SNPs In Gene Research Articles

Insight into adiponectin gene impact on coronary artery disease from a polymorphism case-control study in Iraqi individuals

BackgroundCoronary artery disease (CAD) is a group of diseases caused by plaque formation in the wall of arteries supplying blood to the heart. Adiponectin (ADIPOQ) is an adipocytokine that controls carbohydrate and lipid metabolism, has anti-diabetic properties, and correlates well with cardio-metabolic risk. ADIPOQ gene polymorphism is reported to be associated with CAD in numerous populations. ObjectiveTo explore the impact of adiponectin gene polymorphism, rs2241766 T > G, rs1501299 G > T, rs17300539 G > A, rs266729 G > A, and rs822395 A > C SNPs, on the CAD in the Iraqi population. MethodsA case-control study of 317 healthy individuals and 302 CAD patients was conducted. Standard protocols for measuring serum lipid profile levels were followed. ADIPOQ and insulin levels were estimated using the ELISA method. Genotyping of ADIPOQ gene was carried out using the RFLP technique. ResultsGenotype assessment of rs2241766, rs1501299, rs266729, and rs17300539 SNPs under several inheritance models pointed out significant (P = 0.012–10−4) elevations of the variant alleles in CAD patients in comparison to the control group. The haplotype analysis of the five analyzed SNPs exhibited five disease-susceptible haplotypes; they were GTCGA (OR: 7.6, 95 % CI: 2.55–21.76), TGCAA (P = 0.013), TGGGA (P = 0.046), TGGAA (P = 0.017), and GGGGA (P = 0.032). The linkage disequilibrium (LD) analysis of the five SNPs in the control versus the patient groups revealed significant LD. The variant genotype of the rs2241766 SNP was found to significantly increase the atherogenic lipids and HOMA values and decrease the ADIPOQ and high-density cholesterol (HDL-c) levels. Those of the rs1501299, rs17300539, and rs266729 SNPs were indicated to increase the metabolic parameter values except ADIPOQ and HDL-c magnitudes, which are reduced in the variant carriers. ConclusionThe rs2241766, rs1501299, rs266729, and rs17300539 SNPs of the ADIPOQ gene are risk factors for CAD in Iraqi individuals. Both single nucleotide and haplotype analyses suggested the implication of the ADIPOQ gene in the pathogenesis of the disease. This implication has occurred through lowering ADIPOQ levels and increasing atherogenic lipids.

The GG genotype of rs743572 in CYP17A1 gene regulating the decrease of T/E ratio can be an independent risk factor for MetS-BPH: a retrospective cohort study

PurposeTo confirm if the CYP17A1 gene regulates the ratio of T/E leading to MetS-BPH.Methods824 men, aged 47–88 years, were recruited into this study through consecutive routine physical examination programs and long-term outpatient screening. Several parameters, including SNPs of CYP17A1 gene, total testosterone, estradiol, and the ratio of total testosterone to estradiol (T/E) were obtained for each participant. Based on the diagnosis of BPH, MetS, and MetS-BPH, the participants were divided into BPH and non-BPH groups, MetS and non-MetS groups, and MetS-BPH and non-MetS-BPH groups. Values of the obtained parameters were evaluated using one-way analysis of variance, Student’s t-test, Chi-squared test, and logistic regression analysis.ResultsSNPs of the CYP17A1 gene, including the rs743572 genotypes (GG, GA, and AA), rs3781287 genotypes (GG, GT, TT), and rs4919686 genotypes (CC, CA, and AA), were present in every group. Only the GG genotype of rs743572 was independently associated with BPH (OR = 5.868, 95% CI: 3.363–7.974, P < 0.001), MetS (OR = 7.228, 95% CI: 3.925–11.331, P < 0.001), and MetS-BPH (OR = 3.417, 95% CI: 1.783–5.266, P < 0.001) after adjusting for age. In the population of genotype GG of rs743572, the decrease in T/E ratio was an independent risk factor for BPH (OR = 839.756, 95% CI: 36.978-1334.263, P = 0.001), MetS (OR = 376.988, 95% CI: 12.980-488.976, P < 0.003), and MetS-BPH (OR = 388.236, 95% CI: 24.869-495.363, P = 0.003).ConclusionThe GG genotype of rs743572 in CYP17A1 gene regulating the decrease of T/E ratio can be an independent risk factor for MetS-BPH populations.Trial registration numberChiCTR2200057632 “retrospectively registered”.Date of registrationMarch 15, 2022 “retrospectively registered”.

