Several Single Nucleotide Polymorphisms Research Articles

Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study.

Previous research has suggested a potential link between folic acid supplementary therapy and gastric ulcers. To investigate this relationship further, we conducted a Mendelian randomization (MR) analysis using data from the UK Biobank. Our analysis primarily employed inverse variance-weighted (IVW) methods, including both fixed-effect and random-effect models. To ensure the robustness of our findings, additional methods such as the simple median, the weighted median, and the penalized weighted median were also applied. The MR analysis aimed to explore the causal effect of FA supplementary therapy on gastric ulcers. Seven single nucleotide polymorphisms (SNPs) at genetic loci associated with FA supplementary therapy were identified. Both the random-effect and fixed-effect IVW models indicated that genetically predicted FA supplementary therapy significantly reduced the risk of gastric ulcers (OR, 0.870; 95% CI, 0.826-0.917, p<0.001). This result was consistent across other methods, with similar outcomes observed using the simple median (OR, 0.835; 95% CI, 0.773-0.901, p<0.001), the weighted median (OR, 0.854; 95% CI, 0.794-0.919, p<0.001), and the penalized weighted median (OR, 0.849; 95% CI, 0.789-0.914, p<0.001). Leave-one-out sensitivity analysis confirmed that no individual SNP significantly drove the association between FA supplementary therapy and gastric ulcers. This MR study provides genetic evidence that FA supplementary therapy may decrease the risk of gastric ulcers.

Fine mapping and identification of the downy mildew resistance gene BoDMR2 in Cabbage (Brassica oleracea L. var. capitata).

Cabbage (Brassica oleracea L. var. capitata) is an important crop within the Brassica oleracea species and is extensively cultivated worldwide. In recent years, outbreaks of downy mildew caused by Hyaloperonospora parasitica have resulted in substantial losses in cabbage production. Despite this, there have been limited studies on genes associated with resistance to downy mildew in cabbage. This study identified sister lines exhibiting significant differences in disease resistance and susceptibility. Using bulked segregant analysis followed by sequencing (BSA-seq) and linkage analysis, the cabbage resistance locus BoDMR2 was accurately mapped to an approximately 300kb interval on chromosome 7. Among the candidate genes identified, several single nucleotide polymorphisms (SNPs) and a 3-bp insertion were found within the conserved domain of the Bo7g117810 gene, encoding a leucine-rich repeat domain protein, in susceptible genotypes. Additionally, real-time quantitative polymerase chain reaction (RT‒qPCR) analysis revealed that the expression level of Bo7g117810 in resistant specimens was 2.5-fold higher than that in susceptible specimens. An insertion‒deletion (InDel) marker was designed based on the identified insertion in susceptible materials, facilitating the identification and selection of downy mildew-resistant cabbage cultivars. This study identifies Bo7g117810 as a potential candidate gene associated with adult-stage resistance to downy mildew in cabbage, supported by observed differences in gene sequence and expression levels. Furthermore, the development of an InDel marker I1-3, based on its mutation, provides valuable resources for breeding resistant cabbage cultivars.

