Gene Polymorphisms Research Articles

Iron-Status Indicators and HFE Gene Polymorphisms in Individuals with Amyotrophic Lateral Sclerosis: An Umbrella Review of Meta-analyses and Systematic Reviews.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons. Recent meta-analyses and systematic reviews suggest that HFE gene polymorphisms and iron-associated biomarkers may play a key role in the risk and occurrence of ALS. This umbrella study aimed to explore the roles of HFE gene polymorphisms and iron-associated biomarkers in individuals with ALS. A thorough search of three online scientific databases, namely Scopus, Web of Science, and PubMed, was conducted from their inception until September 13, 2024. The screening and selection processes were executed based on the PICO framework and eligibility criteria, followed by two independent reviewers. The Assessment of Multiple Systematic Reviews (AMSTAR)-2 and GRADE tools were utilized to assess the methodological quality and the certainty of evidence. Through an advanced search, 101 records were retrieved, of which eight meta-analyses and systematic reviews were selected for this umbrella review. A significant increase in iron concentrations was found in individuals with ALS compared to healthy controls (SMD, 0.26; 95% CI - 0.05, 0.57). Conversely, selected meta-analyses reported that serum transferrin concentrations in ALS patients were lower compared to healthy controls (SMD, - 0.15; 95% CI - 0.36, 0.05). Furthermore, mutations in H63D polymorphisms resulted in a 13% significant increase in the risk of ALS (OR, 1.13; 95% CI 1.05, 1.22). Our umbrella study of meta-analyses and systematic reviews reveals that individuals with ALS have lower serum concentrations of transferrin compared to healthy controls. Additionally, the H63D polymorphism in the HFE gene is associated with a slight increase in the risk of ALS. Future research should investigate broader aspects of iron-related biomarkers and HFE genes to elucidate their roles in ALS pathogenesis. Registration: Our umbrella study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42024559032 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024559032 ).

Protective role of hypoxia-induced factor-1α and HIF-1A gene polymorphism in the development of acute pancreatitis

Acute pancreatitis (AP) is an acute surgical disease of the abdominal cavity that becomes severe in 20-30% of patients and has a mortality rate reaching 25%. Hypoxia that occurs during AP may be associated with the activation of a regulatory protein, hypoxia-inducible factor-1á (HIF-1á), which plays an important role in the body’s response to hypoxia. The HIF-1 transcription factor induces the expression of genes involved in cell proliferation, angiogenesis, neurogenesis, erythropoiesis and cellular metabolism, and maintenance of intracellular pH. The purpose of the work is to study the relationship between HIF-1á blood levels and polymorphism of the HIF-1A gene with the criteria of hypoxia, tissue damage and severity of AP. We examined 93 patients with AP of varying severity on days 1 and 3 of the disease, age 48 (39-67) years. We identified 3 groups of patients: with mild AP – 32 people, moderate – 26 people, or severe – 35 people. The comparison group consisted of 25 healthy volunteers, average age 47 (39-56) years. The HIF-1á levels, the presence of HIF-1A gene polymorphism, interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, S100 protein, clinical blood test, and blood gas composition were assessed. In patients with AP, clinical and laboratory signs of acute inflammation, microcirculation disorders, hypoxia and organ dysfunction were observed. With mild severity of AP on days 1-3 of observation, the HIF-1á level exceeded its content in the comparison group. With moderate and severe AP, the production of HIF-1á as a factor of adaptation to hypoxia decreased. A relationship was found between the HIF-1á level and the severity of AP. In the same patients, the HIF-1A gene polymorphism (1772CT, rs11549465) was studied to identify carriage of the C/C, C/T and T/T genotypes. It was determined that among the patients, patients with С/С predominated, in whom the concentration of HIF-1á was lower than in the group with С/T. Mortality among patients with the C/C genotype and severe AP was 47%. In the group with the C/T genotype, all patients were discharged, including those with severe AP. A relationship was found between HIF-1á blood levels and the marker of tissue damage S100, mixed hypoxia – lactate, and acid-base state – pHt. The results allow us to consider HIF-1A genotypes as potential predictors of the severity of AP.