Association between polymorphisms of DNA repair genes and intracranial aneurysms: A systematic review and meta‑analysis.

Intracranial aneurysms (IAs) are present in ~2% of the general population, and genetic factors cannot be excluded for the risk of their development. The gene factors that result in the changes in the vascular extracellular matrix (ECM) may also be a key reason for IAs being hereditary. The VCAN gene [also known as chondroitin sulfate proteoglycan 2 (CSPG2)] plays various roles in maintaining ECM functions. The present systematic review and meta-analysis aimed to investigate all eligible articles involving IAs on the association with germ line SNPs of DNA repair genes (up to January, 2024). The total number of patients was 2,308 [987 cases (poor outcomes) and 1,321 controls (good outcomes)]. The results revealed that rs2287926 G/G genotype and G allele and rs251124 T/T genotype and minor allele T increased the risk of developing IAs. However, further studies are required to examine these gene polymorphisms as screening markers for IAs.

Study of the relationship between genetic variants of IL-18 and the occurrence of inflammatory bowel disease

BackgroundA member of the Interleukin-1 superfamily of cytokines, interleukin-18 (IL-18) is essential to the etiology and progression of inflammatory bowel disease (IBD), a chronic inflammatory illness that affects the digestive system. This study investigated the possible association between two genetic variations, IL-18 rs187238 and IL-18 rs1946518, and IBD in Iraqi patients.MethodsWe evaluated the association of two SNPs of the IL-18 gene at rs187238 and rs1946518 in 54 IBD patients with 19 Crohn’s disease (CD), 35 ulcerative colitis (UC), and 46 healthy controls using PCR-RFLP and PCR-AS techniques for detecting IL-18 rs187238 and IL-18 rs1946518, respectively, by extracting genomic DNA from blood samples.ResultsOur findings indicated no statistically significant variations between the IL-18 rs187238 genotypes and incidences of CD and UC (P = 0.189 and 0.59, respectively). However, the allele frequency showed a significant difference with CD (P = 0.049) but did not show a significant association with UC (P = 0.887). There was no significant association between the genotype and allele frequency of IL-18 rs1946518C/A and CD risk (P = 0.171 and 0.053, respectively). However, there was a significant association between the genotype and allele frequency of IL-18 rs1946518C/A and the risk of developing UC (P = 0.028 and 0.002, respectively).ConclusionThe study revealed statistically significant distinctions between the genetic and allelic frequencies of IL-18 rs1946518 and the probability of developing UC. Nonetheless, there were no significant distinctions between them and CD. According to the research, there were no major differences between IL-18 rs187238 and the two diseases. The frequency of the C allele is connected to CD.

Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population

BackgroundAtherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. ObjectiveTo evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. Material and methods746 individuals from the metropolitan area of ​​Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of 4 SNPs related to the IL-18 signaling pathway was analyzed. ResultsPatients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. ConclusionsHigh levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.