Toxoplasma Gondii In Association with TLR4 Among Regular Hemodialysis Patients

Background: Hemodialysis patients can be considered immunocompromised as they have an increased risk of infections. The activity of Toll -like receptors in defense against infections was observed particularly for Toll like receptor4 molecule. Several single-nucleotide polymorphisms (SNPs) residing in genes encoding Toll -like receptors were reported as significant genetic modifications associated with infections. Aim: To determine the association between Toll- like receptors 4 polymorphisms and the susceptibility to infection with Toxoplasma gondii in hemodialysis patients. Materials and Methods: This case- control study was conducted on 150 patients with hemodialysis and 150 apparently healthy blood donors as control group, the samples were collected in the period from march 2021 to November 2021 from Al-Karama hospital and Al-Yarmouk Teaching Hospital. All patients were investigated for the presence of Toxoplasma gondii and Abs (IgG, IgM) by using ELISA technique and conformation by molecular technique (Real time-PCR). The selected SNPs in Toll- like receptors 4 were amplified by using conventional polymerase chain reaction PCR and then sequencing there polymorphism. Results: In the current study the comparison of median age between patients and controls was with no significant difference, while the laboratory tests revealed significant difference in median level of urea, creatinin , calcium , potassium ,albumin and hemoglobin, and insignificant difference for body mass index and sodium between studied groups. The ratio of females infected with Toxoplasma gondii was higher than infected males. The seropositive result in patients for Toxoplasma gondii - IgG and IgM was 15 and 6 respectively while 19 patients were positive by PCR. However in control group there were 8 patients seropositive for IgG and positive in PCR results while the results of IgM and PCR were negative for all control group. The Polymerase chain reaction (PCR) products of Toll- like receptors 4 genes were subjected for direct sequencing by using Bio edit software. And the resultant sequences were compared with reference sequences in NCBI. The analysis of TLR-4 rs4986790 genotypes were 24(80%) AA and 6(20%) AG in patients while 6 (60%) AA and 4(40%) AG in controls with insignificant difference, while the analysis of TLR-4 rs4986791 genotypes were 24(80%) CC and 6 (20%) CT in patients while 6 (60%) CC and 4(40%) CT in controls with insignificant difference. Conclusion: There was no significant association of Toxoplasma gondii with TLR4 genotypes of rs4986790 and rs4986791 SNPs in hemodialysis patients.

Characterization of SNPs in meat quality-related genes in Argentine Coastal Creole pigs and their potential as a porcine genetic resource.

The Coastal Creole pigs in Argentina are predominantly found in the wild and can trace their lineage directly back to the Iberian breeds introduced by Spanish colonizers. They currently stand as the sole Creole breed in the country recognized by the FAO. However, there exists a dearth of studies assessing their genetic potential within the swine industry. Therefore, this study aimed to genetically characterize the meat quality of Coastal Creole pigs based on seven single nucleotide polymorphisms (SNPs) within the Ryr1, PRKAG3, MC4R, H-FABP, and CAST genes. A total of N = 158 samples were collected from specimens distributed along the coastal region. Our findings revealed all loci to exhibit polymorphism, underscoring the population's remarkable genetic diversity. Furthermore, a higher frequency of alleles favorable for the PRKAG3191I>V/200R>Q, MC4R1426A>G, CAST76872G>A, and Ryr11843C>T genes was observed, while alleles unfavorable predominated for H-FABP1811G>C and CAST638Ser>Arg. The results obtained in this research are highly encouraging, reflecting the genetic potential of these pigs to be utilized in swine production programs.

Genotypes of carboxypeptidase A1 and gamma-glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of intraductal papillary mucinous neoplasm in Japan.

This study aimed to clarify whether several single-nucleotide polymorphisms (SNPs)-related chronic pancreatitis such as carboxypeptidase A1 (CPA1), carboxypeptidase B1 (CPB1), Gamma-glutamyltransferase 1 (GGT1), G-protein-coupled receptor Class C Group 6 Member A (GPRC6A), and serine protease inhibitor, Kazal type 1 (SPINK-1) genotypes were associated with clinical characteristics of patients with intraductal papillary mucinous neoplasm (IPMN) and worrisome features of IPMN. We enrolled 100 patients with IPMN and 116 patients as a control. Serum p-amylase, lipase, trypsin, phospholipase A2 (PLA2), and elastase-1 levels were measured. An Olympus EUS (GF-UCT 260) was used to perform endosonography in 100 patients with IPMN. Total EUS score was evaluated using endosonography. DNA was isolated from the duodenal tissue using a commercial system and polymerase chain reaction (PCR) was performed on 7500 Fast PCR System. There were no associations between glucose tolerances, lipid levels and genotypes of CPA1, GGT1, GPRC6A, and SPINK-1 in patients with IPMN. CPA1 genotype was significantly associated with the pathophysiology of IPMN. Then, GGT1 genotype was also significantly associated with EUS total score and the size of cyst more than 20 mm and more than 30 mm as one of worrisome features of IPMN. Genotypes of carboxypeptidase A1 and gamma-glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of IPMN.