ОЦЕНКА КОРОВ-ПЕРВОТЁЛОК ЧЁРНО-ПЁСТРОЙ ПОРОДЫ ПО ДНК-МАРКЕРАМ, АССОЦИИРОВАННЫХ С ХОЗЯЙСТВЕННО-ПОЛЕЗНЫМИ ПРИЗНАКАМИ

At present time are widely used genetic markers as means in the selection of highly productive animals. Since the genes: CSN3 (kappa-casein), PIT-1 (pituitary-specific transcription factor), PRL (prolactin), GH (somatotropin) are polymorphic and encode various proteins, the study of their influence on the productive traits of cattle is relevant. In this regard, the goal of the work is to determine the influence of complex genotypes of the studied genes on the milk productivity of first-calf cows of the Black-and-White breed bred in the collective farm-breeding plant «Kazminsky» in the Kochubeevsky district of the Stavropol Territory. The place of research is the Department of Genetics and Biotechnology, VNIIOK, a branch of the North Caucasian Federal National Research Center. This article presents the results of DNA genotyping of allelic polymorphism for the CSN3, PIT-1, PRL, GH genes using PCR-RFLP methods in first-calf cows of the Black-and-White breed. It was established that these genes in the studied sample are polymorphic. The frequency of occurrence of the desired CSN3B allele in the studied sample was 0.23. The presence of alleles PIT-1A and PIT-1B of the pituitary-specific transcription factor gene was noted with a frequency of occurrence of 0.52 and 0.48. A feature of the PRL gene polymorphism was the fairly high frequency of occurrence of the PRLA allele (0.60). In this study sample of dairy cattle, the frequency of occurrence of the desired GHL allele of the somatotropin gene was 0.62. All variants of complex genotypes were also identified and their relationship with milk productivity in black-and-white cows was noted. The study sample was dominated by animals carrying complex desirable genotypes, consisting of four and three marker alleles of three and two genes (CSN3AB/PIT-1BB/GHLV; CSN3AB/PIT1AB/GHLL or PIT-1AB/PRLAB/GHLV; PIT-1AA/GHLL ) - 46.7 %. Milk yield per lactation between groups of black-and-white first-calf cows with different complex genotypes ranged from 5839.14 to 8611.33 kg. The mass fraction of fat in milk ranged from 3.93 to 4.04 %, and protein from 2.99 to 3.14 %.

Frequency of FXIII, PAI-1 and ACE gene polymorphisms in women with recurrent pregnancy loss

Frequency of FXIII, PAI-1 and ACE gene polymorphisms in women with recurrent pregnancy loss

MAP2K1 DAMPENS CIGARETTE SMOKE-INDUCED LUNG INFLAMMATION VIA SUPPRESSION OF TYPE I INTERFERON PATHWAY ACTIVATION.

Chronic Obstructive Pulmonary Disease (COPD), comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality worldwide. MAP2K (mitogen-activated protein 2 kinase) pathway activation is present in COPD lung tissue and a genetic polymorphism in Map2k1 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of Map2k1 in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid Map2k1 (LysmCre+Mek1fl) and wild-type mice (Mek1fl). Mice deficient in myeloid Map2k1 had enhanced CS-induced lung inflammation characterized by increased neutrophil recruitment, augmented expression of elastolytic matrix metalloproteinases, and increased type I interferon-stimulated gene expression. The augmented neutrophilic inflammatory response could be abrogated by IFNAR1 blockade. These findings indicate that myeloid Map2k1 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective.

Association of the Single Nucleotide Polymorphisms rs11556218, rs4778889, rs4072111, and rs1131445 of the Interleukin-16 Gene with Ovarian Cancer.

