MTHFR Rs1801133 Research Articles

Using the optimal method-explained variance weighted genetic risk score to predict the efficacy of folic acid therapy to hyperhomocysteinemia.

Genetic risk score (GRS) is a useful way to explore genetic architectures and the relationships of complex diseases. Several studies had revealed many single nucleotide polymorphisms (SNPs) associated with the efficacy of folic acid treatment to hyperhomocysteinemia (HHcy). We aimed to construct and screen out the optimal predictive model based on four GRSs and traditional risk factors. Four GRSs enrolled four SNPs (MTHFR rs1801131, MTHFR rs1801133, MTRR rs1801394, BHMT rs3733890) were presented as follows: (a) simple count genetic risk score (SC-GRS), (b) direct logistic regression genetic risk score (DL-GRS), (c) polygenic genetic risk score (PG-GRS), and (d) explained variance weighted genetic risk score (EV-GRS). We performed a prospective cohort study including 638 HHcy patients. Then we evaluated the associations of four GRSs with folic acid's efficacy and the performance of four GRSs. Four GRSs were independently associated with efficacy of treatment (p < 0.05). When combining GRSs with traditional risk factors, the AUC of the four models were all above 0.900 in the training set (Tradition + SC-GRS: 0.909, Tradition + DL-GRS: 0.909, Tradition + PG-GRS: 0.904, Tradition + EV-GRS: 0.910). And EV-GRS got the highest AUC. When evaluating the models in the testing set, we got the same conclusion that EV-GRS was optimal among four GRSs with the highest AUC (0.878) and the highest increase of AUC (0.008). A more precise predictive model combing the optimal GRS with traditional risk factors was constructed to predict the efficacy of folic acid therapy to HHcy.

Association of MTHFR, BMP4, TGFA and IRF6 Polymorphisms with Non-Syndromic Cleft lip and Palate in North Indian Patients

Background:Non-Syndromic Cleft Lip and Palate (NSCL/P) is a multifactorial birth defect. The world-wide prevalence of NSCL/P is 1 in 1000 live births; it differs with race, ethnicity and gender. The aim of the present study was to find out the status of candidate gene polymorphisms in NSCL/P cases and its association in phenotype of the patients.Methods:We have screened five polymorphisms in four candidate genes MTHFR (rs1801133, rs1801131) BMP4 (rs17563), TGFA (rs1146297) and IRF6 (rs2235371) by restriction fragment length polymorphism and results were validated by Sanger sequencing. Our dataset consists of 200 NSCL/P cases and 200 healthy controls from the Indian population. Statistical data analysis was performed by SPSS software.Results:MTHFR (rs1801133), BMP4 (rs175563) and TGFA (rs11466297) gene polymorphisms showed significant association with NSCL/P and act as a risk factor in the Indian population (p=<0.05). However, MTHFR (rs1801131), and IRF6 (rs2235371) gene polymorphisms did not show significant association with NSCL/P in the Indian population.Conclusion:The result of the study suggests an association between MTHFR (rs1801133), BMP4 (rs175563) and TGFA (rs11466297) polymorphisms with NSCL/P in Indian population.

Association Between SNPs in the One-Carbon Metabolism Pathway and the Risk of Female Breast Cancer in a Chinese Population.

ObjectiveThe aim of this study is to assess the relationship between the single-nucleotide polymorphism (SNP) in the one-carbon metabolism pathway (MTR rs1805087; MTHFR rs1801133; ALDH1L1 rs2002287, rs2276731; DNMT1 rs16999593, rs2228611; DNMT3B rs2424908) and the risk of female breast cancer (BC) in a Chinese population.MethodsA population-based case–control study was conducted, involving a total of 439 BC patients and 439 age-matched healthy controls. We adopted Sequence MASSarray to identify genotyping, and used immunohistochemistry (IHC) to test the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) in tumor tissue.ResultsWe found that rs16999593 (TC/CC vs TT: adjusted OR=1.38, 95% CI: 1.03–1.84, p=0.030) was associated with an increased risk of BC, while rs2228611 was related to a decreased BC risk (GA/AA vs GG: adjusted OR=0.74, 95% CI: 0.56–0.97, p=0.030). In addition, stratified analysis revealed that DNMT1 rs16999593, rs2228611 and ALDH1L1 rs2002287 contributed to the risk of BC, with associations with ER, PR and HER-2 expression.ConclusionIn summary, this study revealed that DNMT1 rs16999593 and rs2228611 were associated with BC risk.

