Wild-type CC Research Articles

Is the HNF4A gene variant paradoxically associated with better prognostic in CAD patients?

Abstract Background The Hepatocyte nuclear factor 4 A (HNF4A) gene was considered to be associated with susceptibility to atherosclerosis and coronary artery disease (CAD). It encodes a protein HNF4α, a genetic transcription factor regulating the genetic expression of thousands of genes playing essential roles in glucose and lipid metabolism. Its abnormal expression is emerging as a critical factor in diabetes, dyslipidemia, and cancer. Loss of function of specific mutations could attenuate its role in CAD pathogenesis and the progression of atherosclerosis. Aim To investigate whether a genetic variant (HNF4α rs1884613 C>G) could be associated with a low genetic function and, paradoxically, a better prognostic in CAD patients. Methods A cohort of 1,718 patients with coronary angiography (>70% stenosis of at least one main coronary vessel) from the GENEMACOR Study was investigated. Thirty-three genetic variants were genotyped using TaqMan assay methodology and HNF4A rs1884613 C>G genotype models were individually studied regarding the occurrence of Major Adverse Cardiovascular Events (MACEs). We used bivariate analysis to evaluate genotypic and allelic differences. Multivariate Cox regression analysis estimated variables independently associated with MACE, and Kaplan-Meier estimate methodology assessed the survival. Results Of the 1,718 CAD patients with the CC wild type, 73.4% had MACE, compared with 66.5% without. CG had 25.2% compared with 30.5% without. Finally, in the GG genotype, only 1.4% had events compared with 3.0% without (p=0.004). Cox regression analysis showed that GG genotype (mutated) is significantly and independently associated with 56% of MACE protection with a hazard ratio (HR) of 0.436; p=0.014. Physical inactivity and type-2 Diabetes remained independently associated with MACE occurrence (Fig.1). Kaplan-Meier cumulative event analysis disclosed that the carriers of the GG genotype were significantly associated with a better event-free time, and CC discloses a worse event-free time (Breslow test, p=0.001) (Fig.2). Conclusions The rs1884613 genetic variant of HNF4A is associated with a better CAD prognosis. This variant could probably induce gene downregulation and HNF4A gene function loss. Modifying and modulating hepatic lipase and lipid metabolism positively affected atherosclerosis progression. Future bioactive modulators for HNF4A variants could raise the possibility that diseases involving diabetes, lipid disorders, and cancer might be amenable to pharmacologic intervention.

Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics.

Despite numerous screening tools for colorectal cancer (CRC), 25 % of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS-mutant HCT116 and SW837 cells, and KRAS wild-type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient-derived primary cells and cultures of patient tumors to predict effective drugs for individualized care.

A descriptive study of the single-nucleotide polymorphisms known to affect the Tacrolimus trough concentration per dose, among a population of kidney failure patients in a tertiary hospital in Ghana