Single nucleotide polymorphisms (SNPs) of the IL-16 gene have been reported to influence the risk of several cancers, but their role in ovarian cancer (OC) has not been studied. Using the restriction fragment length polymorphism (PCR-RFLP) method, we examined four IL-16 SNPs: rs11556218 (T > G), rs4778889 (T > C), rs4072111 (C > T), and rs1131445 (T > C) in blood samples from 413 women of Central European descent, including 200 OC patients and 213 healthy controls. Among the patients, 62% were postmenopausal, 84.5% were diagnosed in late stages (FIGO IIb-IV), and 73.5% had high-grade serous OC (HGSOC). Minor allele frequencies in controls were 9.2% for rs11556218 (G allele), 13.7% for rs4778889 (C allele), 10.4% for rs4072111 (T allele), and 32.3% for rs1131445 (C allele). We found significant associations of rs11556218 (G vs. T allele: OR 2.76, 95% CI 1.84-4.14, p < 0.0001) with elevated OC risk in the whole cohort (p < 0.001) and in both premenopausal (p < 0.001) and postmenopausal (p = 0.001) subgroups. These associations remained significant across heterozygote (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. IL-16 rs4778889 was associated with OC risk predominantly in premenopausal women (p < 0.0001 in almost all models). In the whole cohort, the C allele was associated with OC risk (OR 1.54, CI 95% 1.06-2.23, p = 0.024), and the association of rs4778889 was significant in dominant (p = 0.019), overdominant (p = 0.033), and heterozygote (p = 0.027) models. Furthermore, rs4778889 was linked with HGSOC (p = 0.036) and endometriosis-related OC subtypes (p = 0.002). No significant associations were found for rs4072111 or rs1131445 (p = 0.81 or 0.47, respectively). In conclusion, rs11556218 and rs4778889 SNPs are associated with OC risk, especially in premenopausal women.

Interplay between vertebrate adaptive immunity and bacterial infectivity genes: Bank vole MHC versus Borrelia afzelii OspC.

Coevolution of parasites with their hosts may lead to balancing selection on genes involved in determining the specificity of host-parasite interactions, but examples of such specific interactions in wild vertebrates are scarce. Here, we investigated whether the polymorphic outer surface protein C (OspC), used by the Lyme disease agent, Borrelia afzelii, to manipulate vertebrate host innate immunity, interacts with polymorphic major histocompatibility genes (MHC), while concurrently eliciting a strong antibody response, in one of its main hosts in Europe, the bank vole. We found signals of balancing selection acting on OspC, resulting in little differentiation in OspC variant frequencies between years. Neither MHC alleles nor their inferred functional groupings (supertypes) significantly predicted the specificity of infection with strains carrying different OspC variants. However, we found that MHC alleles, but not supertypes, significantly predicted the level of IgG antibodies against two common OspC variants among seropositive individuals. Our results thus indicate that MHC alleles differ in their ability to induce antibody responses against specific OspC variants, which may contribute to selection of OspC polymorphism by the vole immune system.

The effect of gene polymorphism on ticagrelor metabolism: an in vitro study of 22 CYP3A4 variants in Chinese Han population.

Ticagrelor is a novel oral antiplatelet agent which can selectively inhibit P2Y12 receptor. Bleeding and dyspnea are common adverse reactions of ticagrelor in clinic. The side effects of ticagrelor are correlated with the plasma concentration of ticagrelor. This study aimed to evaluate the catalytic characteristics of 22 CYP3A4 alleles identified in the Chinese Han population on the metabolism of ticagrelor in vitro, focusing on the effect of CYP3A4 polymorphism on ticagrelor metabolism. In this study, insect cells were used to express 22 CYP3A4 variants, which were then incubated with 1-50 µM ticagrelor at 37 °C for 30 minutes to obtain the metabolite (AR-C124910XX). AR-C124910XX was detected by UHPLC-MS/MS to calculate the kinetic parameters, including Km, Vmax and CLint. Compared to the wild-type, most CYP3A4 alleles exhibited significant differences in intrinsic clearance. The intrinsic clearance of CYP3A4*11, *18 and *33 was much higher than that of wild-type; four variants exhibited similar intrinsic clearance values as the wild-type enzyme; The remaining 14 variants showed significantly reduced intrinsic clearance values, ranging from 1.48% to 75.11% of the wild-type; CYP3A4*30 displayed weak or no activity. This study conducted a comprehensive assessment of the effect of CYP3A4 variants on ticagrelor's metabolism. The results suggested that there is allele-specific activity towards ticagrelor in vitro. These findings can provide some insights and predictions for treatment strategies and risk assessments associated with ticagrelor in clinical practice.