DNMT3B (rs2424913) polymorphism is associated with systemic lupus erythematosus alone and with co-existing periodontitis in a Brazilian population.

The association between Periodontitis and Systemic Lupus Erythematosus (SLE) has been primarily based on their similar pathophysiology and both are associated with genetic polymorphisms. Objectives: To investigate an association between the methylation-related gene polymorphisms DNMT3B (rs2424913) and MTHFR (rs1801133) to Systemic Lupus Erythematosus (SLE) and Periodontitis. Methodology: In total, 196 individuals of all genders aged 24 to 60 years old were allocated into four groups based on their systemic and periodontal status, namely: Healthy control (n=60), periodontitis (n=51), SLE (n=47), and SLE + periodontitis (n=38). Individuals with SLE were stratified according to disease activity (SLEDAI) in inactive or active. We performed polymorphism analysis using PCR-RFLP with genomic DNA from mouthwash. We analyzed data using Fisher’s Exact, Chi-square test, and regression models. Results: Periodontal status were similar in subjects with periodontitis alone and combined with SLE. SLE patients with periodontitis had a longer SLE diagnosis than SLE only (p=0.001). For DNMT3 B polymorphism, the periodontitis, SLE, and Inactive SLE + periodontitis groups showed a higher frequency of T allele and TT genotypes compared to healthy controls (p<0.05). Regression analyses showed that the TT genotype is a strong risk factor for periodontitis (OR=4.53; CI95%=1.13–18.05) and also for SLE without periodontitis (OR=11.57; CI95%=3.12–42.84) and SLE with periodontitis (OR=5.27; CI95%=1.25–22.11) when compared to control. Conclusion: SLE patients with periodontitis had a longer length of SLE diagnosis. The DNMT3B (rs2424913) polymorphism was associated with periodontitis and SLE alone or combined with periodontitis. Our study contributes to understanding the genetic mechanisms involved in periodontitis and SLE susceptibility.

Effect of Polymorphisms of ABCB1 and MTHFR on Methotrexate-Related Toxicities in Adults With Hematological Malignancies

Study of the association between single nucleotide polymorphisms (SNPs) of methotrexate (MTX) pathway genes and MTX-related toxicity in the treatment of hematological malignancies is popular. Here, we studied the association between SNPs of MTHFR and ABCB1 and MTX-related toxicity in 157 adult Chinese patients diagnosed with hematological malignancies. Patients were genotyped for MTHFR rs1801131, MTHFR rs1801133, and ABCB1 rs1045642 by fluorescence in situ hybridization. Patients with MTHFR rs1801133T allele had a significantly higher risk of hematopoietic toxicity compared with those with CC genotype (p=0.003). With respect to MTHFR rs1801131, patients with CC and AC genotypes had significantly lower frequency of hematopoietic toxicity than patients with AA genotype (p=0.044). In conclusion, we identified an important influence of the SNPs of ABCB1 and MTHFR on MTX-related hematopoietic toxicity in adults with hematological malignancies. To optimize high-dose (HD)-MTX therapy and reduce related hematopoietic toxicity, it is necessary to detect the SNPs of MTHFR and ABCB1 before initiating HD-MTX and deciding the optimal dose of MTX and duration of leucovorin rescue, according to genetic tests and disease type in adults with hematological malignancies.

Genes and Weightlifting Performance.