BackgroundThe burden of chronic kidney disease (CKD) and kidney failure in Ghana is on the ascendency, with the prevalence of CKD estimated at 13.3%. Patients with CKD who progress to kidney failure require life sustaining kidney replacement therapy (KRT) which is almost exclusively available in Ghana as haemodialysis. Kidney transplantation is considered the best KRT option for patients with irreversible kidney failure due to its relative cost efficiency as well as its superiority in terms of survival and quality of life. However, because transplants may trigger an immune response with potential organ rejection, immunosuppressants such as tacrolimus dosing are required.ObjectiveThis study sought to determine single nucleotide polymorphisms in CYP3A5, CYP3A4 and MDR1 genes that affect the pharmacokinetics of Tacrolimus in a population of Ghanaian patients with kidney failure.MethodThis cross-sectional study comprised of 82 kidney failure patients undergoing maintenance haemodialysis at the Renal and Dialysis unit of Korle-Bu Teaching Hospital (KBTH). Clinical and demographic data were collected and genomic DNA isolated. Samples were genotyped for specific SNPs using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).ResultsParticipants, 58/82 (70.73%) harbored the wildtype CYP3A5*1/*1 AA genotype, 20/82 (24.39%) carried the heterozygous CYP3A5*1/*3 AG genotype, and 4/82 (4.88%) had the homozygous mutant CYP3A5*3/*3 GG genotype. Also, 6/82 (7.32%) carried the wildtype AA genotype, 11/82 (13.41%) had the heterozygous AG genotype, and 65/82 (79.27%) harbored the homozygous mutant GG genotype of CYP3A4*1B (-290 A>G). For MDR1_Ex21 (2677 G>T), 81/82 (98.78%) carried the wildtype GG genotype, while 1/82 (1.22%) had the heterozygous GT genotype. For MDR1_Ex26 (3435 C>T), 63/82 (76.83%) had the wildtype CC genotype, while 18/82 (21.95%) carried the heterozygous CT genotype, and 1/82 (1.22%) harbored the mutant TT genotype.ConclusionSNPs in CYP3A4, CYP3A5, and MDR1 genes in a population of Ghanaian kidney failure patients were described. The varying SNPs of the featured genes suggest the need to consider the genetic status of Ghanaians kidney failure patients prior to transplantation and tacrolimus therapy.

Role of NQO1 Gene Involvement and Susceptibility of T2DM Among Saudi Arabia Population.

NQO1 disruption enhances susceptibility to oxidative stress during hyperglycemia and is a significant contributor to the development and progression of diabetes. Oxidative stress has been linked to several symptoms, including hyperglycemia, reactive oxygen species buildup, high blood pressure, and the expression of inflammatory markers. Therefore, the present research aimed to evaluate the genetic abnormality of NQO1 (rs1800566, C609T) gene polymorphism, expression, and vitamin-D level assessment among Type 2 diabetes mellitus (T2DM) patients. The study included 100 newly diagnosed T2DM cases and 100 healthy individuals as healthy controls. Total RNA was extracted from the whole blood using the TRIzol method, and further cDNA was synthesized, and expression was evaluated. There is a significant difference in NQO1 (rs1800566, C609T) genotype distribution among the T2DM patients and healthy controls (p = 0.04). Compared with the NQO1 CC wild-type genotype, the NQO1 CT heterozygous genotype had an odds ratio of 1.96 (1.08-3.55), and the NQO1 TT mutant type genotype had an odds ratio of 3.31 (0.61-17.77). Significantly decreased expression of NQO1 mRNA was observed with heterozygous CT (p < 0.0001) and homozygous mutant TT genotype (p = 0.0004), compared with homozygous wild-type CC genotype. NQO1 mRNA expression level was also compared with vitamin D levels among the T2DM patients. T2DM patients with vitamin D deficiency had 1.83-fold NQO1 mRNA expression, while vitamin D insufficient and sufficient T2DM cases had 3.31-fold (p < 0.0001) and 3.70-fold (p < 0.0001) NQO1 mRNA expression. It was concluded that NQO1 (rs1800566, C609T) CT and TT genotypes played a significant role in the worseness of type II diabetes mellitus, and decreased expression of NQO1 mRNA expression could be an essential factor for disease worseness as well as hypermethylation could be a factor for reduced expression leading to disease severity. The decreased NQO1 mRNA expression with heterozygous CT and mutant TT genotype associated with vitamin D deficiency may contribute to disease progression.

Genetic analyses of truncated variant rs200185429 in ZNT8 encoding SLC30A8 gene with respect to prediabetes and type 2 diabetes in Bangladeshi population