Single nucleotide polymorphism rs7961894, platelet morphological parameters and lipid profile in children with type 1 diabetes: a potential relationship

Increased cardiovascular risk has been associated with certain platelet morphological parameters, and several single nucleotide polymorphisms (SNPs) have been reported to be linked. Still, little is known about their role among children with type 1 diabetes mellitus (T1DM). So, we aimed to investigate platelet parameters and lipid profile changes in relation to rs7961894 SNP in children with T1DM. Eighty children with T1DM and eighty apparently healthy controls participated in this cross-sectional study. Platelet count, mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), HbA1c, triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol were measured, and atherogenic indices were calculated. Using a real-time polymerase chain allelic discrimination technique, rs7961894 SNP was genotyped. Children with T1DM had significantly higher MPV, PDW, TC, and LDL-C compared to controls. 25% of patients had rs7961894 CT genotype with significantly higher MPV, PDW, PCT, LDL-C, triglycerides, Castelli’s risk index II (CRI II), and atherogenic index of plasma (AIP) compared to CC genotyped patients. MPV correlated significantly with CRI II and AIP, PDW with CRI II, while PCT correlated substantially with HbA1c, LDL-C, CRI II, and AIP. rs7961894 CT genotype was a significant dependent predictor of the changes in MPV, PDW, and PCT in multivariate regression analysis.Conclusion: In children with T1DM, rs7961894 CT genotype is significantly linked to MPV, PDW, and PCT changes, which showed a substantial relationship to CRI II and AIP, highlighting the importance of monitoring these patients to identify potential cardiovascular risks early.What is Known:• Platelets and dyslipidemia are involved in atherosclerosis pathogenesis• Changes in platelet activity and morphological parameters in diabetes mellitus are contradictory• rs7961894 single nucleotide polymorphism is associated with significant changes in mean platelet volume (MPV) with no available data in childrenWhat is New:• Children with type 1 diabetes mellitus exhibited significantly higher values of MPV and platelet distribution width (PDW)• rs7961894 CT genotype was a dependent predictor of the changes in MPV, PDW, and plateletcrit (PCT) values• Diabetic children with the rs7961894 CT genotype showed substantial alterations in lipid parameters with a strong correlation between MPV, PDW, and PCT and Castelli’s risk index II and the atherogenic index of plasma

A comprehensive analysis of the health effects associated with smoking in the largest population using UK Biobank genotypic and phenotypic data

BackgroundSmoking is a widespread behavior, while the relationship between smoking and various diseases remains a topic of debate. ObjectiveWe conducted analysis to further examine the identified associations and assess potential causal relationships. MethodsWe utilized seven single nucleotide polymorphisms (SNPs) known to be linked to smoking extracting genotype data from the UK Biobank, a large-scale biomedical repository encompassing comprehensive health-related and genetic information of European descent. Phenome-wide association study (PheWAS) analysis was conducted to map the association of genetically predicted smoking status with 1,549 phenotypes. The associations identified in the PheWAS were then meticulously examined through two-sample Mendelian randomization (MR) analysis, utilizing data from the UK Biobank (n = 487,365) and the Sequencing Consortium of Alcohol and Nicotine Use (GSCAN) (n = 337,334). This approach allowed us to comprehensively characterize the links between smoking and disease patterns. ResultsThe PheWAS analysis produced 34 phenotypes that demonstrated significant associations with smoking (P = 0.05/1460). Importantly, sickle cell anemia and type 2 diabetes exhibited the most significant SNPs (both 85.71% significant SNPs). Furthermore, the MR analyses provided compelling evidence supporting causal associations between smoking and the risk of following diseases: obstructive chronic bronchitis (IVW: Beta = 0.48, 95% confidence interval (CI) 0.36-0.61, P = 1.62×10−13), cancer of the bronchus (IVW: Beta = 0.92, 95% CI 0.68-1.17, P = 2.02×10−13), peripheral vascular disease (IVW: Beta = 1.09, 95% CI 0.71-1.46, P = 1.63×10−8), emphysema (IVW: Beta = 1.63, 95% CI 0.90-2.36, P = 1.29×10−5), pneumococcal pneumonia (IVW: Beta = 0.30, 95% CI 0.11-0.49, P = 1.60×10−3), chronic airway obstruction (IVW: Beta = 0.83, 95% CI 0.30-1.36, P = 2.00×10−3) and type 2 diabetes (IVW: Beta = 0.53, 95% CI 0.16-0.90, P = 5.08×10−3). ConclusionThis study affirms causal relationships between smoking and obstructive chronic bronchitis, cancer of the bronchus, peripheral vascular disease, emphysema, pneumococcal pneumonia, chronic airway obstruction, type 2 diabetes, in the European population. These findings highlight the broad health impacts of smoking and support smoking cessation efforts.