GENETIC POLYMORPHISMS IN RAD51, RAD52 AND RAD54 GENES OF HOMOLOGOUS RECOMBINATION REPAIR PATHWAY IN BREAST CANCER: A CASE-CONTROL STUDY FROM PUNJAB

A case-control study was conducted on 600 subjects (300 cases and 300 controls) to understand the association of genetic polymorphisms of RAD51 (rs1801320, rs1801321, rs121917739, rs2619681), RAD52 (rs4987207, rs4987208) and RAD54 (rs2295466) genes in breast cancer patients and controls in population of Punjab. Genotyping of the selected SNPs of RAD51 and RAD52 gene was done by PCR-RFLP, whereas ARMS-PCR was used for RAD54 gene polymorphism. Our study identified significant associations between specific SNPs in the RAD51 and RAD52 genes and breast cancer risk. Notably, three RAD51 SNPs (rs1801320, rs1801321, and rs121917739) and one RAD52 SNP (rs4987208) showed significant genotype frequency differences between cases and controls. Genetic model analysis revealed that minor alleles of four RAD51 SNPs (rs1801320, rs1801321, rs121917739, and rs2619681) and two RAD52 SNPs (rs4987207 and rs4987208) were linked to increased breast cancer risk. Haplotype analysis further supported these findings, with 10 RAD51 haplotypes and two RAD52 haplotypes (G-G and T-G) significantly associated with higher breast cancer risk. Additionally, the GT + TT genotype of RAD52 rs4987207 was associated with lower odds of metastasis, while the TG + GG genotype of rs4987208 was linked to lymph node involvement and higher tumor grade.

Genetic variant rs11568818 of matrix metalloproteinase MMP7 associated with newborn weight in pregnant women with fetal growth restriction

Background: Fetal growth restriction is a common complication of pregnancy that has been associated with a variety of adverse perinatal outcomes. The condition carries significant risks of neonatal mortality, major and minor morbidity, and long term health sequelae. The aim of the study: The aim of the study was to study the associations of matrix metalloproteinases gene polymorphism with newborn weight in pregnant women with fetal growth restriction and to evaluate their functional effects. Materials and methods: 98 cases of women with fetal growth restriction were selected as the experimental group. All pregnant women were performed genotyping of 5 SNPs of genes of matrix metalloproteinase (rs1799750 MMP-1, rs243865 MMP-2, rs3025058 MMP-3, rs11568818 MMP-7, rs17577 MMP-9). Results: We found associations of the rs11568818 polymorphism of the MMP-7 gene with newborn weight in women with fetal growth restriction within a recessive model (β = 0.32±0.13, p=0.016 pperm=0.022). This polymorphic locus possesses important functional effects. It is localized in an evolutionarily conserved region, a binding site for regulatory proteins (TBP, CFOS, CJUN), a region of DNase hypersensitivity, and a site of modified histones marking enhancers and promoters in mesenchymal and hematopoietic stem cells, osteoblast cells, adipocytes, and fibroblast cell line lungs, various parts of the brain, lungs, etc., determines the sensitivity of DNA to four transcription factors (Foxa, GR, PLZF, Pou5f1), is associated with the level of mRNA expression of the MMP-7 gene in the lungs, liver, and skeletal muscles. Conclusion: The rs11568818 polymorphism of the MMP-7 gene is associated with a newborn weight.

SNPs in genes related to the repair of damage to DNA in clinical isolates of M. tuberculosis: A transversal and longitudinal approach.

The presence of SNPs in genes related to DNA damage repair in M. tuberculosis can trigger hypermutagenic phenotypes with a higher probability of generating drug resistance. The aim of this research was to compare the presence of SNPs in genes related to DNA damage repair between sensitive and DR isolates, as well as to describe the dynamics in the presence of SNPs in M. tuberculosis isolated from recently diagnosed TB patients of the state of Veracruz, Mexico. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed. Eighty-six isolates from 67 patients from central Veracruz state, Mexico, were sequenced. The results showed several SNPs in 14 genes that were only present in drug-resistant genomes. In addition, by following of 15 patients, it was possible to describe three different dynamics of appearance and evolution of non-synonymous SNPs in genes related to DNA damage repair: 1) constant fixed SNPs, 2) population substitution, and 3) gain of fixed SNPs. Further research is required to discern the biological significance of each of these pathways and their utility as markers of DR or for treatment prognosis.