Zinc transporter ZnT8, encoded by SLC30A8, is expressed highly in pancreatic β-cells that effluxes Zn2+ into insulin granules which is required to secret insulin from the granules. Genome-wide association study identified twelve loss of function mutations in SLC30A8 that play protective role against type 2 diabetes (T2D). This study aimed to find genetic association of a protein truncating variant rs200185429 in Bangladeshi healthy individuals (n = 184), patients with prediabetes (n = 130) and patients with T2D (n = 179). Genetic association study with respect to rs200185429 was performed using TaqMan® probe followed by allelic discrimination plots. Wild type CC genotype was found to be evenly distributed in healthy individuals (96.2 %), patients with prediabetes (95.38 %) and patients with T2D (94.41 %). CT genotype was more prevalent in T2D (5.59 %), less in healthy individuals (3.38 %). However, TT genotype was absent in the study participants. Mutant T allele was neither associated with prediabetes (OR = 1.22, χ2 = 0.12, p = 0.72) nor with T2D (OR = 1.42, χ2 = 0.52, p = 0.47). Similarly, none of the genetic inheritance models showed statistically significant association with T2D. Thus, a large-scale study is warranted to establish our finding regarding the association of rs200185429 with prediabetes and T2D in Bangladeshi population.

The impact of SLCO1B1 single nucleotide polymorphism and non-genetic factors on statin-induced myopathy

Abstract Funding Acknowledgements None. Background Statins, also known as HMG CoA Reductase Inhibitors, are a class of drugs considered the drug of choice for treating hypercholesterolemia. Statins are well tolerated; however, they may cause severe myopathy in 20% to 30% of patients, due to the individual variation regarding its efficacy and related adverse effects. Of these, comes the Single Nucleotide Polymorphism (SNP) T521C of the SLCO1B1 gene that encodes the protein involved in the trafficking of statins from the blood to hepatocytes which is called Organic Anion Transport Protein 1B1 (OATP1B1). The T521C single nucleotide polymorphism (SNP) results in a substitute of valine with alanine resulting in a decreased or lack of functional protein. Purpose The aim is to determine the frequency of the high-risk C allele and to define its impact on statin-induced myopathy in Syrian patients on statins. In addition to the non-genetic factors that may affect the ability to develop statin-induced myopathy. Methods This was an observational case-control study that had ethical approval from Damascus University (No.433/ 2020). The case group included 44 patients on statins who experienced myopathy, 18 patients who had increased creatinine kinase levels (CK), and 26 patients with normal CK levels, while the control group encompassed 56 patients who were taking statins and had no muscular adverse events. The DNA was extracted from each sample and then genotyped using standard sequencing of specific PCR products using a specific pair of primers. Results The age of patients in the case arm ranged between 27 and 84 years with an average ± SD of (58.2 ± 12.7 years), 70% of them were males. In comparison with (53.34 ± 12.4 years) in the control arm, 66% of them were males without a statistically significant differences (p=0.672, 0.057) respectively. The statin type and dose have a statistically non-significant effect, the average statin dose in the case arm and the control arm was 26.02 mg and 31.27 mg respectively (p=0.072). While the statin type treatment varied as 59% used atorvastatin and 39% used rosuvastatin in the case group compared with 71% used atorvastatin and 27% used rosuvastatin in the control group, without a statistically significant difference (p=0.252). The frequency of the C allele reaches 19.3% and is distributed in three genotypes: wild-type TT (68%), heterozygote TC (25%), and homozygote CC (7%) in the case arm, while it does not exceed 8% in the control arm with the absence of the CC genotype. Only a statistically significant difference was found in the frequency of the CC genotype between these two groups (p=0.047). Conclusion Our study is the first to identify the frequency of the 521T&amp;gt;C SNP of the SLCO1B1 gene in Syrian patients taking statins. Our data reveals a high prevalence of risk allele C in the patients who suffer from statin-induced myopathy with a statically significant difference from the control arm (p=0.026).

Associations of Matrix Metalloproteinase-8 Genotypes to Renal Cell Carcinoma in Taiwan.