Exploring Variation in Ovine KRTAP19-5 and Its Effect on Fine Wool Fibre Curvature in Chinese Tan Sheep.

Sheep's wool is known to have unique biological, physical and chemical properties. The fibre primarily consists of proteins, but these have amino acid sequence variation, and at the phenotypic level wool fibre varies considerably. This can affect its utility and value. Unravelling the genetic factors that underpin the protein and phenotypic variability is crucial if we are to contemplate improving wool quality. Accordingly, this study investigates the high glycine and tyrosine content keratin-associated protein 19-5 gene (KRTAP19-5) in sheep. PCR-single strand confirmation polymorphism analysis, coupled with DNA sequencing of a region spanning whole coding sequence, revealed six sequence variants containing seven single nucleotide polymorphisms (SNPs). Five of the SNPs were located within the coding region, with four leading to amino acid changes if expressed. In 247 Chinese Tan sheep derived from 10 sire-lines, and renowned for their distinct 'spring-like' crimped wool at up to approximately 35 days after birth, one of the variants was found to be associated with decreased curvature of the fine wool fibres in the fleece. No associations were detected with other fibre traits or with variation in the heterotypic hair fibres of the Tan sheep. While these findings may be useful for developing gene markers to alter mean wool fibre curvature and improve sheep breeding, many other genes and environmental factors are known to contribute to variation in fibre traits.

Exploring the Influence of Fok1/Apa1 Polymorphic Variants on Adolescent Mental Health and Response to Vitamin D Supplementation in Embryonic Hippocampal Cell Lines.

Several single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) have been observed in association with susceptibility to various pathologies, including autism, major depression, age-related changes in cognitive functioning, and Parkinson's and Alzheimer's diseases. This study aimed to establish the association between Fok1/Apa1 polymorphic variants and anxious/depressive symptoms in nonclinical adolescents from central Italy, with the goal of identifying the risk of developing both symptoms. We found no significant difference in genotype distribution or dominant/recessive models of Fok1/Apa1 VDR polymorphic variants between subjects with anxious/depressive symptoms and controls. HN9.10e cell lines carrying the AA genotype for Fok1 and the CC genotype for Apa1 responded better to treatment with vitamin D3 than cell lines carrying the AG genotype for Fok1 and CA genotype for Apa1. Cell lines carrying the GG genotype for Fok1 and the AA genotype for Apa1 did not respond at all, suggesting avenues for future studies in both the general population and individuals with mental and/or neuropsychiatric disorders. These studies suggest that the level of response to vitamin D3 administered to prevent and/or treat mental or neurological disorders could depend on the polymorphic variants of the vitamin D receptor.

Association of transketolase polymorphisms with diabetic polyneuropathy in the general population: The KORA F4 study.

We recently reported that genetic variability in the TKT gene encoding transketolase, a key enzyme in the pentose phosphate pathway, is associated with measures of diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. Here, we aimed to substantiate these findings in a population-based KORA F4 study. In this cross-sectional study, we assessed seven single nucleotide polymorphisms (SNPs) in the transketolase gene in 952 participants from the KORA F4 study with normal glucose tolerance (NGT; n=394), prediabetes (n=411), and type 2 diabetes (n=147). DSPN was defined by the examination partof the Michigan Neuropathy Screening Instrument (MNSI) using the original MNSI > 2 cut-off and two alternative versions extended by touch/pressure perception (TPP) (MNSI>3) and by TPP plus cold perception (MNSI > 4). After adjustment for sex, age, BMI, and HbA1c, in type 2 diabetes participants, four out of seven transketolase SNPs were associated with DSPN for all three MNSI versions (all p≤0.004). The odds ratios of these associations increased with extending the MNSI score, for example, OR (95% CI) for SNP rs62255988 with MNSI>2: 1.99 (1.16-3.41), MNSI>3: 2.27 (1.26-4.09), and MNSI>4: 4.78 (2.22-10.26); SNP rs9284890 with MNSI>2: 2.43 (1.42-4.16), MNSI>3: 3.46 (1.82-6.59), and MNSI>4: 4.75 (2.15-10.51). In contrast, no associations were found between transketolase SNPs and the three MNSI versions in the NGT and prediabetes groups. The link of genetic variation in transketolase enzyme to diabetic polyneuropathy corroborated at the population level strengthens the concept suggesting an important role of pathways metabolising glycolytic intermediates in the evolution of diabetic polyneuropathy.

