Heterozygous Mutant Genotypes Research Articles

The association between vitamin D receptor gene polymorphism FokI and type 2 diabetic kidney disease and its molecular mechanism: a case control study

BackgroundThe role of the vitamin D receptor single nucleotide polymorphism FOKI (VDR-FOKI) (rs2228570) in genetic susceptibility to type 2 diabetic kidney disease (T2DKD) remains uncertain. This study investigated the relationship between VDR-FOKI and T2DKD within the Chinese Plateau Han population and analyzed the underlying mechanisms.MethodsA total of 316 subjects were enrolled, including 44 healthy adults, 114 individuals with type 2 diabetes mellitus (T2DM), and 158 patients with T2DKD. According to the 2023 American Diabetes Association Diabetes Guidelines, patients with T2DKD were categorized into low-medium-risk and high-risk groups based on estimates of glomerular filtration rate and urinary albumin-to-creatinine ratio. The VDR-FokI genotypes of all participants were identified using the Taqman probe and classified as homozygous mutant genotypes (C/C or FF), heterozygous mutant genotypes (C/T or Ff), and homozygous wild genotypes (T/T or ff). Plasma levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase activity (SOD) were assessed in T2DKD patients with FF and ff genotypes. Additionally, the levels of plasma VDR, GPX4, and P53 were determined using ELISA, while the relative expressions of VDR mRNA, GPX4 mRNA, and TP53 mRNA in whole blood were measured by RT-qPCR.ResultsThe T2DM patients with the ff genotype exhibited a 2.93-fold increased likelihood of developing T2DKD compared to those with the FF genotype (ORadjusted = 2.93; 95% CI: 1.142–7.513). Additionally, they were 2.01 times more likely to develop T2DKD than individuals with the FF and Ff genotypes (ORadjusted = 2.01; 95% CI: 1.008–4.006). However, no significant differences in VDR-FokI genotype distribution were observed between the healthy control group and the T2DM group, as well as between the low-medium-risk and high-risk groups of T2DKD. Furthermore, T2DKD patients with the ff genotype had significantly higher plasma levels of MDA compared to those with the FF genotype. In contrast, plasma GSH and SOD content was significantly lower in the ff genotype patients (P < 0.05). Additionally, the GPX4 concentration in ff genotype patients was significantly lower than in FF genotype patients [14.88 (11.32,22.39) vs. 12.76 (8.55,13.75), P = 0.037]. Nevertheless, no statistically significant difference was observed in the expression of VDRmRNA, GPX4mRNA, TP53mRNA, plasma VDR, and plasma P53.ConclusionsThe ff genotype of VDR-FokI is a risk factor for T2DKD, and the potential mechanism may be related to ferroptosis. However, It is not associated with T2DM or the progression of T2DKD.

Genetic Variants in the Adhesive G Protein-Coupled Receptor ADGRG6 are Associated with Increased Susceptibility to COPD in the Elderly Han Chinese Population of Southern China.

Mutations in ADGRG6 are associated with a variety of cancers and multiple types of diseases. However, the impact of genetic variations in ADGRG6 on chronic obstructive pulmonary disease (COPD) susceptibility has not yet been evaluated. Considering the high prevalence of COPD among the elderly population in China, this study specifically targets the elderly Han population in Southern China as the study subject. Following the acquisition of participants' whole-genome DNA, genotyping was conducted using the Agena MassARRAY platform. The online tool 'SNPStats', which utilizes logistic regression, was employed to analyze and assess the correlation. Multi-factor dimensionality reduction was utilized to clarify the impact of "SNP-SNP" interactions on COPD risk. The False-Positive Report Probability (FPRP) was applied to determine whether significant results are noteworthy findings. The mutant allele "C" of rs11155242 was a protective genetic factor against COPD susceptibility (OR = 0.57, 95% CI = 0.36 to 0.91, p = 0.017). The heterozygous mutant genotype "CA" of rs11155242 was found to be significantly associated with reduced COPD risk (CA Vs AA: OR = 0.53, 95% CI = 0.32 to 0.90, p = 0.018). ADGRG6-rs11155242 was found to be strongly associated with a reduced risk of COPD in males, non-smokers, and subjects with a BMI below 24 kg/m2 (OR < 1, p < 0.05). The FPRP analysis indicated that the positive results identified in this study are noteworthy new findings. The mutant allele "C" and mutant genotype "CA" of rs11155242 act as protective genetic factors against COPD susceptibility. This study will provide a new research direction for the personalized prevention and treatment of COPD in the elderly Han population in southern China, and lay a potential scientific basis.