A recent case-control study identified 28 DNA polymorphisms associated with strength athlete status. However, studies of genotype-phenotype design are required to support those findings. The aim of the present study was to investigate both individually and in combination the association of 28 genetic markers with weightlifting performance in Russian athletes and to replicate the most significant findings in an independent cohort of Japanese athletes. Genomic DNA was collected from 53 elite Russian (31 men and 22 women, 23.3 ± 4.1 years) and 100 sub-elite Japanese (53 men and 47 women, 21.4 ± 4.2 years) weightlifters, and then genotyped using PCR or micro-array analysis. Out of 28 DNA polymorphisms, LRPPRC rs10186876 A, MMS22L rs9320823 T, MTHFR rs1801131 C, and PHACTR1 rs6905419 C alleles positively correlated (p < 0.05) with weightlifting performance (i.e., total lifts in snatch and clean and jerk in official competitions adjusted for sex and body mass) in Russian athletes. Next, using a polygenic approach, we found that carriers of a high (6–8) number of strength-related alleles had better competition results than carriers of a low (0–5) number of strength-related alleles (264.2 (14.7) vs. 239.1 (21.9) points; p = 0.009). These findings were replicated in the study of Japanese athletes. More specifically, Japanese carriers of a high number of strength-related alleles were stronger than carriers of a low number of strength-related alleles (212.9 (22.6) vs. 199.1 (17.2) points; p = 0.0016). In conclusion, we identified four common gene polymorphisms individually or in combination associated with weightlifting performance in athletes from East European and East Asian geographic ancestries.

MTHFR and MDR1 Gene Polymorphisms in Yakut Patients with Non-Syndromic Orofacial Clefts

The aim of our study was to investigate the relationship between the MDR1 and MTHFR gene polymorphisms and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Yakut population in the Republic of Sakha (Yakutia). Methods and Results: The sample of examined persons consisted of 60 children with NSCL/P. The NSCL/P group was divided into the CLP (cleft lip with cleft palate) subgroup (n=31), CLO (cleft lip only) subgroup (n=14), and CPO (cleft palate only) subgroup (n=15). The comparison group (control) included 174 healthy volunteers who did not have relatives with OFCs. The study of the MDR1 rs1045642 SNP and the MTHFR rs1801133 SNP was performed by PCR and RFLP analysis. Analysis of the frequency distribution of alleles and genotypes depending on the severity of clefts showed that the carriage of the TT homozygous genotype of the MDR1 rs1045642 SNP was associated with significant risk for the development of NSCL/P (OR=2.52, 95% CI: 1.19-5.32, P=0.02). Analysis of the recessive model (TT vs CC + TC) also found a significant risk of NSCL/P with the TT genotype carriage (OR=2.20, 95% CI: 1.06-4.57, P=0.04). Analysis of the over-dominant model (TC vs TT + CC) showed that the heterozygous TC genotype had a protective effect (OR=0.41; 95% CI: 0.22-0.77, P=0.01) on the development of NSCL/P. Subgroup analysis according to NSCL/P subtypes (CLO, CPO and CLP) showed that the MDR1 rs1045642 SNP was significantly associated with a high risk of CPO in three genetic models: heterozygous [(TT vs TC): OR=5.03; 95% CI: 1.55-16.32; P=0.01], recessive [(TT vs CC + TC): OR=3.96; 95% CI: 1.32-11.95; P=0.02], and over-dominant [(TC vs TT + CC): OR=0.23; 95% CI: 0.08-0.66; P=0.01]. Conclusion: A study of two SNPs in the MDR1and MTHFR genes revealed a statistically significant increased risk for NSCL/P in carriers of the TT genotype of the MDR1 rs1045642 SNP.