Renal cell carcinoma (RCC) presents a formidable clinical challenge due to its aggressive behavior and limited therapeutic options. Matrix metalloproteinase-8 (MMP-8) has recently emerged as a potential biomarker and therapeutic target for various cancers. However, the genetic involvement of MMP-8 in RCC has remained largely obscure. This study aimed to elucidate the role of MMP-8 genotypes in RCC susceptibility. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to scrutinize the genotypes of MMP-8 C-799T (rs11225395), Val436Ala (rs34009635), and Lys460Thr (rs35866072) among 118 RCC patients and 590 controls. Furthermore, potential associations between MMP-8 genotypes and age, sex, smoking, alcohol consumption, hypertension, diabetes, and family history status in relation to RCC risk were assessed. No significant disparities in the distribution of MMP-8 rs11225395, rs34009635, and rs35866072 genotypes were observed between the RCC case and control cohorts (p>0.05). Individuals with CT and TT genotypes at MMP-8 rs11225395 exhibited 0.86- and 0.80-fold RCC risks, respectively (OR=0.57-1.31 and 0.42-1.55, p=0.5585 and 0.6228, respectively). Intriguingly, hypertensive individuals carrying the MMP-8 rs11225395 CT or TT genotype demonstrated an elevated risk for RCC compared to those with wild-type CC genotype (p=0.0440). No interactions of MMP-8 genotypes with age, sex, smoking, alcohol consumption, or diabetes status were evident (all p>0.05). No significant association was discerned for MMP-8 rs34009635 or rs35866072 genotypes. MMP-8 genotypes appear to have a modest influence on individual susceptibility to RCC. Hypertensive patients with the CT or TT MMP-8 rs11225395 genotype may have an elevated risk of RCC.

Association of Matrix Metalloproteinase-9 Genotypes With Lung Cancer Risk in Taiwan.

Matrix metalloproteinase-9 (MMP-9) expression is upregulated in various diseases, including lung cancer. However, the role of MMP-9 genotype in lung cancer susceptibility remains uncertain. This study aimed to clarify the contribution of MMP-9 promoter rs3918242 genotypes to the risk of lung cancer in Taiwan. The MMP-9 rs3918242 genotypes of 358 lung cancer patients and 716 healthy controls were determined using polymerase chain reaction-restriction fragment length polymorphism methodology. Individuals carrying the variant CT or TT genotype of MMP-9 rs3918242 did not demonstrate an increased risk of lung cancer compared to wild-type CC carriers [odds ratio (OR)=1.11 and 1.85, 95% confidence interval (95%CI)=0.82-1.48 and 0.91-3.76; p=0.5541 and 0.1280, respectively]. Moreover, individuals carrying the T allele did not show a higher lung cancer risk compared to those with the C allele (OR=1.21, 95%CI=0.95-1.54, p=0.1444). However, a significant association was observed between the MMP-9 rs3918242 TT genotype and lung cancer risk among non-smokers (OR=5.48, 95%CI=1.31-22.89, p=0.0181). The presence of the TT genotype for MMP-9 rs3918242 may indicate an elevated risk of lung cancer among non-smokers.

Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation.

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.

The Mediating Effect of the Choline-to-Betaine Ratio on the Association Between PEMT rs7946 and Digestive System Cancer: A Nested Case–Control Study in a Chinese Population

BackgroundThe enzyme phosphatidylethanolamine N-methyltransferase (PEMT) is responsible for synthesizing phosphatidylcholine by methylating phosphatidylethanolamine. We hypothesized that a polymorphism of the PEMT gene, rs7946, is involved in carcinogenesis. ObjectivesWe aimed to investigate the relationship between PEMT rs7946 and digestive system cancer and examine possible effect modifiers and mediators. MethodsWe conducted a nested, case–control study within the China H-type Hypertension Registry Study, including 751 cases and 1:1 matched controls. To assess the association of PEMT rs7946 and digestive system cancer, we estimated odds ratios with 95% confidence intervals (CIs) using conditional logistic regression. We used the bootstrap test to examine the potential mediating effects of related metabolites. ResultsOur results revealed that wild-type homozygous CC genotype carriers of PEMT rs7946 had a significantly increased risk [odds ratio (OR): 1.31; 95% CI: 1.04, 1.66; P = 0.023] compared with the TT/CT combined genotypes. The effect was found to be more pronounced in individuals with a lower choline-to-betaine ratio (<0.412, P-interaction = 0.021). Furthermore, the mediation analysis indicated that the choline-to-betaine ratio played a significant role in mediating 13.55% of the association between PEMT rs7946 and digestive system cancer (P = 0.018). ConclusionsOur study suggested that PEMT rs7946 may affect risk of digestive system cancer through direct and indirect pathways, and the choline-to-betaine ratio may partially mediate the indirect effect.This trial was registered at Chinese Clinical Trial Registry as ChiCTR1800017274.