Bleeding Events Associated with Rivaroxaban Therapy in Naive Patients with Nonvalvular Atrial Fibrillation: A Longitudinal Study from a Genetic Perspective with INR Follow-Up.

Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.

Missense mutations in the CITED2 gene may contribute to congenital heart disease

BackgroundCongenital heart disease (CHD) is a lifelong abnormality present from birth. Multiple studies have shown that mutations in genes involved in heart development could cause congenital heart disease. The CITED2 gene works as a transcription factor in the hypoxic pathway for the development of the heart. Therefore, five CHD types, ventricular septal defect, atrial septal defect, atrioventricular septal defect, tetralogy of fallot, and patent ductus arteriosus, were evaluated by conducting a targeted single nucleotide polymorphism (SNP) analysis of the CITED2 gene variant rs375393125 (T > C). This study aimed to identify the association of CITED2 gene mutations in CHD patients.MethodsThree hundred fifty samples, 250 from patients and 100 from controls, were collected for this genetic analysis. Allele-specific PCR and gel electrophoresis were used to identify the target missense mutations. The genotypic results of the CHDs were further validated through Sanger sequencing.ResultsThe frequency of the homozygous mutant (CC) in CHD patients was 48.4%, and of the heterozygous mutant (TC) genotype was 11.4%; these percentages are higher than controls (1%). The control samples had only one heterozygous TC and no homozygous CC genotype. The chi-square value was obtained at 103.9 with a probability of 0.05, more significant than the significance value of 21.03. The odds ratio was 43.7, which is > 1. The calculated value of ANOVA was 11.6, which was more significant than the F critical value of 3.7. As a result of sequencing, the mutant sample of each selected CHD type was found heterozygous or homozygous, and the results were like those obtained through conventional PCR.ConclusionThe samples of CHD patients showed mutations. Therefore, the CITED2 gene SNP might be associated with CHD.

Association Analysis of MMP-13 (rs2252070) Gene Polymorphism and the Susceptibility to Chronic Periodontitis.

Chronic periodontitis is a multifactorial inflammatory condition influenced by genetic factors. Matrix metalloproteinase(MMP)-13, serving as a crucial enzyme involved in extracellular matrix remodeling, is associated with the degradation of periodontal tissues. Therefore, this study assesses the genetic link between the MMP-13 (rs2252070) genetic variation and chronic periodontitis in a Southern Indian demographic. The study was conducted at Saveetha Dental Collegein Chennai, India. It involved a total of 100 subjects,50 individualsaffected with periodontitis (classified as stage II and above, American Association of Periodontology 2018 criteria) and 50 individuals who were periodontally healthy or were diagnosed as having mild gingivitis. We isolated DNAfrom the blood samples obtained from the participants. Specific primers that flank the BsrI region of the MMP-13 receptor gene were used in the process of DNA amplification. Subsequently, a restriction fragment length analysis using the BsrI enzyme was carried out for genotyping of the amplicon. Based on the restriction fragment length polymorphism pattern, we obtained certain genotypes. These were further recorded and followed by statistical analysis. We conducted a chi-square test to draw a comparison in terms of their genotype and allele frequencies. We calculated the odds ratio, along with 95% confidence intervals. The frequency of genotypes and distribution of MMP-13 polymorphism did not exhibit a statistically significant difference at χ2 degrees of freedom (P = 0.913). We inferred from our study that there was no significant difference between the groups concerning homozygous and heterozygous mutant genotypes (AA vs. AG + GG), with a P-value of 0.6871. The observed frequencies of GG (47% vs. 43%) and AG+AA (41% vs. 42%) genotypes did not indicate a significant difference between the groups. Similarly, there was no noteworthydistinction between the A allele (62% vs. 65%) and G allele (38% vs. 35%) in the case and control groups. Thefindings of the study reveal that there is no correlation between MMP-13 (rs2252070)gene polymorphism and periodontitis.

