Polymorphisms In Metabolism Genes Research Articles

Effects of genetic polymorphism on the development of hepatocellular carcinoma in patients with metabolic-associated fatty liver disease. Review

Non‑alcoholic fatty liver disease (NAFLD) takes the first place among liver diseases in the countries with developed economies. In the year 2020, the group of experts proposed a new term, metabolic‑associated fatty liver disease, that allows to specify the diagnosis, to divide different NAFLD phenotypes and to optimize its treatment. The course of metabolic‑associated liver disease can range from mild forms (simple nonalcoholic steatosis, characterized by the accumulation of triglycerides in liver cells) up to an aggressive course with the development of cirrhosis and hepatocellular carcinoma (HCC). Aggressive course of the disease is observed in patients with type 2 diabetes mellitus, high body mass index, abdominal obesity and histologically confirmed steatohepatitis. Epidemiological and genetic studies have shown an association between the morphological stage of metabolic‑associated liver disease and hereditary factors. Progression to HCC is common in patients with severe steatohepatitis, although recent literature data showed a significant increase in the proportion of patients with F1/F2 fibrosis and НСС. This is due to the presence of metabolic syndrome and gene polymorphism. Three main genes can be singled out, the polymorphism of which is associated with the development of metabolic‑associated liver disease, insulin resistance, dyslipidemia, and fibrogenesis: PNPLA3, TM6SF2 and GCKR. Recently, an MBOAT7 gene polymorphism has been also identified, it peculiarly increases the risk of steatohepatitis development in patients who are alcohol abusers and/or have chronic viral hepatitis C. Detection of polymorphisms in these genes is useful for identifying groups at high risk for disease progression. Early diagnosis of HCC and risk stratification will allow to diagnose the disease at an early stage and optimize its treatment.

Study on the associations between liver damage and antituberculosis drug rifampicin and relative metabolic enzyme gene polymorphisms

ABSTRACT The occurrence of antituberculosis drug-induced liver injury affects the effectiveness of antituberculosis treatments. Understanding the mechanism and risk factors of such liver injury may improve the outcomes of those patients who received antituberculosis treatments. In this study, 2,255 pulmonary tuberculosis patients were included. Their medical records were reviewed, questionnaire surveys, liver function tests at the end of February (including patients with uncomfortable symptoms during the intensive treatment period), and blood samples were saved. Afterward, cases of liver damage were determined using Chinese liver damage criteria. The genotype of all participants was determined using the PCR-LDR method. Finally, the association between genetic polymorphism and ATB-DILI susceptibility was assessed using the univariate Logistic regression models. Among the 2,255 tuberculosis patients who received rifampicin, 612 (27.1%) had antituberculosis drug-induced liver injury. We observed higher proportions of older age, male, and lower levels of AST, ALT, and TBil among patients with liver injury. Results of univariate of logistic regression models showed that patients with CYP2C19 were more likely to have liver injury compared with no such genotypes patients (all P < 0.05). Patients with tuberculosis with older age and genetic polymorphism of CYP3A4, CYP2C9, and CYP2C19 who received long-term rifampicin treatment were more likely to have antituberculosis drug-induced liver injury. It is important for healthcare providers to carefully evaluate and monitor rifampicin use for these patients.

The Impact of Associations of Various Polymorphisms of Common Metabolic Genes with Muscle Energy Metabolism: An Overview

The Impact of Associations of Various Polymorphisms of Common Metabolic Genes with Muscle Energy Metabolism: An Overview

Association analysis between adverse drug reactions to cytarabine therapy and single nucleotide polymorphisms in cytarabine metabolic genes in patients with hematopoietic tumor

Association analysis between adverse drug reactions to cytarabine therapy and single nucleotide polymorphisms in cytarabine metabolic genes in patients with hematopoietic tumor

Metabolic enzyme gene polymorphisms predict the effects of antioxidant treatment on idiopathic male infertility.

To explore the relationship between genetic polymorphisms of metabolic enzymes such as CYP1A1, CYP2D6, GSTM1, GSTT1, and GSTP1 and idiopathic male infertility. By observing the efficacy of antioxidants in the treatment of idiopathic male infertility, the effect of metabolic enzyme gene polymorphisms on antioxidant therapy in patients with idiopathic male infertility was prospectively studied. This case–control study included 310 men with idiopathic infertility and 170 healthy controls. The cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) genotypes in peripheral blood samples were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). The idiopathic male infertility group was treated with vitamin C, vitamin E, and coenzyme Q10 for 3 months and followed up for 6 months. GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) in the idiopathic male infertility groups were more common than those in the control group. The sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients with GSTM1(−), GSTT1(−), and GSTM1/T1(−/−) were lower than those in wild-type carriers, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2’-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher. Therefore, oxidative damage may play an important role in the occurrence and development of idiopathic male infertility, but antioxidant therapy is not effective in male infertility patients with GSTM1 and GSTT1 gene deletions.

Polymorphisms in Genes of Lipid Metabolism Are Associated with Type 2 Diabetes Mellitus and Periodontitis, as Comorbidities, and with the Subjects' Periodontal, Glycemic, and Lipid Profiles.