ACE gene polymorphism and susceptibility to hypertension in a Jordanian adult population.

Hypertension is one of the most common and complicated disorders associated with genetic and environmental risk factors. The angiotensin-converting enzyme (ACE) is important in the renin-angiotensin-system pathway. The gene expression of ACE has been investigated as a possible hypertension marker. This study investigates the association between polymorphisms within the ACE1 and ACE2 genes and hypertension susceptibility in a Jordanian population. The study comprised a total of 200 hypertensive patients and 180 healthy controls. A polymerase chain reaction (PCR) was performed to genotype the candidate polymorphism (rs4646994) of the ACE1gene. The Luminex DNA array technique was used for genotyping SNPs (rs4359, rs4344, rs4341, rs4343, and rs2106809) of the ACE1 and ACE2 genes. Our findings suggest no association between SNPs and hypertension regarding allelic and genotypic frequencies. However, rs4359 was significantly associated with diet (pP = 0.049), know HTN (P = 0.042), and number of years DM (P = 0.003). rs4341 was associated with diet (P = 0.032), peripheral vascular disease (P = 0.005), and chronic kidney disease (p = 0.049). While rs4343 was associated with diet (P = 0.031), diabetes mellitus (P = 0.032), and other medication (P = 0.025). Furthermore, the haplotypes of four SNPs of the ACE1 gene showed no significant association with HTN patients and healthy controls. Our findings indicate no association between the polymorphisms in the ACE gene and the risk of hypertension development in the Jordanian adult population.

Identification of high-risk non-synonymous SNPs (nsSNPs) in DNAH1 and DNAH17 genes associated with male infertility: a bioinformatics analysis.

Male infertility is a significant reproductive issue affecting a considerable number of couples worldwide. While there are various causes of male infertility, genetic factors play a crucial role in its development. We focused on identifying and analyzing the high-risk nsSNPs in DNAH1 and DNAH17 genes, which encode proteins involved in sperm motility. A total of 20 nsSNPs for DNAH1 and 10 nsSNPs for DNAH17 were analyzed using various bioinformatics tools including SIFT, PolyPhen-2, CADD, PhD-SNPg, VEST-4, and MutPred2. As a result, V1287G, L2071R, R2356W, R3169C, R3229C, E3284K, R4096L, R4133C, and A4174T in DNAH1 gene and C1803Y, C1829Y, R1903C, and L3595P in DNAH17 gene were identified as high-risk nsSNPs. These nsSNPs were predicted to decrease protein stability, and almost all were found in highly conserved amino acid positions. Additionally, 4 nsSNPs were observed to alter post-translational modification status. Furthermore, the interaction network analysis revealed that DNAH1 and DNAH17 interact with DNAH2, DNAH3, DNAH5, DNAH7, DNAH8, DNAI2, DNAL1, CFAP70, DNAI3, DNAI4, ODAD1, and DNAI7, demonstrating the importance of DNAH1 and DNAH17 proteins in the overall functioning of the sperm motility machinery. Taken together, these findings revealed the detrimental effects of identified high-risk nsSNPs on protein structure and function and highlighted their potential relevance to male infertility. Further studies are warranted to validate these findings and to elucidate the underlying mechanisms.