Genetic Association of ICAM-1 (rs5498) Gene Polymorphism With Susceptibility to Stage II Grade B Periodontitis: A Case-Control Study in South Indian Population.

In the contemporary perspective, periodontitis is considered a complex issue triggered and perpetuated by bacteriabut strongly influenced by the way the body reacts to bacterial plaque. Recent research has indicated that variations in genes might have an impact on the development of periodontitis. This study was conducted to explore a probable link between the genetic variations in intercellular adhesion molecule-1 (ICAM-1) represented by rs5498 and the occurrence of periodontitis. Methods: A total of 100 participants, 50 with periodontitis and 50 with periodontally healthy or mild gingivitis, were recruited for this study. Whole blood drawn from the participants was used to obtain genomic DNA. The ICAM-1 gene polymorphism (rs5498) was determined using polymerase chain reaction (PCR) amplification and digestion. The ICAM-1 gene's flanking primers were used to amp up the DNA. For statistical analysis, the genotype that was analyzed using the pattern of restriction fragment length polymorphism was recorded. The Chi-square test compared genotype and allele frequency distributions between both groups. The odds ratio with 95% confidence intervals with each individual allele or genotype was used to compute the risk. Statistical significance was established in all tests when the p-value was less than 0.05. There was no discernible difference between the genotype frequencies of patients and controls χ2df (P = 0.6065). The findings demonstrated that no significant difference was present between the two groups for homozygous or heterozygous mutant genotypes (AA vs. AG+GG; P = 0.6854). There was no discernible difference in the detected frequencies of the A allele (58% vs. 61%), G allele (42% vs. 39%), TT (16% vs. 24%), AG (40% vs. 36%), and TT genotypes in the studied groups. According to the results of the current investigation, the ICAM-1 (rs5498) gene polymorphism is not associated with periodontitis in the population investigated.

Association of SLC22A1, SLC47A1, and KCNJ11 polymorphisms with efficacy and safety of metformin and sulfonylurea combination therapy in Egyptian patients with type 2 diabetes.

Multidrug and toxin extrusion transporter 1 (MATE1), encoded by the SLC47A1 gene and single nucleotide polymorphisms of organic cation transport 1, may impact metformin's responsiveness and side effects. Inward-rectifier potassium channel 6.2 (Kir 6.2) subunits encoded by KCNJ11 may affect the response to sulfonylurea. This study aimed to evaluate the association between SLC22A1 rs72552763 and rs628031, SLC47A1 rs2289669 and KCNJ11 rs5219 genetic variations with sulfonylurea and metformin combination therapy efficacy and safety in Egyptian type 2 diabetes mellitus patients. This study was conducted on 100 cases taking at least one year of sulfonylurea and metformin combination therapy. Patients were genotyped via the polymerase chain reaction-restriction fragment length polymorphism technique. Then, according to their glycated hemoglobin level, cases were subdivided into non-responders or responders. Depending on metformin-induced gastrointestinal tract side effects incidence, patients are classified as tolerant or intolerant. KCNJ11 rs5219 heterozygous and homozygous mutant genotypes, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and AG), and mutant alleles of both polymorphisms were significantly related with increased response to combined therapy. Individuals with the SLC22A1 (rs72552763) GAT/del genotype and the SLC22A1 (rs628031) AG and AA genotypes were at a higher risk for metformin-induced gastrointestinal tract adverse effects. The results implied a role for SLC47A1 rs2289669 and KCNJ11 rs5219 in the responsiveness to combined therapy. SLC22A1 (rs628031) and (rs72552763) polymorphisms may be associated with increased metformin adverse effects in type 2 diabetes mellitus patients.

Unraveling the Genetic Associations of DENND1A (rs9696009) and ERBB4 (rs2178575) with Infertile Polycystic Ovary Syndrome Females in Pakistan.