Comparison of wild-type and high-risk PNPLA3 variants in a human biomimetic liver microphysiology system for metabolic dysfunction-associated steatotic liver disease precision therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using "patient biomimetic twins" constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages.

Impacts of Matrix Metalloproteinase-9 Promoter Genotypes on Asthma Risk.

The overexpression of matrix metalloproteinase-9 (MMP9) has been observed in asthmatic patients, yet the role of MMP9 genotype in determining asthma susceptibility remains unresolved. This study aimed to elucidate the contribution of MMP9 promoter rs3918242 genotype to asthma risk in Taiwan. A cohort comprising 453 non-asthmatic healthy controls and 198 asthmatic cases was assembled, and the MMP9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism methodology. Our findings indicated that people carrying the variant CT or TT genotype of MMP9 rs3918242 did not demonstrate an elevated risk of asthma compared to wild-type CC carriers (odds ratio=1.28 and 1.72, 95% confidence interval=0.87-1.87 and 0.72-4.13; p=0.2417 and 0.3201, respectively). Furthermore, individuals carrying the T allele at MMP9 rs3918242 did not exhibit a higher risk of asthma than those carrying the C allele (odds ratio=1.31, 95% confidence interval=0.96-1.79, p=0.0869). Interestingly, a positive association was observed between MMP9 rs3918242 CT or TT genotypes and the severity of asthma symptoms among asthmatic patients (p=0.0035). Although the T allele at MMP9 rs3918242 was not associated with asthma risk, it may serve as a predictor for asthma symptom severity. These findings warrant validation in larger and more diverse populations to further elucidate the significance of MMP9 in asthma etiology.

Polymorphisms of CCSER1 Gene and Their Correlation with Milk Quality Traits in Gannan Yak (Bos grunniens).

Coiled-coil serine-rich protein 1 (CCSER 1) gene is a regulatory protein gene. This gene has been reported to be associated with various economic traits in large mammals in recent years. The aim of this study was to investigate the association between CCSER1 gene single nucleotide polymorphisms (SNPs) and Gannan yaks and to identify potential molecular marker loci for breeding milk quality in Gannan yaks. We genotyped 172 Gannan yaks using Illumina Yak cGPS 7K liquid microarrays and analyzed the correlation between the three SNPs loci of the CCSER1 gene and the milk qualities of Gannan yaks, including milk fat, protein and casein. It was found that mutations at the g.183,843A>G, g.222,717C>G and g.388,723G>T loci all affected the fat, protein, casein and lactose traits of Gannan yak milk to varying extents, and that the milk quality of individuals with mutant phenotypes was significantly improved. Among them, the milk fat content of AG heterozygous genotype population at g.183,843A>G locus was significantly higher than that of AA and GG genotype populations (p < 0.05); the casein and protein content of mutant GG and CG genotype populations at g.222,717C>G locus was significantly higher than that of wild-type CC genotype population (p < 0.05); and the g.388,723G>T locus of the casein and protein contents of the mutant TT genotype population were significantly higher (p < 0.05) than those of the wild-type GG genotype population. These results provide potential molecular marker sites for Gannan yak breeding.