Prediction of the most deleterious non-synonymous SNPs in the human IL1B gene: evidence from bioinformatics analyses

BackgroundPolymorphisms in IL1B play a significant role in depression, multiple inflammatory-associated disorders, and susceptibility to infection. Functional non-synonymous SNPs (nsSNPs) result in changes in the encoded amino acids, potentially leading to structural and functional alterations in the mutant proteins. So far, most genetic studies have concentrated on SNPs located in the IL1B promoter region, without addressing nsSNPs and their association with multifactorial diseases. Therefore, this study aimed to explore the impact of deleterious nsSNPs retrieved from the dbSNP database on the structure and functions of the IL1B protein.ResultsSix web servers (SIFT, PolyPhen-2, PROVEAN, SNPs&GO, PHD-SNP, PANTHER) were used to analyze the impact of 222 missense SNPs on the function and structure of IL1B protein. Five novel nsSNPs (E100K, T240I, S53Y, D128Y, and F228S) were found to be deleterious and had a mutational impact on the structure and function of the IL1B protein. The I-mutant v2.0 and MUPro servers predicted that these mutations decreased the stability of the IL1B protein. Additionally, these five mutations were found to be conserved, underscoring their significance in protein structure and function. Three of them (T240I, D128Y, and F228S) were predicted to be cancer-causing nsSNPs. To analyze the behavior of the mutant structures under physiological conditions, we conducted a 50 ns molecular dynamics simulation using the WebGro online tool. Our findings indicate that the mutant values differ from those of the IL1B wild type in terms of RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds.ConclusionsThis study provides valuable insights into nsSNPs located in the coding regions of IL1B, which lead to direct deleterious effects on the functional and structural aspects of the IL1B protein. Thus, these nsSNPs could be considered significant candidates in the pathogenesis of disorders caused by IL1B dysfunction, contributing to effective drug discovery and the development of precision medications. Thorough research and wet lab experiments are required to verify our findings. Moreover, bioinformatic tools were found valuable in the prediction of deleterious nsSNPs.

The Influence of Taste Genes on Body Fat and Alcohol Consumption.

Dietary intake and alcohol consumption might be influenced by genetic variations in taste receptor genes. The objectives of this study were to examine the relationship between polymorphisms in the bitter taste receptor genes TAS2R13 (rs1015443) and TAS2R38 (rs1726866, rs10246939, and rs713598) as well as alcohol consumption and body fat percentage in college students. Four hundred and two students with a mean age of 20.2 years participated in this study. An NIH Diet History Questionnaire (DHQ II) was used to collect data on their dietary intake, while an AUDIT survey was used to determine their level of alcohol consumption. Bitter taste receptor gene polymorphisms were assessed by TaqMan allelic discrimination assays. Despite significant associations between TAS2R13 (rs1015443) and certain aspects of alcohol consumption, including the frequency of alcohol intake, no significant associations were found between TAS2R13 (rs1015443) and alcohol consumption after accounting for confounding variables in the regression model. Neither association was found regarding percent of body fat. In contrast, ethnicity and gender significantly influenced percent of body fat (p < 0.001), while no significant association was observed between TAS2R13 (rs1015443) and percent of body fat. Likewise, TAS2R38 (rs1726866, rs10246939, and rs713598) demonstrated no significant association with alcohol consumption and percent of body fat. These results were controlled for confounding factors, such as ethnicity and gender. Body fat percentage and alcohol consumption may be influenced by ethnicity, gender, and age rather than SNPs of TAS2R13 and TAS2R38 genes. Assessing taste genes' interactions with diet and body composition might be useful in identifying human disease risk.

Haplotype analysis on association between C-reactive protein gene and susceptibility to type 2 diabetes mellitus in Chinese Han population : CRP gene and type 2 diabetes mellitus.