PolycysticOvary Syndrome (PCOS) is a complex genetic disorder in reproductive-aged women which is associated with comorbidities of reproductive, metabolic, cardiovascular, endocrine, and psychological nature. PCOS is the most common cause of anovulatory infertility. Pathogenesis of PCOS involves strong interaction between environmental and genetic factors. Many Single-Nucleotide Polymorphisms (SNPs) have been associated with PCOS in different populations. Currently, very limited association studies of PCOS and infertility have been done on Pakistani population. The variants DENND1A rs9696009 and ERBB4 rs2178575 are significantly associated with PCOS in Chinese and European populations. These candidate genes regulate the production of androgen hormone, Anti-Mullerian Hormone (AMH), and luteinizing hormone. All these hormones are involved pathogenesis of PCOS and infertility. The aim of the study is to find an association of DENND1A rs9696009 and ERBB4 rs2178575 variants with PCOS in infertile Pakistani females. In this case-control study, 300 infertile females were recruited. The cases (n = 160) were infertile female diagnosed with PCOS (Rotterdam Criteria), and controls (n = 140) were infertile women with no evidence of PCOS. The genomic DNA was isolated, and genotyping was done by PCR-Restriction fragment length polymorphism and further validated by DNA Sanger Sequencing. The Chi-Square analysis showed rs2178575 (ERBB4) was significantly associated with infertility (χ2 = 10.282, p = 0.005852) while rs9696009 (DENND1A) did not show any significant association (χ2 = 3.10, p = 0.212036). Furthermore, multinomial logistic regression analysis was performed and revealed that rs2178575 (ERBB4) heterozygous genotypes (GA) and mutant genotypes (AA) decrease the risk of infertility by 0.541 times (OR = 0.541, 95% CI = 0.314-0.930, p = 0.026) and 0.416 times (OR = 0.416, 95% CI = 0.228-0.757, p = 0.004), respectively, compared to wild-type genotype (GG). The ERBB4 variant is significantly associated with PCOS infertile women and genetically indicated that ERBB4 (rs2178575) decreases the risk of infertility in females having PCOS.

The association between body mass index elevation and differentiation in vitamin D receptor gene expression, genetic polymorphism, and oxidative stress in adult Egyptian individuals

Vitamin D plays a central role in maintaining calcium, phosphorus, and bone homeostasis in close interaction with the parathyroid hormone. Obesity is a significant health problem worldwide, particularly in developed nations. The current study was carried out to investigate the possible relationship between body mass index (BMI) elevation and differentiation in 25-hydroxyvitamin D (VD), vitamin D receptor (VDR) gene expression, and genetic polymorphism besides oxidative stress in adult Egyptian individuals. This was done to explore the mechanisms underlying the suggested role of the VD/VDR complex in the pathogenesis of obesity. A total of 70 subjects (30 obese, 25 overweight, and 15 normal, age: 20–50 years, without other chronic diseases) were selected. The study focused on the determination of VD, VDR gene polymorphism, VDR gene expression, alkaline phosphatase, calcium, phosphorus, glucose, lipid profile, oxidative stress including, oxidant (malondialdehyde), and anti-oxidants (reduced glutathione and superoxide dismutase). The results showed that elevation in BMI led to the percentage of the Ff 'allele' becoming predominant, while the percentage of the FF 'allele' was in the normal BMI range. Also, BMI elevation caused significant reductions in VD and VDR expression, with significant elevations in alkaline phosphatase and the levels of calcium and phosphate in serum. Also, oxidative stress increases with increasing BMI. Elevation in BMI causes a reduction in VD concentration and VDR gene expression levels. Also, the percentage of heterozygous mutant genotype Ff 'allele' is predominantly in the obese human, in contrast to normal subjects, where the percentage of homozygous wild genotype FF 'allele' is predominant. In general, the genetic expression and polymorphism of VD and VDR can be used as a genetic marker for predisposition, diagnosis, prognosis, and progression of obesity.

Analysis of CYP2C19 gene polymorphism and influencing factors of pharmacological response of clopidogrel in patients with cerebral infarction in Zhejiang, China.