ANALYSIS OF AN ASSOCIATION OF POLYMORPHIC VDR AND MTHFR GENE VARIATS WITH VITAMIN D STATUS IN BELARUSIAN WOMEN

Vitamin D is important for bone health and is also involved in maintaining the immune system and cell proliferation. Vitamin D status is a major healthcare concern worldwide. Gene variants, involved in vitamin D metabolism, may be associated with vitamin D status and the effectiveness of vitamin D supplementation. The aim of this work was to analyze the association of VDR rs7975232, rs1544410, rs731236, rs2228570 and rs11568820, MTHFR rs1801133 gene variants with the 25(OH)D level in Belarusian women. In total, 602 individuals, meeting the inclusion criteria,&#x0D; were recruited into the study. The study results demonstrated an association of the rs1544410 T/T and rs731236 G/G variants with an increased 25(OH)D level, and rs11568820 A/G + A/A and rs1801133 A/A with a reduced 25(OH)D level. G-G-G allelic combination carriers had a significantly increased (β = 3.5; 95 CI 1.4-5.7, p = 0.0015) vitamin D level. The identified markers may play an important role in optimizing vitamin supplementation and preventing complex diseases.

Associations of molecular genetic predictors of type 2 diabetes mellitus with hyperglycemia in extremely low birth weight infants

Hyperglycemia in premature newborns is an independent risk factor for death, so blood glucose testing is widely used in the practice of neonatal intensive care units.Objective: to evaluate the associations of the frequency of carriage of allelic variants of polymorphic loci of genes predisposing to type 2 diabetes mellitus in newborns with extremely low body weight and hyperglycemia.Methods. The study design is prospective, controlled, single – center, non-randomized. Genomic DNA samples were studied in newborn infants with extremely low body weight (ELBW) (n = 105). Previously, we compared the distribution of allele frequencies of the studied genes between a group of newborns with ELBW and a population sample of adults (control). Then, the distribution of allele frequencies of the genes was compared depending on the presence of hyperglycemia in newborns with ELBW. For the analysis, loci with already known association with the development of type 2 diabetes mellitus were selected ‒ ADRB2 (rs1042713) and (rs1042714), ADRB3 (rs4994), GNB3 (rs5443), PPARA (rs4253778), PPARD (rs2016520), TCF7L2_IVS3 (rs7903146) and TCF7L2_IVS4 (rs12255372), PPARGC1A (rs8192678), MTHFR (rs1801131), PPARG (rs1801282), MTNR1B (rs10830963), SIRT1 (rs7069102).Results. In newborns with ELBW, we found a more frequent occurrence of the mutant allele A of the polymorphic locus rs8192678 in the PPARGC1A gene and the allele C of the polymorphic locus rs4253778 in the PPARA gene, in contrast to the adult population sample. But in newborns with ELBW, hyperglycemia is most likely associated with the carrier of the allele C rs1801282 of the PPARG gene (χ2 = 18.972, p &lt; 0.001) and the allele T rs7903146 in the TCF7L2 gene (χ2 = 11.496, p &lt; 0.001).Conclusions. The carriage of the allele С rs1801282 of the PPARG gene is characterized by the presence of a strong conjugation with hyperglycemia in newborns with extremely low body weight. It is desirable to monitor the level of glycemia in the conditions of neonatal intensive care units, taking into account the carriage of genes predisposing to hyperglycemia.

A Meta-Analysis for Association of XRCC3 rs861539, MTHFR rs1801133, IL-6 rs1800795, IL-12B rs3212227, TNF-α rs1800629, and TLR9 rs352140 Polymorphisms with Susceptibility to Cervical Carcinoma.