ZNF259 rs964184 genetic variant is associated with metabolic syndrome in a Portuguese population

Abstract Background Zinc finger protein (ZPR1) encoded by the ZNF259 gene has been associated with defects in transcription and cell cycle progression. Additionally, the promoter site of ZPR1 binds to peroxisome proliferator-activated receptor gamma (PPARG), which plays a crucial role in insulin sensitivity and obesity. It's not consensual in its association with Metabolic Syndrom (MetS). Aim To estimate the influence of the ZNF259 rs964184 variant in MetS appearance. Methods A case-control study was performed with 3134 subjects (mean age 52.8 ± 8.1 years, 76.4% male) recruited from the Research Unit database, a regional quality clinical registry of hospital admissions. 1756 were patients with MetS and 1378 controls without MetS. MetS was diagnosed according to the International Diabetes Federation (IDF) criteria. The ZNF259 rs964184 C&amp;gt;G was genotyped with the TaqMan PCR assay (Applied Biosystems 7300 Real-Time). The bivariate analysis evaluated the genotypic and allelic distribution in the two groups, with and without MetS. Multivariate Logistic Regression assessed the variables independently associated with MetS. Results There were significant differences in genotype and allele distributions for the ZNF259 C&amp;gt;G variant between patients with MetS and without MetS. Wild-type genotype CC was increased in the non-MetS group, whereas the risk GG was higher in patients with MetS (P=0.008). Similarly, C allele frequencies were significantly higher in the non-MetS group, while the G allele was highly present MetS population (P=0.002). After multivariate logistic regression, GC genotype (OR=1.23; 95%CI:1.05–1.45; p=0.011) and GG genotype (OR=1.59; 95%CI:1.01–2.50; p=0.047) remained as independent risk factors for Metabolic Syndrome. Conclusions This study presents novel data and findings that may have important implications for assessing MetS risk in our population. For the first time in a Portuguese population, we demonstrated that ZNF259 genetic changes are significantly associated with more than 60% increased probability of having Metabolic Syndrome.

Lower overall survival in male patients with advanced disease undergoing allogeneic hematopoietic stem cell transplantation is associated with CYP1B1 Leu432Val polymorphism.

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. In a single-center retrospective study, 382 patients who underwent allogeneic hematopoetic stem cell transplantation and their donors were genotyped for CYP1B1 C432G polymorphism by reverse transcription polymerase chain reaction. One hundred and sixty-nine patients (44%) were homozygous wild-type (wt) gene CC, 157 (41%) heterozygous CG and 56 (15%) homozygous gene mutated GG. Of interest, mutated CYP1B1 was more common in male (62%) than in female patients (48%) P=0.006, unlike in donors. Five-year estimate for overall survival (OS) was 58±4% (CC) versus 48±3% (CG and GG), P=0.048. Surprisingly, this difference was only evident in males (P=0.024): OS 58±6% versus 42±4%, whereas it was virtually absent in females. Importantly, this difference was only evident in male patients with advanced disease (AD) (n=118, P=0.002): OS 44±8% (CC) versus 32±6% (CG) versus 6±6% (GG), whereas it was virtually absent in male patients with early disease. One-year non-relapse mortality in male patients with AD was 8±4% (CC) versus 21±5% (CG) versus 50±12% (GG), P=0.002. Three-year relapse rate in male patients with AD was 31±7% (wt) versus 42±6% (mut), P=0.04. Multivariate analysis for OS in male patients with AD revealed CYP1B1 polymorphism as the only prognostic factor: RR 1.78, P=0.001. In conclusion, these results suggest that male patients with AD and mutant CYP1B1 polymorphism have lower OS after allogeneic hematopoetic stem cell transplantation due to a higher non-relapse mortality and a higher relapse rate.

Enhanced recovery in patients with gestational diabetes mellitus and MTHFR 677 TT genotype after taking high-dose folic acid supplements during mid-late pregnancy: an open-label interventional study.