Analysis of the Effects of SAA1 Gene Polymorphisms on Renal Involvement in a Familial Mediterranean Fever Jordanian Population

Analysis of the Effects of SAA1 Gene Polymorphisms on Renal Involvement in a Familial Mediterranean Fever Jordanian Population

Evaluation of the relationship between TLR1(RS4833095) gene polymorphism and disease in patients with ulcerative colitis in the Turkish population

Background: Ulcerative Colitis is a multifactorial disease which is characterized by recurrent periods of inflammation in the mucosal layer of the colon. Toll-like receptors (TLRs) are a class of transmembrane pattern recognition receptors that play a key role in the induction of pro/anti-inflammatory genes and in the control of adaptive immune responses. In this study, we aimed to evaluate the relation between TLR1(rs4833095) single nucleotide polymorphism and ulcerative colitis. Methods: The study included 90 patients with ulcerative colitis and a healthy control group consisting of 90 people. Taken medical treatment, laboratory data, colonoscopy findings, extraintestinal manifestations of patients included in this study were recorded. TLR1(rs4833095) single nucleotide polymorphism was studied with RT-PCR methods. Results: There was no increased risk for ulcerative colitis in patients with ulcerative colitis who has TLR1(rs4833095) single nucleotide polymorphism in Turkish population (p&gt;0.05). There was no association between TLR 1(rs4833095) single nucleotide polymorphism and the spread of the disease in the colon, severity of disease and treatment required for remission in our study(p&gt;0.05). Conclusion: In the Turkish population, TLR1 (rs4833095) single nucleotide polymorphism was evaluated and no significant difference was found between the patients with ulcerative colitis and the control group.

Nerve growth factor gene polymorphisms may be associated with heroin dependence in women but do not mediate specific personality traits.

Heroin dependence (HD) is a complex disease with a substantial genetic contribution and is associated with traits of impulsivity and specific personality traits. The neurotrophic factor nerve growth factor (NGF) may mediate the reward processes in HD. This study aims to investigate whether NGF gene polymorphisms are associated with the co-occurrence of HD and impulsivity/specific personality traits in HD patients. To minimize the potential confounding effects of population stratification, we selected a homogeneous Han Chinese population and recruited 1364 participants (831 HD patients and 533 healthy controls). In addition, 163 female HD patients completed the Chinese version of the Barratt Impulsiveness Scale Version 11 (BIS-11), and 440 HD patients completed the Chinese version of the Tridimensional Personality Questionnaire (TPQ) for subsequent analysis. We identified three polymorphisms with altered allele and genotype frequency in HD patients versus controls (p = 0.035 for rs2254527; p = 0.005 for rs6678788; p = 0.006 for rs7523654), especially in the female subgroup. Four associations identified via haplotype analysis were significant in the female subgroup (p = 0.003 for T-T-A haplotype and p = 0.002 for C-C-A haplotype in block 1; p = 0.011 for T-T haplotype and p = 0.009 for C-T haplotypes in block 2), but not in the male subgroup. Male HD patients had higher novelty-seeking (NS) scores, and female HD patients had higher harm avoidance (HA) scores. However, there was no significant association between the selected NGF polymorphisms and BIS or TPQ scores in HD patients. NGF variants may contribute to the risk of HD development in females but do not mediate the relationship between impulsivity and specific personality traits in the female population.

Evaluation of Fat Mass and Obesity Associated (FTO) Gene Polymorphism in Male Androgentic Aloplecia Patients

Evaluation of Fat Mass and Obesity Associated (FTO) Gene Polymorphism in Male Androgentic Aloplecia Patients

Study of adiponectin gene (rs1501299) polymorphism and serum adiponectin level in patients with primary knee osteoarthritis