Tp53 Genetic Mutations in Chronic Lymphocytic Leukemia Patients in Iraq

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a malignant clonal proliferative condition of mature CD5+ B cells, with a 4.2/100,000 annual incidence rate and the median age at diagnosis is 72 years. CLL impacts mainly the elderly in Western nations. About 4%–10% of patients have 17p deleted at diagnosis, which includes tumor-suppressor protein (TP53) gene deletions and/or mutations. However, TP53 can also be acquired during the course of the disease, with a predictable incidence of 42%–45% in refractory CLL. Even when this mutation develops in a small percentage of neoplastic cells, the attending of subclonal TP53 changes has been linked to a bad prognosis. TP53 mutations are correlated with significantly lower lifespan and indicate impaired tolerance to chemoimmunotherapy, making them among the most powerful prognostic markers-guiding treatment decisions in CLL. MATERIALS AND METHODS: This cross-sectional study was performed at different centers in Iraq, including Euphrates Center for Cancerous Tumors, Najaf, and the Hematology center-medical City, Baghdad, Imam al Hussien Medical City, Karbala, from October 2023 to June 2024, with patients diagnosed by blood film and immunophenotyping CLL, included 63 patients. RESULTS: DNA Sequencing of TP53 genes investigated by Sanger technique to detect TP53 variations. All potential genotype variations of the TP53 gene were detected across several single-nucleotide polymorphisms (SNPs). CONCLUSIONS: The vast majority, 93% of our patients, carry variant-type mutations of TP53. The genotype of SNP rs1597359353 was found P &lt; 0.05, which is significant according to the White blood count (WBCs) count, although all patients on treatment or follow-up had TP53 mutations.

Impact of Interleukin-17 Receptor A Gene Variants on Asthma Susceptibility and Clinical Manifestations in Children and Adolescents.

Several single nucleotide polymorphisms (SNPs) in multiple interleukin receptor genes could be associated with asthma risk and/or phenotype. Interleukin-17 (IL-17) has been implicated in tissue inflammation and autoimmune diseases. As no previous studies have uncovered the potential role of IL17 receptor A (RA) gene variants in asthma risk, we aimed to explore the association of four IL17RA SNPs (i.e., rs4819554A/G, rs879577C/T, rs41323645G/A, and rs4819555C/T) with asthma susceptibility/phenotype in our region. TaqMan allelic discrimination analysis was used to genotype 192 individuals. We found that the rs4819554 G/G genotype significantly reduced disease risk in the codominant (OR = 0.15, 95%CI = 0.05-0.45, p < 0.001), dominant (OR = 0.49, 95%CI = 0.26-0.93, p = 0.028), and recessive (OR = 0.18, 95%CI = 0.07-0.52, p < 0.001) models. Similarly, rs879577 showed reduced disease risk associated with the T allele across all genetic models. However, the A allele of rs41323645 was associated with increased disease risk in all models. The G/A and A/A genotypes have higher ORs of 2.47 (95%CI = 1.19-5.14) and 3.86 (95%CI = 1.62-9.18), respectively. Similar trends are observed in the dominant 2.89 (95%CI = 1.47-5.68, p = 0.002) and recessive 2.34 (95%CI = 1.10-4.98, p = 0.025) models. For the rs4819555 variant, although there was no significant association identified under any models, carriers of the rs4819554*A demonstrated an association with a positive family history of asthma (71.4% in carriers vs. 27% in non-carriers; p = 0.025) and the use of relievers for >2 weeks (52.2% of carriers vs. 28.8% of non-carriers; p = 0.047). Meanwhile, the rs4819555*C carriers displayed a significant divergence in the asthma phenotype, specifically atopic asthma (83.3% vs. 61.1%; p = 0.007), showed a higher prevalence of chest tightness (88.9% vs. 61.5%; p = 0.029), and were more likely to report comorbidities (57.7% vs. 16.7%, p = 0.003). The most frequent haplotype in the asthma group was ACAC, with a frequency of 22.87% vs. 1.36% in the controls (p < 0.001). In conclusion, the studied IL17RA variants could be essential in asthma susceptibility and phenotype in children and adolescents.