Background:In spite of substantial declines in both incidence and mortality rates in the past 50 years, cervical cancer remains one of the leading causes of cancer associated mortality among women globally. We performed this meta-analysis to explore the role of XRCC3 rs861539, MTHFR rs1801133, IL-6 rs1800795, IL-12B rs3212227, TNF-α rs1800629 and TLR9 rs352140 polymorphism with susceptibility to cervical carcinoma. Methods:The search databases include PubMed, SciELO, MedRxiv, Web of Science, Scopus, Cochrane Library, China National Knowledge Infrastructure, and China Biology Medicine disc up to 30 June 2021. The language is limited to English and Chinese. The comparison between the polymorphisms and cervical cancer was assessed using pooled odds ratio (OR) and 95% confidence interval (CI). The data are statistically analyzed by Comprehensive Meta-Analysis (CMA) 2.0 software. Results:A total of 59 studies including seven studies with 1,112 cases and 1,233 controls on XRCC3 rs861539, 14 studies with 2,694 cases and 3349 controls MTHFR rs1801133, four studies with 1,121 cases and 1,109 controls on IL-12B rs3212227, seven studies with 1,452 cases and 2,186 controls on IL-6 rs1800795, 20 studies with 4,781 cases and 4909 controls on TNF-α rs1800629, and seven studies with 1743 cases and 2292 controls on TLR9 rs352140 were included. There was a significant association between XRCC3 RS861539, TNF-α rs1800629, and IL-6 rs1800795 polymorphisms and an increased risk of cervical carcinoma in overall population. However, the MTHFR rs1801133, IL-12B rs3212227 and TLR9 rs352140 polymorphisms were not associated. Conclusion:The pooled analysis showed that XRCC3 RS861539, TNF-α rs1800629, and IL-6 rs1800795 were associated with cervical carcinoma susceptibility, but not MTHFR rs1801133, IL-12B rs3212227 and TLR9 rs352140 polymorphisms.

Cryptogenic Stroke in the Young: Role of Candidate Gene Polymorphisms in Indian Patients with Ischemic Etiology.

Strokes that remain without a definite cause even after an extensive workup, termed cryptogenic strokes, constitute up to 30-40% of ischemic strokes (ISs) in the young. Some of them can have a genetic basis. However, the well-established genetic causes account for only a small percentage of these cases. To evaluate the association of cryptogenic young IS with 16 candidate gene polymorphisms. A case-control study with cryptogenic young IS patients (South and North Indians; n = 105) and age, sex, and ethnicity-matched controls (n = 215). Genotyping was carried out by PCR-RFLP method using DNA extracted from the blood. Association of the genotypes with the disease was studied using Chi-square test. MTHFR rs1801133 and KNG1 rs710446 showed significant statistical association with cryptogenic young IS (P = 0.0261 and 0.0157, respectively) in the Indian population. Significant association of KNG1 rs710446 (P 0.0036) and FXII rs1801020 (P 0.0376) with cryptogenic young stroke in South Indian males, SERPINC1 rs2227589 in South Indian female patients (P = 0.0374), and CYP4V2 rs13146272 in North Indian males (P = 0.0293) was observed. Our study indicates that in the Indian population MTHFR rs1801133, KNG rs710446, FXII rs1801020, SERPINC1 rs2227589, CYP4V2 rs13146272, and FXIII V34L may be significant risk factors for cryptogenic IS in the young. In addition, ethnicity and gender play a significant role. Further studies with larger sample size are required to completely establish these polymorphisms as risk factors for cryptogenic IS in young Indians.

Sarcopenia, Obesity, and Sarcopenic Obesity: Relationship with Skeletal Muscle Phenotypes and Single Nucleotide Polymorphisms.