BackgroundWe aimed to study, for the first time in the Egyptian population, the relationship between the serum adiponectin level in knee osteoarthritis (KOA) patients and its correlation with clinical, radiological, and ultrasonographic characteristics. Additionally, investigate the relationship between the adiponectin (ADIPOQ) gene rs1501299 (+ 276G/T) polymorphism and KOA susceptibility and severity.MethodsThis case-control study enrolled 40 patients with primary KOA and 40 matched controls. All patients underwent physical examination of the knee, pain assessment using the visual analogue scale (VAS), and functional evaluation by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Severity of KOA was assessed by Kellgren Lawrence (KL) grading scale and ultrasonography grading systems. Serum adiponectin levels and adiponectin (ADIPOQ) gene single nucleotide polymorphism (SNP) (rs1501299) genotyping were done for all patients and controls.ResultsThe study included 40 patients with primary symptomatic KOA and 40 controls with comparable age, sex, and body mass index. The genotype of the rs1501299 (+ 276G/T) polymorphism of the ADIPOQ gene was determined using TaqMan allelic discrimination. An enzyme-linked immunosorbent test was used to measure the level of serum adiponectin. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score was used to assess functional capability, while the visual analogue scale was utilised to assess knee pain. Using the Kellgren-Lawrence (KL) grading method and global femoral cartilage (GFC) ultrasound grading, the severity of KOA was assessed. No significant differences between patients and controls as regards the genotype distributions and allele frequencies (p = 0.400, p = 0.507, respectively) of ADIPOQ gene rs1501299 (+ 276G/T) polymorphism. Furthermore, serum adiponectin level was significantly higher in the patients compared to healthy subjects (p < 0.001). Additionally, adiponectin level had a significant negative correlation with disease severity as evaluated by KL and GFC grading (r=-0.351, p = 0.027 and r=-0.397, p = 0.011, respectively).ConclusionsThe ADIPOQ gene rs1501299 (+ 276G/T) polymorphism was not associated with KOA severity or vulnerability. The level of adiponectin considerably reduced as the severity of KOA rose, indicating that adiponectin may have a preventive effect in KOA.

BsmI, ApaI and FokI variants of vitamin D receptor gene polymorphism as predictors of response to treatment in immune thrombocytopenia patients

BsmI, ApaI and FokI variants of vitamin D receptor gene polymorphism as predictors of response to treatment in immune thrombocytopenia patients

Assessing the association between common functional Nuclear Factor Kappa-b gene polymorphisms (NFKB1, NFKBIZ, NFKBIA) and Alzheimer´s disease

The Nuclear Factor Kappa-b (NF-Κb) pathway has been implicated in the pathogenesis of Alzheimer´s disease (AD). We determined whether common variants in the NF-Κb genes were associated with the risk of developing late-onset AD (LOAD). A total of 639 Spanish LOAD and 500 controls were genotyped for the NFKB1 rs28362491/rs7667496, NFKBIA rs696, NFKBIZ rs3217713 and APOE-Ɛ2/3/4 polymorphisms. Rs7667496 C was increased in the patients (p<0.001) with the CC genotype showing a significant risk (CC vs T+, OR= 1.58, 95 %CI=1.25–2.01). The CC genotype was significantly associated with LOAD after correction by APOE-4+ genotypes, age and sex (p=0.0003, OR=1.88, 95 %CI=1.28–2.78). The NFKB1 rs28362491 I - rs7667496 C haplotype was significantly increased in the patients (p=0.02). NFKBIA and NFKBIZ variants were not associated with the risk of LOAD in our population. In conclusion, NFKB1 variants were associated with the risk of LOAD in our population. This finding encourages further studies to determine the involvement of the NF-kB components in LOAD.

Beta cell specific ZnT8 gene deficiency and resulting loss in zinc content significantly improve insulin secretion

Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood.A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets.These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.

Macrophage Migration Inhibitory Factor Gene Polymorphism in Acute Coronary Syndrome.