Certain genetic and non-genetic factors may cause damaged platelet inhibition by clopidogrel. We aimed to determine the effect of cytochrome P4502C19 (CYP2C19) polymorphism, along with other clinical factors, on the platelet response to clopidogrel in patients with acute ischemic stroke (AIS). A total of 214 patients with AIS receiving clopidogrel at a maintenance dose of 75 mg daily admitted to the Ningbo First Hospital between 1 January 2020, and 31 December 2021, were enrolled. Platelet aggregation analysis was performed to determine clopidogrel resistance. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to determine CYP2C19 genotype. Other laboratory data on complete blood count and biochemical parameters were taken from patient medical files. Among the 214 AIS patients treated with clopidogrel in the Ningbo population, the incidence of clopidogrel resistance was approximately 43.9%, and the distribution of CYP2C19 genotypes was highest for CYP2C19(*1/*2) (43.0%), followed by CYP2C19 (*1/*1) (38.8%). The distribution of alleles *1, *2, *3, and *17 was 62.1, 32.5, 4.9, and 0.5%, respectively. A chi-squared test showed that the gene frequencies of alleles *2 and *3 were significantly higher in the clopidogrel-resistant group than in the clopidogrel-sensitive group (p < 0.001), and a Mann-Whitney U-test showed that high HCY levels were significantly correlated with clopidogrel resistance (p < 0.001). Multi-factor logistic regression analysis demonstrated that mutant heterozygous genotype [OR 2.893; 95% confidence interval (CI) 1.456-5.748; p = 0.002], mutant homozygous genotype (OR 4.741; 95% CI 1.828-12.298; p = 0.001), and high HCY levels (OR 1.209; 95% CI 1.072-1.362; p = 0.002) were significantly associated with clopidogrel resistance. According to our results, carrying the CYP2C19*2/*3 allele and high HCY levels are independent risk factors for clopidogrel resistance after clopidogrel therapy in patients with AIS. These two factors should be considered prior to clopidogrel administration.

Association of methylenetetrahydrofolate reductase polymorphism and male infertility in type 2 diabetes mellitus patients

INTRODUCTION: As per World Health Organization, Infertility is a condition which is characterized by not getting conceived with more than 1-year of unprotected sexual intercourse without usage of any contraceptive aids. Folate has a significant role in the metabolism of the cells, like nucleic acids synthesis, gene expression by means of remethylation of the homocysteine into methionine. In the males, deficiency of folate leads to reduced proliferation of the sperm cells. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase genes result in alterations of the methylations resulting pathological conditions being a potential risk factor for male infertility. MATERIALS AND METHODS: A total of 100 diabetic infertile males were selected as the study group and 100 nondiabetic fertile males were included as the control group. Blood samples were analyzed for the MTHFR polymorphisms. DNA extraction was done and the extract is subjected to polymerase chain reaction amplification. The resultant is subjected to electrophoresis for MTHFR gene allele confirmation. Statistical analysis was done using IBM SPSS Statistics 20 package. Chi-square test, odds ratio has been done and P &lt; 0.05 is considered statistically significant. RESULTS: Genotype frequencies of MTHFR C677T, A1298C in all the subjects were analyzed for the Hardy–Weinberg law of genetic equilibrium. Mutant polymorphisms of MTHFR C677T, i.e., thymine-thymine and cytosine-thymine were increased significantly. Similarly, MTHFR A1298C mutant polymorphisms, i.e. adenine-cytosine, cytosine-cytosine were increased significantly in the infertile group than in the fertile group. DISCUSSION: Mutations of both MTHFR C677T, A1298C are found to be linked with lowered enzyme activity. We found that the occurrence of mutant homozygous and mutant heterozygous genotypes was increased in a diabetic male infertile group when compared to nondiabetic fertile group. Hence, it can be concluded that presence of single-nucleotide polymorphisms of MTHFR will increase the risk of infertility in diabetic male population.

Genetic profile of MIF single nucleotide polymorphism (rs755622 G>C) in hepatocellular carcinoma among Egyptian patients.

To evaluate the role of MIF gene polymorphism rs755622 G>C in occurrence and progression of hepatocellular carcinoma (HCC) among a cohort of Egyptian patients. This case-control study was conducted on 50 patients with HCC after chronic viral hepatitis and 50 healthy volunteers, recruited between July 2021 and January 2022. All patients with HCC were evaluated for severity of liver disease using a Child-Pugh score, and TNM and BCLC scoring systems. MIF 173 G>C (rs755622) single nucleotide polymorphism was performed for all participants by polymerase chain reaction using restriction fragment length polymorphism technique (RFLP-PCR). Overall results showed significantly higher frequencies of GG (wild homozygous genotype) and mutant heterozygous genotype GC and G allele (OR = 6.303, 95% CI: 3.374-11.775) among patients with HCC compared to the control group (p = 0.001) for all. Also, significantly higher frequency of genotype GG was detected among patients with advanced Child scores (B and C) (p = 0.039) and TNM stages (III and IV) (p = 0.013). There was significantly higher frequency of the G allele among patients with multiple hepatic focal lesions compared to those with a single focal lesion (p = 0.01). An obvious role of MIF (rs755622) gene polymorphism could have an important role in susceptibility and progression of HCC among patients with chronic viral hepatitis induced liver cirrhosis.

