was carried out using SPSS version 21. The Chi-square test was used to determine the difference in SNP rs528557 genotypes and alleles between controls and COPD.ResultsThe findings of this study revealed that the G allele was present in all COPD cases (100%) and 72% of control (p = < 0.001). The minor C allele was 14% and 32% in COPD patients and control, respectively. The G/G genotype is overrepresented in cases (25.5%) than in the control (9.2%). The C/C genotype is overrepresented in controls (3.8%) than in COPD patients (0.9%).ConclusionThe findings of this study demonstrate a significant association of the ADAM 33 gene (SNP, i.e., S2 (rs528557) with COPD pathophysiology in the studied group.

Polymorphism of IL13 (rs1295685) Gene and Its Serum Level in a Sample of Iraqi Patients with Allergic Asthma

Interleukin 13 (IL-13) is an immune-regulatory cytokine, primarily secreted by activated T Helper-Type (Th) 2 cells, which inhibits inflammatory cytokine production in allergic asthma. Single nucleotide polymorphism SNP (1295685A˃G) of the IL-13 gene and its serum level was included in a case-control study on 60 Iraqi asthmatics and 60 controls. ELISSA-linked immune-sorbent assay was used to estimate blood serum levels. The real-time high-resolution melting polymerase-chain-reaction (Real-time PCR-HRM) method was used to determine this variant. The results showed that the mean level of IL-13 was high in asthmatic patients compared to the control group (22.90 pg/ml vs.13.99 pg/ml), respectively, and significant differences were (p=0.0001). ROC curve analysis of IL-13 described an AUC of 0.882. Regarding the allele and genotype of (A˃G 1295685) SNP, there were clear differences between patients and the control group, as the frequency of the GG +AG genotype was significantly higher (p=0.001) in patients compared to the control group (81.7%vs.23.3%) respectively, and the G allele frequency was higher in patients compared to the control group (48.8% vs. 16.6%) respectively, with significant difference (p=0.001). In conclusion, increased levels of IL-13 in serum and the presence of the G allele, GG + AG genotype in the IL13 gene may be associated with the pathogenesis of allergic asthma in Iraqi adult patients. Keywords: Allergic Asthma, IL-13, SNP, RT-HRM-PCR