RHC genotyping in Chinese Han population

BackgroundThe Rh blood group system is characterized by its complexity and polymorphism, encompassing 56 different antigens. Accurately predicting the presence of the C antigen using genotyping methods has been challenging. The objective of this study was to evaluate the accuracy of various genotyping methods for predicting the Rh C and to identify a suitable method for the Chinese Han population.MethodsIn total, 317 donors, consisting 223 D+ (including 20 with the Del phenotype) and 94 D− were randomly selected. For RHC genotyping, 48C and 109bp insertion were detected on the Real-time PCR platform and −292 substitution was analyzed via restriction fragment length polymorphism (RFLP). Moreover, the promoter region of the RHCE gene was sequenced to search for other nucleotide substitutions between RHC and RHc. Agreement between prediction methods was evaluated using the Kappa statistic, and comparisons between methods were conducted via the χ2 test.ResultsThe analysis revealed that the 48C allele, 109bp insertion, a specific pattern observed in RFLP results, and wild-type alleles of seven single nucleotide polymorphisms (SNPs) were in strong agreement with the Rh C, with Kappa coefficients exceeding 0.8. However, there were instances of false positives or false negatives (0.6% false negative rate for 109bp insertion and 5.4-8.2% false positive rates for other methods). The 109bp insertion method exhibited the highest accuracy in predicting the Rh C, at 99.4%, compared to other methods (P values≤0.001). Although no statistical differences were found among other methods for predicting Rh C (P values>0.05), the accuracies in descending order were 48C (94.6%) > rs586178 (92.7%) > rs4649082, rs2375313, rs2281179, rs2072933, rs2072932, and RFLP (92.4%) > rs2072931 (91.8%).ConclusionsNone of the methods examined can independently and accurately predict the Rh C. However, the 109bp insertion test demonstrated the highest accuracy for predicting the Rh C in the Chinese Han population. Utilizing the 109bp insertion test in combination with other methods may enhance the accuracy of Rh C prediction.

Abstract 158: The Role Of Ehbp1 In Hypercholesterolemia

Background: Despite aggressive lowering of cholesterol, conventional lipid-lowering therapies only modestly lower cardiovascular risk in the population. Therefore, identifying novel hypercholesterolemia-risk targets is of critical importance. Human genome-wide association studies (GWAS) have revealed that several single-nucleotide polymorphisms (SNPs) in EHBP1 , the gene that encodes EH domain binding protein 1 (EHBP1), an endocytic trafficking regulator, are associated with serum cholesterol. However, the mechanisms underlying this association and the role of EHBP1 in cholesterol metabolism are unknown. We hypothesize that EHBP1 is a novel hypercholesterolemia risk factor. The goal of this study is to explore the role of EHBP1 in hypercholesterolemia and its underlying mechanisms. Methods: Hepatocyte EHBP1 was silenced by intravenous injection (IV) of AAV8-H1-shEhbp1 in wild-type (WT), Apoe-/- and Ldlr-/- mice, followed by Western Diet feeding to induce hypercholesterolemia and atherosclerosis. Primary murine and human hepatocytes were isolated for in vitro mechanistic studies. We also leveraged publicly available human genetic studies and unbiased scRNA datasets to support our study. Results: Individuals with the EHBP1 rs10496099 T&gt;C variant have decreased serum cholesterol and reduced liver EHBP1 expression. Consistent with the human data, our in vivo study with hypercholesterolemic mice shows that EHBP1 silencing in hepatocytes decreases plasma total and LDL/VLDL cholesterol. Our in vitro study with primary hepatocytes reveals that EHBP1 deficiency eliminates sortilin (SORT1)-mediated PCSK9 secretion and induces LDLR-mediated LDL uptake. Mechanistically, we found that EHBP1 silencing abolishes the homeostasis of the retromer complex, a protein complex that helps retrograde and stabilize sortilin. Conclusion: Hepatocyte EHBP1 promotes sortilin-mediated PCSK9 secretion by maintaining retromer homeostasis, leading to LDLR degradation and hypercholesterolemia. Our study elucidates a novel link between EHBP1 and other cholesterol-associated loci (e.g., SORT1 , PCSK9 , and LDLR) and provides new mechanistic insight into the role of EHBP1 in hepatic cholesterol metabolism and hypercholesterolemia.