Background Acute coronary syndrome (ACS) is a result of the interplay between genetic and environmental risk factors. A unique cytokine macrophage migration inhibitory factor (MIF), expressed by inflammatory cells, acts via a cluster of differentiation 74 (CD74) and a cluster of differentiation 44 (CD44) receptors, leading to the recruitment of mononuclear neutrophils and lymphocytes. This cascade results in exaggerated inflammation and atherosclerosis. MIF's distinctive characteristics and functions make it an essential target for achieving therapeutic atherosclerosis regression, setting it apart from other cytokines. Hence, this study aims to detect the MIF gene polymorphism in ACS patientsand to assess the incidence of in-hospital major adverse cardiac events (MACE). Methodology This study was conducted in a tertiary care hospital. A total of 90 patients who had ACS were enrolled, of which 83 were included, and seven patients were excluded based on exclusion criteria (four cases of old myocardial infarction, two cases of valvular heart disease, and one case of dilated cardiomyopathy). After detailed clinical examination, laboratory evaluation, and genetic test, patients were divided into two groups based on MIF gene mutation. Five patients who had positive MIF gene mutationwere termed as group A (n=5), and 78 patients with negative MIF gene mutation were termed as group B (n=78). The statistical analysis for the collected data was done using IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, USA). Results Out of the 83 patients in this study, the male gender was predominant; there were three male patients in group A (n=3; 60%) and 48 male patients in group B (n=48; 61.5%). The most common age group was between 60 and 69 years; two of five patients (n=2; 40%) in group A and 30 out of 78 patients (n=30; 38.4%) in group B belonged to this age group. The common symptomwas chest pain present infive patients in group A (n=5; 100%) and 76 patients (n=76; 97.5%) in group B. A common risk factor in group A patientswas tobacco chewing, seen in three patients (n=3; 60%), and group B smoking was the most common risk factor seen in 30 patients (n=30; 38.5%). The most common ECG finding in group A was ST-elevation myocardial infarction (STEMI), seen in three patients(n=3; 60%), and in group B, the commonest ECG finding was non-ST-elevation myocardial infarction (NSTEMI) seen in 23 patients (n=23; 29.5%). The most common MACE was heart failure seen in two patients in group A (n=2; 40%) and in 50 patients in group B (n=50; 64.1%), followed by arrhythmias seen in one patient in group A (n=1; 20%), and eight patients in group B (n=8; 10.3%). Conclusion This study demonstrated a significant positive association betweenMIF gene polymorphism and the occurrence of cardiovascular events like myocardial infarction, with a statistically significant p-value (p=0.001). This study showed the presence of the disease in young age groups and individuals without conventional risk factors, underscoring the importance of genetic studies. Genetic risk factors independently contribute to the pathophysiology of coronary artery disease; hence, understanding the mechanisms of these genes and incorporating genetic testing into standard clinical practice can help future research to developtherapeutic agents that can specifically target these genes.

Abstract C086: Somatic mutation variations in minority populations at the University of New Mexico Comprehensive Cancer Center

Abstract The global burden of cancer underscores the urgency to understand its genetic underpinnings. Genetic testing has revolutionized clinical practice, identifying driver mutations crucial for tumorigenesis, including TP53, PIK3CA, KRAS, PTEN, and ARID1A. However, minority populations are underrepresented in major genomic projects, hindering tailored therapies. Variations in genetic polymorphisms among ethnicities, exemplified by distinct patterns in mutations like BRCA and EGFR, underscore the imperative for diversity in genomic research. We conducted a retrospective study at the University of New Mexico Comprehensive Cancer Center, analyzing 5,045 patients' genetic testing data. Significant differences in somatic gene mutation frequencies and survival outcomes were observed across racial and ethnic groups, highlighting the importance of personalized approaches in cancer care. Specific gene mutations, such as IDH1, JAK2, KITX11, and TP53, were associated with distinct survival outcomes. Integrating genetic testing into routine practice could enhance patient stratification and treatment efficacy. Future research should explore underlying mechanisms and include larger, diverse populations to advance personalized medicine in oncology. Citation Format: Isabella Doan, Jonathan Coy, Bernard Tawfik. Somatic mutation variations in minority populations at the University of New Mexico Comprehensive Cancer Center [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C086.