To explore the relationship between folic acid supplementation and the recovery rate of gestational diabetes mellitus (GDM) in women with methylenetetrahydrofolate (MTHFR) 677 TT genotypes in mid-late pregnancy. 9, 096 pregnant women were recruited with their MTHFR gene genotyped. 5,111 women underwent a 75-g oral glucose tolerance test (OGTT) and 2,097 were confirmed with GDM. The association between MTHFR genotypes and GDM risk was estimated using logistic and log-binomial regression, with age and parity set as the covariates to control their confounding effects. Further assessment of GDM risk on glucose levels was done using the ANCOVA model. As an open-label intervention study, 53 GDM patients with TT genotype were prescribed 800μg/day of folic acid as the high-dose group, while 201 GDM patients were given 400μg/day as the standard-dose group at their 24-28 weeks of pregnancy. A rate ratio (RR) of GDM recovery was estimated at each available time point for both groups. The time-to-GDM persistence events were analyzed with the Kaplan-Meier method and Cox-regression model. The trend of glucose levels over time was estimated using the linear model. MTHFR 677 TT genotype has no significant association with the glucose levels and GDM risk, with an adjusted OR of 1.105 (95% CI 0.853, 1.431; p=0.452) and an adjusted PR of 1.050 (95% CI 0.906, 1.216; p=0.518) compared to the wildtype CC group. Patients in the high-dose group (n=38; 15 drop-outs; 40.69 days (95% CI 33.22, 48.15)) recovered from GDM approximately 27 days faster than those in the standard-dose group (n=133; 68 drop-outs; 68.09 days (95% CI 63.08, 73.11)). Concomitantly, the RR of GDM recovery rose and reached 1.247 (95% CI 1.026, 1.515) at 100 days of treatment with the standard-dose group as reference. High-dose folic acid supplement intake in mid-late pregnancy is associated with faster GDM relief in patients with MTHFR 677 TT genotype compared to the standard dose, which would be served as a novel and low-cost alternative therapy for the treatment of GDM.

Abstract 3344: Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility

Abstract The purpose of our study was to investigate whether genetic variations in lncRNA H19 were associated with susceptibility to childhood leukemia. 266 childhood leukemia patients and 266 healthy controls were enrolled in Taiwan, and two single nucleotide polymorphisms (SNPs), rs2839698 and rs217727, in H19 were genotyped and analyzed. There was a significant difference in the genotypic distribution of rs2839698 between patients and healthy controls (p=0.0277). Compared to the wild-type CC genotype, the heterozygous variant CT and homozygous variant TT genotypes were associated with significantly increased risks of childhood leukemia with an adjusted odds ratio (OR) of 1.46 (95% confidence interval [CI], 1.08-2.14, p=0.0429) and 1.94 (95%CI, 1.15-3.31, p=0.0169), respectively (p for tread=0.0277). The difference in allelic frequencies between childhood leukemia patients and controls was also significant (T versus C, adjusted OR = 1.53, 95%CI, 1.13-1.79, p=0.0077). There were no significant differences in the genotypic and allelic distributions of rs217727 between cases and controls. Our results indicated that H19 SNP rs2839698, but not rs217727, may serve as a novel susceptibility marker for childhood leukemia. Citation Format: Chia-Wen Tsai, Wen-Shin Chang, Chao-Chun Chen, Pei-Chen Hsu, Yun-Chi Wang, Jen-Sheng Pei, Da-Tian Bau. Early detection biomarkers of LncRNA H19 genotypes for determining childhood leukemia susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3344.

Association of Matrix Metalloproteinase-2 Genotypes With Prostate Cancer Risk.

Prostate cancer is one of the most commonly diagnosed malignancies among males, especially in Western populations. Matrix metalloproteinase-2 (MMP-2) plays a critical role in extracellular regulation and metastasis. However, its genotypes have seldom been examined among patients with prostate cancer (PCa). Therefore, the purpose of the study was to evaluate the association of genotypes at MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) with PCa risk in a Taiwanese cohort. The profiles of MMP-2 rs243865 and rs2285053 genotypes were examined among 218 PCa patients and 436 healthy controls by polymerase chain reaction-restriction fragment length polymorphism methodologies. The percentages of wild-type CC, and variant CT and TT genotypes on MMP-2 rs243865 were 88.5, 10.6, and 0.9% in the PCa case group and 85.6, 13.5, and 0.9% in the control group, respectively (p for trend=0.5544). The allelic frequency distribution showed that the variant T allele at MMP-2 rs24386 5 was not associated with PCa risk (p=0.3250). As for MMP-2 rs2285053, the results were also non-significant. In addition, there was no association between the genotypes of MMP-2 rs243865 or rs2285053 with age or smoking status on PCa risk. rs11568818 and rs11568819 at MMP-2 promoter region played minor roles in determining individual PCa risk.