Obesity may aggravate the effects of sarcopenia on skeletal muscle structure and function in the elderly, but no study has attempted to identify the gene variants associated with sarcopenia in obese women. Therefore, the aims of the present study were to: (1) describe neuromuscular function in sarcopenic and non-sarcopenic women with or without obesity; (2) identify gene variants associated with sarcopenia in older obese women. In 307 Caucasian women (71 ± 6 years, 66.3 ± 11.3 kg), skeletal muscle mass was estimated using bioelectric impedance, and function was tested with a 30 s one-leg standing-balance test. Biceps brachii thickness and vastus lateralis cross-sectional area (VLACSA) were measured with B-mode ultrasonography. Handgrip strength, maximum voluntary contraction elbow flexion (MVCEF), and knee extension torque (MVCKE) were measured by dynamometry, and MVCKE/VLACSA was calculated. Genotyping was performed for 24 single-nucleotide polymorphisms (SNPs), selected based on their previous associations with muscle-related phenotypes. Based on sarcopenia and obesity thresholds, groups were classified as sarcopenic obese, non-sarcopenic obese, sarcopenic non-obese, or non-sarcopenic non-obese. A two-way analysis of covariance was used to assess the main effects of sarcopenia and obesity on muscle-related phenotypes and binary logistic regression was performed for each SNP to investigate associations with sarcopenia in obesity. There were no significant obesity * sarcopenic status interactions for any of the investigated muscle-related phenotypic parameters. Neither sarcopenia nor obesity had a significant effect on biceps brachii thickness, but sarcopenia was associated with lower VLACSA (p = 0.003). Obesity was associated with lower MVCEF (p = 0.032), MVCKE (p = 0.047), and MVCKE/VLACSA (p = 0.012) with no significant effect of sarcopenia. Adjusted for age and height, three SNPs (ACTN3 rs1815739, MTHFR rs1801131, and MTHFR rs1537516) were associated with sarcopenia in obese participants. Sarcopenia was associated with a smaller muscle size, while obesity resulted in a lower muscle quality irrespective of sarcopenia. Three gene variants (ACTN3 rs1815739, MTHFR rs1801131, and MTHFR rs1537516) suspected to affect muscle function, homocysteine metabolism, or DNA methylation, respectively, were associated with sarcopenia in obese elderly women. Understanding the skeletal muscle features affected by sarcopenia and obesity, and identification of genes related to sarcopenia in obese women, may facilitate early detection of individuals at particular risk of sarcopenic obesity.

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Toxicity and Efficacy in Non-Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and risk of radiation-induced thoracic toxicity (RITT). There is an urgent need to identify genetic determinants that can explain patients' likelihood to develop recurrence and RITT following CRT. <h3>Materials/Methods</h3> We performed comprehensive genomic profiling, using a 474-cancer and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients' clinical and genomic features were correlated with progression-free survival (PFS), overall survival (OS), and high-grade RITT development, after CRT. <h3>Results</h3> A total of 122 patients were enrolled (median age, 62 years; 87% males). Of these, the majority (n = 84, 69%) had squamous cell carcinoma (SCC) and the remaining 38 (31%) were adenocarcinoma (ADC). Median PFS and OS of the cohort were 11.4 and 34.6 months, respectively. No clear survival difference was seen between the histological subtypes or other clinical features, other than an association between smoking history and an unfavorable outcome (PFS HR = 1.89 [95% CI, 1.11-3.21], <i>P</i> = 0.02; OS HR = 1.59 [0.80-3.16], <i>P</i> = 0.19). Genetic association analysis identified alterations in NOTCH2, KEAP1, FGFR1/3 alterations as potential risk factors of CRT resistance, with reduced PFS and OS compared with patients carrying the respective wild-type genes. The rates of grade 2 or higher (high-grade) radiation-induced pneumonitis and esophagitis were 32% and 13%, respectively. Polymorphisms in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis, respectively. Moreover, XRCC5 (rs3835) was also associated with an earlier occurrence of high-grade esophagitis. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles associated with an increased susceptibility to RITT overall. <h3>Conclusion</h3> Our results provide a set of clinically usable predictive biomarkers for chemo-radiotherapy toxicity and efficacy. These findings suggest that pre-treatment testing for a combination of genetic variants, which likely act together to confer resistance or toxicity after CRT, might be clinically useful.

NOTCH3 rs1043996 Polymorphism Is Associated with the Occurrence of Alcoholic Liver Cirrhosis Independently of PNPLA3 and TM6SF2 Polymorphisms