We aimed to evaluate the impact of C-reactive protein (CRP) gene polymorphism, additional gene-gene interaction, and haplotypes on susceptibility to type 2 diabetes mellitus (T2DM). SNPstats online software ( https://www.snpstats.net/start.htm ) was employed to evaluate the association between CRP gene and T2DM risk. High-order interactions among SNPs was tested using generalized multifactor dimensionality reduction, and the testing balanced accuracy, training balanced accuracy and cross-validation consistency were calculated. The SHEsisPlus ( http://shesisplus.bio-x.cn/SHEsis.html ) online software was used for haplotype analysis. A total of 730 T2DM patients and 765 controls were enrolled. The T allele of rs1205 is associated with increased susceptibility to T2DM, OR (95% CI) were 1.51 (1.13-2.01), 1.44 (1.10-1.89) and 1.25 (1.01-1.54) for codominant, dominant and over-dominant models, respectively. We also found that minor allele of rs2794521 is associated with decreased susceptibility to T2DM under codominant and recessive models, OR (95%CI) were 0.38 (0.18-0.79) and 0.37 (0.16-0.80) for codominant and recessive models, respectively. No significant gene-gene interaction existed among CRP gene SNPs, allinteraction p- values were more than 0.05. Haplotype analyses suggested the CGCA haplotype containing rs1205-C, rs1130864-G, rs2794521- C and rs3093059- A allele was associated with decreased risk of T2DM, OR (95% CI) = 0.83 (0.68-0.98), P = 0.047. Minor allele of rs1205 was associated with increased T2DM risk. Minor allele of rs2794521 and the CGCA haplotype were associated with decreased T2DM risk.

Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in human FOXP4 gene: An in-silico study

In humans, FOXP gene family is involved in embryonic development and cancer progression. The FOXP4 (Forkhead box protein P4) gene belongs to this FOXP gene family. FOXP4 gene plays a crucial role in oncogenesis. Single nucleotide polymorphisms are biological markers and common determinants of human diseases. Mutations can largely affect the function of the corresponding protein. Therefore, the molecular mechanism of nsSNPs in the FOXP4 gene needs to be elucidated. Initially, the SNPs of the FOXP4 gene were extracted from the dbSNP database and a total of 23124 SNPs was found, where 555 nonsynonymous, 20525 intronic, 1114 noncoding transcript, 334 synonymous were obtained and the rest were unspecified. Then, a series of bioinformatics tools (SIFT, PolyPhen2, SNAP2, PhD SNP, PANTHER, I-Mutant2.0, MUpro, GOR IV, ConSurf, NetSurfP 2.0, HOPE, DynaMut2, GeneMANIA, STRING and Schrodinger) were used to explore the effect of nsSNPs on FOXP4 protein function and structural stability. First, 555 nsSNPs were analyzed using SIFT, of which 57 were found as deleterious. Following, PolyPhen2, SNAP2, PhD SNP and PANTHER analyses, 10 nsSNPs (rs372762294, rs141899153, rs142575732, rs376938850, rs367607523, rs112517943, rs140387832, rs373949416, rs373949416 and rs376160648) were common and observed as deleterious, damaging and diseases associated. Following that, using I-Mutant2.0 and MUpro servers, 7 nsSNPs were found to be the most unstable. GOR IV predicted that these seven nsSNPs affect protein structure by altering the protein contents of alpha helixes, extended strands, and random coils. Following DynaMut2, 5 nsSNPs showed a decrease in the ΔΔG value compared with the wild-type and were found to be responsible for destabilizing the corresponding protein. GeneMANIA and STRING network revealed interaction of FOXP4 with other genes. Finally, molecular dynamics simulation analysis revealed consistent fluctuation in RMSD and RMSF values, Rg and hydrogen bonds in the mutant proteins compared with WT, which might alter the functional and structural stability of the corresponding protein. As a result, the aforementioned integrated comprehensive bioinformatic analyses provide insight into how various nsSNPs of the FOXP4 gene change the structural and functional properties of the corresponding protein, potentially proceeding with the pathophysiology of human diseases.