A novel deleterious oxytocin variant is associated with the lower twinning ratio in Awassi ewes

This study aimed to assess the possible association of oxytocin (OXT) gene with reproductive traits in two groups of Awassi ewes that differ in their reproductive potentials. Sheep were genotyped using PCR—single-stranded conformation polymorphism approach. Three genotypes were detected in exon 2, CC, CA, and AA, and a novel SNP was identified with a missense effect on oxytocin (c.188C > A → p.Arg55Leu). A significant (p < 0.01) association of p.Arg55Leu with the twinning rate was found as ewes with AA and CA genotypes exhibited, respectively a lower twinning ratio than those with the wild-type CC genotype. The deleterious impact of p.Arg55Leu was demonstrated by all in silico tools that were utilized to assess the effect of this variant on the structure, function, and stability of oxytocin. Molecular docking showed that p.Arg55Leu caused a dramatic alteration in the binding of oxytocin with its receptor and reduced the number of interacted amino acids between them. Our study suggests that ewes with AA and CA genotypes showed a lower reproductive performance due to the presence of p.Arg55Leu, which caused damaging impacts on oxytocin and is binding with the OXT receptor. The utilization of the p.Arg55Leu could be useful for improving Awassi reproductive potential.

JAK-STAT signaling pathway-related gene single nucleotide polymorphisms and susceptibility to ankylosing spondylitis in eastern Chinese Han population.

A case-control study was utilized to investigate the relationship between genetic variation of JAK-STAT signaling pathway-related genes and the susceptibility to ankylosing spondylitis (AS). Fifteen SNPs in the JAK-STAT signaling pathway-related genes from 660 AS patients and 646 healthy controls were genotyped using iMLDR technology (JAK1: rs2230587, rs2230588, rs2780815, rs310241; JAK2: rs2274472, rs2230722, rs2230724, rs10758669; STAT1: rs10199181, rs1547550, rs2066802, rs45463799, rs6718902; STAT3: rs3744483; STAT5A: rs1135669). Allele analysis revealed that the T allele of STAT1 rs6718902 was a protective agent for male AS patients (OR = 0.765, 95% CI = 0.644-0.909). Inheritance models showed that GG + CG as well as GG genotypes of STAT1 rs1547550 had a significant risk of developing AS in males (OR = 5.374, 95%CI = 2.505-11.526; OR = 5.186, 95%CI = 2.412-11.153). The TT + CT and TT genotypes at STAT1 rs6718902 were observed to be associated with a significantly decreased risk of AS compared to CC genotypes among male patients and male controls (OR = 0.637, 95%CI = 0.485-0.837; OR = 0.597, 95%CI = 0.422-0.845). Furthermore, the genotypes of JAK1 gene rs2230588, rs2780815, and rs310241 were correlated with the severity of clinical conditions in female AS patients, while the JAK2 rs2230724 genotypes may affect disease ability in male AS patients. These findings indicated that JAK-STAT signaling pathway-related gene single nucleotide polymorphisms may be associated with AS susceptibility in eastern Chinese Han population. Key Points • The T allele of rs6718902 on the STAT1 gene may be a protective agent for male AS patients. • STAT1 rs1547550 GG + CG and GG genotypes were observed to be connected with a risk of male AS patients. However, STAT1 rs6718902 TT + CT and TT genotypes reduced the susceptibility risk of male AS patients compared to wild-type CC. • The JAK1 genes rs2230588, rs2780815, and rs310241 may affect disease functional status in female AS patients, while the JAK2 rs2230724 genotype was related to disease activity in male AS patients.