Genetic variants of the GLP-1R gene affect the susceptibility and glucose metabolism of gestational diabetes mellitus: a two-center nested case‒control study

BackgroundGestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism.MethodsA two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI60) and OGTT-derived disposition index (DI).ResultsMutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI60 (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis.ConclusionsTag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.

Association of vitamin D deficiency and vitamin D receptor (VDR) gene single-nucleotide polymorphism (rs7975232) with risk of preeclampsia

Background Preeclampsia has a multifactorial-yet-elusive etiology. Recent reports suggest a link between preeclampsia and vitamin D (VD) metabolic axis. Genetic variations like single-nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) gene can alter the metabolic role of VD, which have been shown by several genetic association studies. However, there is discordance among these studies. Objective The current study aimed to investigate the association of VDR gene polymorphism (ApaI) and VD deficiency with risk of developing preeclampsia. Patients and Method In this case–control study, 40 preeclamptic and 40 normotensive pregnant women were compared for VD status and VDR gene polymorphism. Serum 25-hydroxyvitamin-D [25(OH) D] level was determined by enzyme-linked immunosorbent assay (ELISA) and VDR gene polymorphism Apa1 was analyzed by Allele specific polymerase chain reaction (AS-PCR) using sequence specific primers. Results Serum levels of 25(OH) D were very low but comparable in both preeclamptic and normotensive pregnant women. The difference between the two groups were not statistically significant (p = .423). VDR gene polymorphism ApaI (rs7975232) was found not to have significant association with the risk of developing preeclampsia. The frequencies of wild genotype (GG) in preeclamptic and normotensive women were 27.5% and 22.5% respectively. A total of 25% of preeclamptic women had mutant homozygous genotype (TT) and 17.5% of normotensive women had mutant homozygous genotype. The frequency of mutant heterozygous genotype (GT) in preeclamptic patients was 47.5% and in normotensive women was 60%. The variation of wild and mutant genotypes between the two groups was not statistically significant (p > .05). Conclusion This study showed that VDR gene polymorphism (ApaI) and VD deficiency are not associated with the risk of preeclampsia.

Study the relationship between polymorphisms of pre-miRNA regions and expression of mature miRNA in samples of Iraqi infertile men

Polymorphisms that increase risk factor for male infertility is one of the most studied infertility genetic factor however polymorphisms within pre- miRNA sequences have not extensively documented. This study aimed to highlighted association between idiopathic male infertility and, hsa-mir-196a-2 rs11614913Polymorphism genotyping and expression level of mature miRNA were done in semen samples of Iraqi fertile and infertile male in order to study impact of polymorphism on expression level of mature miRNA andstudy correlationbetween both of polymorphism genotype and mature miRNA expression level with quality of semen parameters. Results of this study demonstrated that homozygous mutant (TT) and heterozygous mutant (CT) genotypes of pre-miRNA regions (hsa-miRNA-196a-2, rs11614913) were significantly (P ≤ 0.01) higher in patients group when compared with control and associated with idiopathic Asthenozoospermia, Oligoasthenozoospermia and specifically Azoospermia.Correlation between polymorphism genotype and semen parameters exhibits that genotype obviously impacts semen parameters. Analyzing correlation between polymorphism genotype and expression elucidated that mutant homozygous (TT) genotype increasing expression level of mature miRNA. Elevated level of miRNA-196a-5p exhibitednegative correlation with semen parameter.