Survey of target site mutations linked with insecticide resistance in Italian populations of Aphis gossypii.

Aphis gossypii is a worldwide agricultural pest that causes high levels of economic losses by feeding and transmitting virus diseases. It is usually controlled by chemical insecticides, but this could lead to the selection of resistant populations. Several single nucleotide polymorphisms (SNPs) have been identified associated with insecticide resistance. Monitoring activities to detect the presence of such mutations in field populations can have an important role in insect pest management but, currently, no information on Italian strains is available. The presence of target site mutations conferring resistance to different insecticides was analysed in Italian field collected populations of A. gossypii with an allele specific approach (QSGG, Qualitative Sybr-Green Genotyping). Primers were designed to detect mutations in genes coding acetylcholinesterase (S431F), nicotinic acetylcholine receptor (R81T) and voltage-gated sodium channel (M918L and L1014F). S431F was widespread but with high variability across populations. R81T was detected for the first time in Italy but only in two populations. The L1014F mutation (kdr) was not found, while in the samples showing the M918L two different nucleotidic substitutions were detected. Mutant allele frequencies were, respectively, 0.70 (S431), 0.31 (M918) and 0.02 (R81). Further analysis on the voltage-gated sodium channel gene showed the presence of eight haplotypes and one non-synonymous mutation in the gene coding region. Multiple target-site mutations were detected within Italian populations. The combinations of genotypes observed in certain locations could affect negatively the control of this pest. Preliminary insights on the genetic structure in the Italian populations of A. gossypii were acquired. © 2024 Society of Chemical Industry.

A Simplified Screening Model to Predict the Risk of Gestational Diabetes Mellitus in Caucasian and Latin American Pregnant Women.

The pathophysiology of gestational diabetes mellitus (GDM) comprises clinical and genetic factors. In fact, GDM is associated with several single nucleotide polymorphisms (SNPs). This study aimed to build a prediction model of GDM combining clinical and genetic risk factors. A total of 1588 pregnant women from the San Carlos Cohort participated in the present study, including 1069 (67.3%) Caucasian (CAU) and 519 (32.7%) Latin American (LAT) individuals, and 255 (16.1%) had GDM. The incidence of GDM was similar in both groups (16.1% CAU and 16.0% LAT). Genotyping was performed via IPLEX Mass ARRAY PCR, selecting 110 SNPs based on literature references. SNPs showing the strongest likelihood of developing GDM were rs10830963, rs7651090, and rs1371614 in CAU and rs1387153 and rs9368222 in LAT. Clinical variables, including age, pre-pregnancy body mass index, and fasting plasma glucose (FPG) at 12 gestational weeks, predicted the risk of GDM (AUC 0.648, 95% CI 0.601-0.695 in CAU; AUC 0.688, 95% CI 0.628-9.748 in LAT), and adding SNPs modestly improved prediction (AUC 0.722, 95%CI 0.680-0.764 in CAU; AUC 0.769, 95% CI 0.711-0.826 in LAT). In conclusion, adding genetic variants enhanced the prediction model of GDM risk in CAU and LAT pregnant women.

Pain-related single nucleotide polymorphisms: association with lumbar spinal stenosis patient experience and non-surgical treatment outcomes.

Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G).

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene that causes autistic phenotypes when deleted or duplicated. Observations from clinical cases and animal models also suggest that changes of RAI1 expression levels contribute to autism. Previously, we used a bioinformatic approach to identify several single nucleotide polymorphisms (SNPs) located within the 5'-region of RAI1 that correlate with RAI1 mRNA expression in the human brain. In particular, the SNP rs4925102 was identified as a candidate cis-acting regulatory variant, the genotype of which may affect the binding of transcription factors that influence RAI1 mRNA expression. In this study, we provide experimental evidence based on reporter gene, chromatin immunoprecipitation (ChIP), and chromatin conformation capture (3C) assays that rs4925102 regulates RAI1 mRNA expression in an allele-specific manner in human cell lines, including the neuroblastoma-derived cell line SH-SY5Y. We also describe a statistically significant association between rs4925102 genotype and autism spectrum disorder (ASD) diagnosis in a case-control study and near-statistically significant association in an Autism Genome Project (AGP) transmission disequilibrium (TDT) study using Caucasian subjects.