Abstract C084: Genetic polymorphism rs3820282 and WNT4-mediated metabolic plasticity contributes to differential therapy response in ovarian cancer clear carcinoma

Abstract Purpose of research: Ovarian clear cell carcinoma (OCCC) is a rare and notoriously chemoresistant gynecologic malignancy that is more likely to affect patients of Asian race. Unlike the more common tubo-ovarian high-grade serous carcinoma, OCCC is rising in incidence. Previous work highlights the increased risk of reproductive pathology associated with single nucleotide polymorphism (SNP) rs3820282, a genetic variant that is also overrepresented in people of Asian race. In particular, rs3820282 results in increased WNT4 expression and is associated with metabolic reprogramming and elevated phospho-AMPK as demonstrated in murine models and primary human tumors. We hypothesize the WNT4/rs3820282 regulatory axis in OCCC mediates the response to chemotherapy via metabolic plasticity. Methods: Using SNP-variant genotype (OVTOKO) and wild-type (TOV-21G) OCCC cell lines, we manipulated the expression of WNT4 via short interfering RNA knockdown and lentiviral overexpression. We evaluated the proliferation and survival of cells in nutrient deprivation conditions. We used Agilent Seahorse to evaluate metabolic outputs of oxidative phosphorylation in the presence of cytotoxic stress conditions (platinum chemotherapy [cisplatin]), antimetabolic agents [metformin and dimethyl malonate], lipid- and glucose-deprived media, and fatty acid oxidation and glycolysis inhibition). We used immunoblotting to measure total AMPK and phospho-AMPK as signals of cellular response to metabolic stress. To evaluate the effect of WNT4 on response to chemotherapy, we measured changes in the half-maximal inhibitory concentration (IC50) of cisplatin. Results: Knockdown and overexpression of WNT4 in variant and wild-type OCCC cells altered cellular proliferation and survival in nutrient deprivation conditions. Seahorse cellular energetics conducted in variant OCCC cells demonstrated that WNT4 knockdown mitigates the metabolic detriment of cytotoxic and metabolic stress conditions with the opposite trend observed in wild-type WNT4 overexpressing OCCC cells. The variant phenotype is consistent with models of high-grade serous carcinoma. Over five experiments, WNT4 knockdown reduced the IC50 of cisplatin in variant cells (mean log fold change -0.29, range -0.91 to 0.07). While WNT4 knockdown led to a modest increase in total AMPK protein expression, in lipid- and glucose-deprived conditions WNT4 loss significantly attenuated phospho-AMPK levels. Conclusions: Genetically variant OCCC cells exposed to metabolic and antineoplastic stressors demonstrate metabolic plasticity which is regulated by WNT4. Knockdown of WNT4 induces metabolic rigidity that may convey increased susceptibility to chemotherapy, as indicated by the WNT4-induced reduction in cisplatin IC50. The SNP is highly prevalent in people of Asian race, and further investigation of this axis of metabolic reprogramming represents an opportunity to further understand an established cancer disparity and improve chemotherapeutic response in ovarian clear cell carcinoma. Citation Format: Julia Dexter, Madeleine Shackleford, Sydney Robinson, Matthew Sikora, Benjamine Bitler. Genetic polymorphism rs3820282 and WNT4-mediated metabolic plasticity contributes to differential therapy response in ovarian cancer clear carcinoma [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C084.

Application of nutrigenomics and metagenomics in livestock

Nutrigenomics tools, such as transcriptomics referring to RNA, proteomics referring to protein molecules and metabolomics referring to metabolites, can be used to effectively explore the events at molecular level occurring in a genome that receives signals from various nutrients and responds to them through different metabolic processes in the living organism. Nutrigenomics has the potential to identify personalized diets, elucidate diet-related diseases, pinpoint genes associated with diet-gene interactions, and detect gene polymorphisms influenced by significant nutritional and environmental factors affecting genetic expression. Limited information is available on the dietary impact on gene expression associated with reproductive and productive traits in livestock. However, this might be feasible to initiate an understanding of the significance of the connection between specific nutrients or dietary ingredients and the gene expression regulation. Utilizing nutrigenomic approaches will augment researchers’ capacities to uphold animal health, optimize animal performance, and enhance the milk quality and meat quality. Despite being rapidly advancing science, nutrigenomics is still in its early phase. Metagenomics is emerging as a robust and efficient approach for the metagenome sequencing derived from environmental samples. Investigating the gut microflora of various livestock and poultry species holds the potential to identify probiotic communities possessing both immunity-boosting properties and growth-promoting. Analyzing the diversity of gut microbes’ aids in identifying strains that contribute to animals’ adaptability to their native conditions. This approach is optimal for unveiling the phylogenetic and evolutionary connections between contemporary species and the ancestors of livestock and poultry