Gli-similar 3 (GLIS3) rs7020763 (C&gt;G) polymorphism in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a heterogeneous group of metabolic disorders characterized by the incapability of pancreatic beta cells to increase insulin secretion to compensate for insulin resistance in the peripheral tissues. T2DM is a multi-factorial disease including several environmental factors with the presence of genetic predisposition. The transcription factor GLI-Similar 3 (GLIS3) has an important role in the development, survival and proliferation of pancreatic beta-cells and insulin gene expression regulation. Accordingly, genome-wide association studies have shown that GLIS3 gene polymorphism may confer risk to type 2 diabetes mellitus T2DM. The present study intended to investigate the association between GLIS3 rs7020673 gene polymorphism and type 2 diabetes mellitus and its impact on glycemic control among Egyptian population. This study was conducted on 100 Egyptian patients diagnosed asT2DM patients and 100 age- and sex-matched non-diabetic normal controls. All subjects underwent full history taking, thorough clinical examination, routine laboratory investigations including fasting blood glucose (FBG), fasting insulin and hemoglobin A1c (HbA1c). Detection of rs7020673 polymorphism of GLIS3 gene was done by real-time polymerase chain reaction (PCR) and verified by sanger sequencing. Genotype and allele frequencies of rs7020673 did not differ between case and control groups. Regarding the heterozygous mutant genotype (GC), it was statistically less frequently distributed in diabetic patients (53%) versus controls (67%). Therefore, it can be considered as a negative risk factor for T2DM (OR: 0.5098, 95% CI (0.2827-0.9193), (P&lt; 0.05). In conclusion, our study indicated that the GC mutant genotype may be proposed as a negative risk factor for T2DM in Egyptian population.

Association of SRXN1 Receptor Gene Polymorphism with Susceptibility to Periodontitis.

Emerging evidence suggests that oxidative stress forms a key component in the etiopathogenesis of periodontitis. Literature evidence have shown potential antioxidants responsible for combating the pro-oxidants which stress the periodontium, but the peroxiredoxin-sulfiredoxin system is explored very minimally in periodontal disease. Thus, the present study was aimed to evaluate the genetic association of SRXN1 receptor gene polymorphism (rs6053666). A total of 100 subjects were recruited for this study, which included 50 Periodontitis patients (Stage II and above based on the criteria of American Association of Periodontology-2018) and 50 periodontally healthy or mild gingivitis. Genomic DNA was extracted from the whole blood collected from the subjects. DNA was amplified using specific primers flanking the BtgI region of the SRXN1 receptor gene. The amplicon was further subjected to genotyping using restriction fragment length using BtgI enzyme. The genotype obtained based on the restriction fragment length polymorphism pattern was recorded and used for statistical analysis. The distribution of genotypes and allele frequencies in the periodontitis and control groups were compared using the Chi-square test. The risk associated with individual alleles or genotypes was calculated as the odds ratio with 95% confidence intervals. Statistical significance in all tests was determined at P < 0.05. The genotype frequency and distributions of SRXN1 receptor BtgI polymorphism did not differ significantly at ꭕ2df (P = 0.557). Our study results showed that homozygous and heterozygous mutant genotypes had no significant difference (CC vs. CT + TT) between the periodontitis patients and control group with a P = 0.4266. The detected frequency of CT (38% vs. 34%) and TT (42% vs. 52%) genotype showed no significant difference between control and test group. There was no significant difference in C allele (39% vs. 31%) and T allele (61% vs. 69%) between the test and control group. The present study denotes that SRXN1 receptor gene polymorphism is not associated with periodontitis in the study group analyzed.

Impact of Methionine Synthase Reductase Polymorphisms in Chronic Myeloid Leukemia Patients.