Alcoholic liver cirrhosis (ALC) is the most common indication for liver transplantation (LT) in Croatia and presents a risk factor for the development of hepatocellular carcinoma (HCC). However, genetic susceptibility has not yet been systematically studied. We aimed to investigate the contribution of the risk polymorphisms PNPLA3 rs738409, EGF rs4444903, TM6SF2 rs58542926, MTHFR rs1801133, previously identified in other populations and, additionally, the contribution of Notch-related polymorphisms (NOTCH1 rs3124591, NOTCH3 rs1043996 and rs1044116, NOTCH4 rs422951). The study included 401 patients. The ALC group consisted of 260 LT candidates, 128 of whom had histopathologically confirmed HCC, and 132 of whom were without HCC. The control group included 141 patients without liver disease. Genotyping was performed by PCR using Taqman assays. The patients’ susceptibility to ALC was significantly associated with PNPLA3 rs738409, TM6SF2 rs58542926, and NOTCH3 rs1043996 polymorphisms. These polymorphisms remained significantly associated with ALC occurrence in a logistic regression model, even after additional model adjustment for sex and age. Cirrhotic patients with the PNPLA3 GG genotype demonstrated higher activity of ALT aminotransferases than patients with CC or CG genotypes. The susceptibility to the development of HCC in ALC was significantly associated with PNPLA3 rs738409 and EGF rs4444903 polymorphisms, and logistic regression confirmed these polymorphisms as independent predictors.

Investigation of ACE rs4646994, MTHFR rs1801133 and VDR rs2228570 Genotypes in Jordanian Patients with Fibromyalgia Syndrome.

Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread body pain, weakness in certain parts of the body (critical points), low pain tolerance, sleep disturbances, and fatigue. This syndrome is considered rare in Jordan. The research aimed to find out the association of the angiotensin converting enzyme, methylenetetrahydrofolate reductase, and vitamin D receptor (ACE, MHFTR, and VDR, respectively) genotypes with FMS among Jordanian patients. This work included 22 FM patients and 22 healthy individuals of Jordanian Arabic origin. The ACE rs4646994, MTHFR rs1801133, and VDR rs2228570 genotypes were determined using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism. No associations between ACE rs4646994, MTHFR rs1801133, and VDR rs2228570 with the vulnerability of a person for the development of FMS were found. However, we found an association between the ACE rs4646994 genotype and restless leg among FM patients. Based on the result from this study, it appears that the ACE rs4646994 genotype is associated with restless leg among FMS patients of Jordanian origin. Further clinical investigations with larger sample sizes are required to confirm these findings and understand the molecular mechanism of ACE rs4646994 genetic variant in the restless leg syndrome among FM patients.

Single Nucleotide Polymorphisms in Apolipoprotein B, Apolipoprotein E, and Methylenetetrahydrofolate Reductase Are Associated With Serum Lipid Levels in Northern Chilean Subjects. A Pilot Study.

Characterization of allelic variants is relevant to demonstrate associations among genetic background and susceptibility to develop cardiovascular diseases, which are the main cause of death in Chile. Association of APOB, APOE, and MTHFR polymorphisms with higher lipid levels and the risk of developing hypertension and cardiovascular diseases have been described. Thus, the aim of this study was to assess genotype distribution and relative allelic frequency of ApoB rs693, ApoE rs7412, ApoE rs429358, MTHFR rs1801131, and MTHFR rs1801133 allelic variants and their effects on lipid profile in young healthy men and women from Northern Chile. A group of 193 healthy subjects were enrolled for this study. Genotyping of rs693 (APOB), rs7412 and rs429358 (APOE), and rs1801131 and rs1801133 (MTHFR) polymorphisms were performed by real time PCR. In addition, lipid profiles were determined and associated to genetic data. The genotype distribution was APOB rs693 (CC = 37%, CT = 41%, and TT = 22%), APOE rs7412/rs429358 (E4 = 0.06, E3 = 0.91, and E2 = 0.03), MTHFR rs1801131 (AA = 57%, AC = 30%, and CC = 13%), and MTHFR rs1801133 (CC = 20%, CT = 47%, and TT = 33%). The association of the genetic variants with plasma lipid levels showed that women, but not men, carrying APOB mutated allele (T) and Apo E4 allele presented lower values of total cholesterol when compared with C/C homozygous genotype or E3 allele, respectively (p < 0.05). In addition, a subgroup analysis revealed that ApoB C/C homozygous women exhibited higher values of HDL-C when compared with men carrying identical genotype (p < 0.01). On the other hand, women carrying E4 allele exhibited lower values of triglycerides when compared with male carrying identical genotype (p < 0.05). Finally, women carrying mutate allele (C) for MTHFR rs1801131 showed lower levels of triglycerides when compared with A/A homozygous genotype (p < 0.05) and lower levels of LDL-C for MTHFR rs1801133 in females carrying (T) allele when compared with males carrying identical genotype (p < 0.05). In summary, the present data showed that APOB, APOE, and MTHFR single nucleotide polymorphisms are associated to lipid levels in a gender-dependent manner among healthy subjects from Northern Chile, especially in women.