Integrative regulation of hLMR1 by dietary and genetic factors in nonalcoholic fatty liver disease and hyperlipidemia.

Long non-coding RNA (lncRNA) genes represent a large class of transcripts that are widely expressed across species. As most human lncRNAs are non-conserved, we recently employed a unique humanized liver mouse model to study lncRNAs expressed in human livers. We identified a human hepatocyte-specific lncRNA, hLMR1 (human lncRNA metabolic regulator 1), which is induced by feeding and promotes hepatic cholesterol synthesis. Recent genome-wide association studies (GWAS) found that several single-nucleotide polymorphisms (SNPs) from the hLMR1 gene locus are associated with blood lipids and markers of liver damage. These results suggest that dietary and genetic factors may regulate hLMR1 to affect disease progression. In this study, we first screened for nutritional/hormonal factors and found that hLMR1 was robustly induced by insulin/glucose in cultured human hepatocytes, and this induction is dependent on the transcription factor SREBP1. We then tested if GWAS SNPs genetically linked to hLMR1 could regulate hLMR1 expression. We found that DNA sequences flanking rs9653945, a SNP from the last exon of the hLMR1 gene, functions as an enhancer that can be robustly activated by SREBP1c depending on the presence of rs9653945 major allele (G). We further performed CRISPR base editing in human HepG2 cells and found that rs9653945 major (G) to minor (A) allele modification resulted in blunted insulin/glucose-induced expression of hLMR1. Finally, we performed genotyping and gene expression analyses using a published human NAFLD RNA-seq dataset and found that individuals homozygous for rs9653945-G have a higher expression of hLMR1 and risk of NAFLD. Taken together, our data support a model that rs9653945-G predisposes individuals to insulin/glucose-induced hLMR1, contributing to the development of hyperlipidemia and NAFLD.

Prediction of antipsychotics efficacy based on a polygenic risk score: a real-world cohort study.

Background: Response to antipsychotics is subject to a wide interindividual variability, due to genetic and non-genetic factors. Several single nucleotide polymorphisms (SNPs) have been associated with response to antipsychotics in genome-wide association studies (GWAS). Polygenic risk scores (PRS) are a powerful tool to aggregate into a single measure the small effects of multiple risk alleles. Materials and methods: We studied the association between a PRS composed of SNPs associated with response to antipsychotics in GWAS studies (PRSresponse) in a real-world sample of patients (N = 460) with different diagnoses (schizophrenia spectrum, bipolar, depressive, neurocognitive, substance use disorders and miscellaneous). Two other PRSs composed of SNPs previously associated with risk of schizophrenia (PRSschizophrenia1 and PRSschizophrenia2) were also tested for their association with response to treatment. Results: PRSresponse was significantly associated with response to antipsychotics considering the whole cohort (OR = 1.14, CI = 1.03-1.26, p = 0.010), the subgroup of patients with schizophrenia, schizoaffective disorder or bipolar disorder (OR = 1.18, CI = 1.02-1.37, p = 0.022, N = 235), with schizophrenia or schizoaffective disorder (OR = 1.24, CI = 1.04-1.47, p = 0.01, N = 176) and with schizophrenia (OR = 1.27, CI = 1.04-1.55, p = 0.01, N = 149). Sensitivity and specificity were sub-optimal (schizophrenia 62%, 61%; schizophrenia spectrum 56%, 55%; schizophrenia spectrum plus bipolar disorder 60%, 56%; all patients 63%, 58%, respectively). PRSschizophrenia1 and PRSschizophrenia2 were not significantly associated with response to treatment. Conclusion: PRSresponse defined from GWAS studies is significantly associated with response to antipsychotics in a real-world cohort; however, the results of the sensitivity-specificity analysis preclude its use as a predictive tool in clinical practice.