Highlights What are the main findings? Our objective was to determine the relationship between the methionine synthase reductase polymorphisms (MTRR and MTR) and the risk of developing chronic myeloid leukemia (CML) in Sudanese Patients. What is the implication of the main finding? Here, we report that the heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with a decreased risk of developing CML in the Sudanese population asa protective factor.Our findings will help to increase the understanding of MTRR A66G polymorphism and its association with CML risk in the Sudanese population. Introduction： Metabolism methionine and of folate play a vital function in cellular methylation reactions, DNA synthesis and epigenetic process.However, polymorphisms of methionine have received much attention in recent medical genetics research. Objectives: To ascertain whether the common polymorphisms of the MTRR (Methionine Synthase Reductase) A66G gene could play a role in affecting susceptibility to Chronic Myeloid Leukemia (CML) in Sudanese individuals. Methods: In a case-controlled study, we extracted and analyzed DNA from 200 CML patients and 100 healthy control subjects by the PCR-RFLP method. Results: We found no significant difference in age orgender between the patient group and controls. The MTRR A66G genotypes were distributed based on the Hardy-Weinberg equilibrium (p > 0.05). The variation of MTRR A66G was less significantly frequent in cases with CML (68.35%) than in controls (87%) (OR = 0.146, 95% CI = 0.162–0.662, p < 0.002). Additionally, AG and GG genotypes and G allele were reducing the CML risk (Odds ratio [OR] = 0.365; 95% CI [0.179–0.746]; p = 0.006; OR = 0.292; 95% CI [0.145–0.590]; p = 0.001 and OR = 0.146; 95% CI [0.162–0.662]; p = 0.002 and OR = 2.0; 95% CI [1.3853–2.817]; respectively, (p = 0.000)). Conclusions: Our data demonstrated that heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with decreased risk of developing CML in the Sudanese population.

Metabolic Analysis of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms (MTHFR 677C

Neural tube defects (NTDs)are among the most prevalent and debilitating birth defects with their causes are still unknown, despite mounting evidence that genetic and/or environmental factors may play a role. We aimed to analyze two single nucleotide polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene, serum folate and vitamin B12 status among a cohort of Egyptian children with NTDs and their mothers. A case-control study has been conducted on 50 Egyptian children with various types of NTDs and their mothers. They were comparable with 50 unrelated healthy, age and sex matched children and their mothers (50) selected as controls. Pediatric and neurosurgical assessments were performed to the included cases. Serum folate and vitamin B12 were measured using ELISA kits. MTHFR 677C<T (rs1801133) and MTHFR1298A<C (rs1801131) were analyzed by restriction fragment length polymorphism using polymerase chain reaction. Lumbosacral meningomyelocele was the most frequent NTDs (50%). Significantly lower serum folate and vitamin B12 among cases and case mothers compared to the control and control mothers (p<0.05 for all). Significantly higher frequencies of both heterozygous mutant (CT) and homozygous mutant (TT) genotypes, and mutant T allele of MTHFR 677C<T among case mothers compared to control mothers (p<0.05 for all), with lack of significant differences of this SNP between pediatric groups. Mutant homozygous (AA) genotype and mutant A allele of MTHFR 1298A<C among control mothers were significantly frequent compared to case mothers (p<0.05 for both), with OR 6.081 and 7.071, [95%CI were 3.071-11.287 and 3.296-15.172, respectively]. Significantly frequent wild homozygous (CC) genotype and normal C allele of MTHFR 1298A<C among children with NTDs compared to the controls (p<0.05 for both), with OR 0.231 and 0.754, [95%CI were 0.095-0.561and 0.432-1.317, respectively].Low serum folate and B12 are frequently common among children with NTDs and their mothers. MTHFR 677C<T in mothers could be considered as genetic risk factors for development of NTDs in their children, while MTHFR1298A<C could be protective genetic factor against NTDs development.

POLYMORPHISMS OF THE PROGESTERONE RECEPTOR GENE IN ENDOMETRIOSIS PATIENTS OF SOUTH SUMATRA, INDONESIA

Polymorphisms of the progesterone receptor gene alter the expressions of two receptor isoforms involved in the regulation of progesterone's antiproliferative effect in endometriotic tissue. This study aims to identify the +331G/A polymorphism of the progesterone receptor gene in endometriosis patients in Palembang, South Sumatra. Identification of +331G/A single-nucleotide polymorphism (SNP) was conducted on 42 endometriosis patients through polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). In this study, twenty-six (61.9%) subjects had heterozygous mutant genotype for the +331G/A SNP. No subject with homozygous mutant genotype for the +331G/A polymorphism was identified. The frequencies of polymorphic alleles for the +331G/A polymorphism was 30.9%. In conclusion, the +331G/A progesterone receptor gene polymorphism was present in endometriosis patients in Palembang, South Sumatra. This finding may warrant further studies to determine whether this polymorphism play a role in the development of endometriosis in the Indonesian population.