Variants of candidate genes associated with the risk of obstructive sleep apnea

The researches on the associations between different candidate genes and obstructive sleep apnea (OSA) are inconsistent. Here, we performed a comprehensive qualitative and quantitative analysis to estimate the contribution of variants from candidate genes to the risk of OSA. Qualitative analysis was conducted to find the relationships for all included genes. Then, quantitative analysis of both allele models and genotype models was applied to evaluate the risk variants for OSA. Furthermore, a similar analysis was performed in different ethnic groups. We included 152 publications containing 75genes for qualitative analysis. Among them, we included 93 articles containing 28 variants from 16genes for quantitative analysis. Through allele models, we found 10 risk variants for OSA (rs1801133 of MTHFR, ɛ4 of ApoE, -1438G/A of 5-HT2A, -308G/A of TNF-α, Pro1019Pro of LEPR, rs1130864 and rs2794521 of CRP, D/I of ACE, LPR and VNTR of 5-HTT) with the ORs of 1.21-2.07 in global population. We found that the variant of ɛ2 of ApoE could uniquely decrease the risk of OSA in the East Asian subgroup, while the other 6 variants, including ɛ4 in ApoE, -308G/A in TNF-α, Pro1019Pro in LEPR, D/I in ACE, LPR and VNTR in 5-HTT, could increase the risk of OSA. As for the European subpopulation, we only found that -308G/A in TNF-α could increase the risk for OSA. Eleven variants from the candidate genes are associated with the risk of OSA, which also show ethnicity differences in East Asian and European subgroups.

Association of MTHFR and ABCB1 polymorphisms with MTX-induced mucositis in Chinese paediatric patients with acute lymphoblastic leukaemia, lymphoma or osteosarcoma-A retrospective cohort study.

MTX pharmacology and toxicity involve several metabolizing enzymes and transporters whose functions have been suggested to be altered by genetic polymorphisms. The current study is to investigate the relationship between the genetic variation and MTX-induced adverse drug effects. A total of 80 paediatric patients (aged 1-14years) were enrolled in this study. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 scoring system. Genotyping was performed by MassARRAY Assay method. Data were analysed using Spss statistical package version 17.0 and Plink v1.07 software. The HWE was tested by a chi-square test. The Fisher's exact test (chi-squaretest) was used to compare the distributions of genotypes between cases and controls. OR and 95%CI were applied to evaluate the association of genetic variants with the presence of mucositis using unconditional logistic regression. Mucosal inflammatory injuries were found in 28 children. SNPs of rs1128503 (p=0.0022, OR=3.04, 95%CI=1.39-6.64) and rs1045642 (p=0.0052, OR=2.38, 95%CI=1.15-5.00) located in the gene of ABCB1 and SNPs of rs1801133 (p=0.040, OR=2.50, 95%CI=1.06-5.88) located in the gene of MTHFR show marked impacts on the risk of developing mucositis. SNPs of ABCB1 rs1128503, rs1045642 and MTHFR rs1801133 can be risk predictor for MTX-induced mucositis in Chinese paediatric patients diagnosed with acute lymphoblastic leukaemia, lymphoma or osteosarcoma.

Gene-Gene Interactions of Gemcitabine Metabolizing-Enzyme Genes hCNT3 and WEE1 for Preventing Severe Gemcitabine-Induced Hematological Toxicity.

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case\u2013control study

BackgroundPrenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations.MethodsThis study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model.ResultsHigher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30–15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02–1.25)].ConclusionsPrenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.