Genetic insights into fetal kidney development: Variants in HNF1A and PKHD1 genes

The orchestration of fetal kidney development involves the precise control of numerous genes, including HNF1A, HNF1B and PKHD1. Understanding the genetic factors influencing fetal kidney development is essential for unraveling the complexities of renal disorders. This study aimed to search for disease-causing variants in HNF1A, HNF1B, PKHD1 genes, among fetus and babies or via parental samples, using sanger sequencing, NGS technologie and MLPA.The study revealed an absence of gene deletions and disease-causing variants in the HNF1B gene. However, five previously SNPs in the HNF1A gene were identified in four patients (patients 1, 2, 3, and 4). These include c.51C > G (Exon1, p. Leu17=), c.79A > C (Exon1, p. Ile27Leu), c.1375C > T (Exon7, p. Leu459=), c.1460G > A (Exon7, p. Ser487Asn), and c.1501 + 7G > A (Intron7). Additionally, in addition to previously SNPs identified, a de novo heterozygous missense mutation (p.E508K) was detected in patient 4. Furthermore, a heterozygous mutation in exon 16 (p. Arg494*; c.1480C > T) was identified in both parents of patient 5, allowing predictions of fetal homozygosity.Bioinformatic analyses predicted the effects of the c.1522G > A mutation (p.E508K) on splicing processes, pre-mRNA structures, and protein instability and conformation. Similarly, the c.1480C > T mutation (p. Arg494*) was predicted to introduce a premature codon stop, leads to the production of a shorter protein with altered or impaired function.Identification of variants in the HNF1A and in PKHD1 genes provides valuable insights into the genetic landscape of renal abnormalities in affected patients. These findings underscore the heterogeneity of genetic variants contributing to renal disorders and emphasize the importance of genetic screening.

G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients.

Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes and genotoxic drugs used to treat MM, non-canonical secondary DNA structures (four-stranded G-quadruplex structures) can affect accumulation of somatic mutations and chromosomal abnormalities in the tumor cells of MM patients. Here, we tested the hypothesis that G-quadruplex structures may influence the distribution of somatic mutations in the tumor cells of MM patients. We sequenced exomes of normal and tumor cells of 11 MM patients and analyzed the data for the presence of G4 context around points of somatic mutations. To identify molecular mechanisms that could affect mutational profile of tumors, we also analyzed mutational signatures in tumor cells as well as germline mutations for the presence of specific SNPs in DNA repair genes or in genes regulating G-quadruplex unwinding. In several patients, we found that sites of somatic mutations are frequently located in regions with G4 context. This pattern correlated with specific germline variants found in these patients. We discuss the possible implications of these variants for mutation accumulation and specificity in MM and propose that the extent of G4 context enrichment around somatic mutation sites may be a novel metric characterizing mutational processes in tumors.

Thick Ascending Limbs (TALs)-specific deletion of ALMS1 (Alstrom syndrome 1) increases surface NKCC2 expression and NaCl reabsorption in the TAL

The regulation of NKCC2 mediated NaCl reabsorption in Thick Ascending Libs (TALs) is essential to salt homeostasis and blood pressure regulation. Previously, our lab showed that NKCC2 activity is regulated by membrane traffcking and inhibiting endocytosis enhanced surface NKCC2 expression and NaCl reabsorption. We also found that ALMS1, a protein mutated in Alström syndrome, is expressed in TALs. Whole animal gene deletion of ALMS1 caused hypertension, and inhibits NKCC2 endocytosis, increasing its surface expression and renal NaCl reabsorption. Little is known about additional functions of ALMS1, however, global gene deletion of ALMS1 induces obesity, and that, in turn may affect TAL and NKCC2 function. We hypothesized that ALMS1 is a part of protein complex that binds apical NKCC2 in TALs and promotes its endocytosis. To dissect the specific role of ALMS1 in TALs, without interference of systemic effects, we studied surface NKCC2 expression and TAL mediated Na transport after inducible deletion of ALMS1 in TALs. To do this, we generated a loxP flanked exon 7 ALMS1 transgenic mouse line, that we crossed with TAL specific inducible Umod-ERT2 Cre mice (Umod-ALMS1 KO). 3 weeks after inducing Cre expression with tamoxifen, ALMS1 expression in TAL suspensions decreased by 85% (p&lt;0.01) (n=5). In Umod-ALMS1 KO TALs the surface to total NKCC2 ratio, was increased by 37±15% compared to control floxed ALMS1 (p&lt;0.01) (n=5). Recombinant ALMS1 (GST-Carboxyl terminus-ALMS1), or immunoprecipitation of ALMS1, pulled down NKCC2 from TAL lysates (n=3), suggesting that the mechanism by which ALMS1 regulates surface NKCC2 involves protein-protein interactions. Three weeks after inducing ALMS1 deletion, we measured bumetanide-induced natriuresis (4h) as an index of NKCC2-mediated NaCl absorption. We found that bumetanide induced UNa excretion was enhanced in Umod-ALMS1 KO, compared to control (control: 110±7 vs Umod-ALMS1 KO: 173±26 μmols Na/4h, p&lt;0.01). We conclude that ALMS1, binds NKCC2 to regulate its surface expression. Depletion of ALMS1, specifically in the TAL enhances surface NKCC2 and TAL NaCl reabsorption. Our data indicate that regulation of the ALMS1-NKCC2 interaction in the TAL is important for renal NaCl reabsorption. Decreased ALMS1 function or expression increased TAL NaCl reabsorption and this may contribute to the hypertension and kidney disease that is associated with SNPs in the ALMS1 gene in the general population, or in patients with Alstrom Syndrome. NIH R01, Henry Ford Fund. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Validation of Bos taurus SNPs for Milk Productivity of Sahiwal Breed (Bos indicus), Pakistan.

The aim of the present study was the validation of the already reported Bos taurus SNPs in the Sahiwal breed. A total of nine SNPs of the casein gene were studied. Out of nine, seven Bos taurus SNPs of casein protein genes were found to be significantly associated with milk productivity traits. The genomic DNA was extracted from the mammary alveolar endothelial cells of a flock of 80 purebred Sahiwal lactating dams available at Khizrabad Farm near Sargodha. New allele-specific primers were designed from the NCBI annotated sequence database of Bos taurus to obtain 100 nt-long PCR products. Each dam was tested separately for all the SNPs investigated. Animals with genotype GG for the SNPs rs43703010, rs10500451, and 110323127, respectively, exhibited high milk yield. Similarly, animals with genotype AA for the SNPs rs11079521, rs43703016, and rs43703017 showed high milk yield consistently. For the SNP rs43703015, animals with genotype CC showed high milk productivity. These above-mentioned SNPs have previously been reported to significantly up-regulate casein protein contents in Bos taurus. Our results indicated SNPs that significantly affect the milk protein contents may also significantly increase per capita milk yield. These finding suggest that the above-mentioned reported SNPs can also be used as genetic markers of milk productivity in Sahiwal cattle.

Exposure to heavy metals, antioxidant status, and the interaction of single nucleotide polymorphisms in the genes CAT rs7943316, GSTP1 rs1695, as well as GSTM1 and GSTT1 genes, among workers in occupational settings

Individuals working in diverse fields are consistently exposed to work-related pollutants that can impact their overall health. The current study investigated the presence of pollutants in seven different occupational groups and their impact on human health. Biochemical and genetic approaches were employed. Heavy metals were determined by ICP-MS technique. Oxidative stress biochemical markers and molecular analysis of the glutathione transferases gene SNPs (GSTT1, GSTM1, GSTP1), catalase (CAT, rs7943316), and superoxide dismutase (SOD, rs17880487) was carried out. The results revealed a significantly higher quantity of Cd among five occupational groups. Catalase, malonaldehyde, and glutathione was significantly dysregulated. Molecular analysis of the gene SNPs suggests a probable relationship between the antioxidants and the phenotypic expression of the CAT, GSTP1, GSTT1, and GSTM1 SNPs. It is concluded that chronic exposure to occupational contaminants like Cd affects human health through oxidative stress in association with some of their gene SNPs.

A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P=0.017; 50% vs. 39%, P=0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.