Background Type 2 diabetes mellitus (T2DM) and periodontitis (P) commonly occur as comorbidities, but the commonalities in the genetic makeup of affected individuals is largely unknown. Since dyslipidemia is a frequent condition in these individuals, we investigate the association of genomic variations in genes involved in lipid metabolism with periodontal, glycemic, lipid profiles, and the association with periodontitis and T2DM (as comorbidities). Methods Based on clinical periodontal examination and biochemical evaluation, 893 subjects were divided into T2DM+P (T2DM subjects also affected by periodontitis, n = 205), periodontitis (n = 345), and healthy (n = 343). Fourteen single-nucleotide polymorphisms (SNPs) were investigated: LDLR gene (rs5925 and rs688), APOB (rs676210, rs1042031, and rs693), ABCC8 (rs6544718 and 6544713), LPL (rs28524, rs3735964, and rs1370225), HNF1A (rs2650000), APOE (rs429358 and rs7412), and HNF4A (rs1800961). Multiple linear and logistic regressions (adjusted for covariates) were made for all populations and stratified by sex and smoking habits. Results Individuals carrying APOB-rs1042031-CT (mainly women and never smokers) had a lower risk of developing periodontitis and T2DM (T2DM+P); altogether, this genotype was related with healthier glycemic, lipid, and periodontal parameters. Significant disease-phenotype associations with gene-sex interaction were also found for carriers of APOB-rs1676210-AG, HNF4A-rs1800961-CT, ABCC8-rs6544718-CT, LPL-rs13702-CC, and LPL-rs285-CT. Conclusions Polymorphisms in lipid metabolism genes are associated with susceptibility to T2DM-periodontitis comorbidities, demonstrating gene-sex interaction. The APOB-rs1042031 was the most relevant gene marker related to glucose and lipid metabolism profiles, as well as with obesity and periodontitis.

Predictive Value of Folic Acid Metabolism Gene Polymorphisms in Pregnancy for Birth Defects

Predictive Value of Folic Acid Metabolism Gene Polymorphisms in Pregnancy for Birth Defects

Maternal trichloroethylene exposure and metabolic gene polymorphisms may interact during fetal cardiovascular malformation

This study aimed to analyze the potential association between trichloroethylene (TCE) exposure and congenital heart disease (CHD) and to explore the effect of metabolic enzyme gene polymorphisms on heart development. A multicenter case-control study was conducted. The trichloroethylene concentrations were measured by UPLC-MSMS in urine. Fourteen SNPs in the GSTA1, GSTP1, MPO, NAT1, NAT2, CYP1A1, CYP1A2, CYP2E1 and EPHX1 genes were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. A total of 283 cases and 331 controls with maternal urine and/or venous blood were included in the present study. The median NAcDCVC was 7.65 ng/mL in the case group and 7.43 ng/mL in the control group. There was no significant difference in the NAcDCVC concentration between the CHD subtypes and controls (P > 0.05). The GA/AA of GSTA1 rs3957357 could increase the risk of CHDs under the dominant model (aOR = 2.26, 95 % CI: 1.31, 3.90), but other SNPs were not associated with CHDs (P > 0.05). GA or AA genotypes of GSTA1 rs3957357 with lower levels of TCE exposure were 3.53 times at risk relative to mothers carrying the wild type genotype. In conclusion, maternal exposure to trichloroethylene alone is not associated with the occurrence of fetal CHD and CHD subtypes. Maternal GSTA1 rs3957357 may increase the risk of CHD in offspring. TCE exposure and metabolic gene polymorphisms probably interact with each other to induce fetal cardiovascular malformation, but larger sample size studies are needed to confirm this hypothesis.

Polymorphisms at CYP enzymes, NR1I2 and NR1I3 in association with virologic response to antiretroviral therapy in Brazilian HIV-positive individuals.

Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes' genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.

3'-UTR Polymorphisms in Thymidylate Synthase with Colorectal Cancer Prevalence and Prognosis.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related mortality in Western countries. Polymorphisms in one-carbon metabolism and angiogenesis-related genes have been shown to play important roles in tumor development, progression, and metastasis for many cancers, including CRC. Moreover, recent studies have reported that polymorphisms in specific microRNA (miRNA)-binding regions, which are located in the 3′-untranslated region (UTR) of miRNA-regulated genes, are present in a variety of cancers. Here, we investigated the association between two thymidylate synthase (TYMS or TS) 3′-UTR polymorphisms, 1100T>C [rs699517] and 1170A>G [rs2790], and CRC susceptibility and progression in Korean patients. A total of 450 CRC patients and 400 healthy controls were enrolled in this study, and genotyping at the TS locus was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) or TaqMan allelic discrimination assays. We found that TS 1170A>G genotypes, as well as the TS 1100T-1170G and 1100C-1170A haplotypes, are strongly associated with CRC. The TS 1100TC+CC type was associated with a poor survival (OS and RFS) rate. In addition, levels of the TS 1100C and TS 1170G allele were found to be significantly increased in CRC tissue. Our study provides the first evidence for 3′-UTR variants in TS genes as potential biomarkers of CRC prognosis and prevention.

Folate metabolizing gene polymorphisms and genetic vulnerability to preterm birth in Korean women.

The folate metabolism that converts homocysteine to methionine is closely related to the accumulation of homocysteine. Increased homocysteine levels lead to an impaired antithrombotic function of the vascular endothelium and uterine-placental circulation, resulting in abnormal pregnancy outcomes. Previous studies have reported that gene polymorphisms in folate metabolism are associated with the development of preterm birth (PTB) in various populations. we performed a case-control study to evaluate the association between five polymorphisms in folate metabolic genes (MTHFR, MTR, MTRR, TCN2) and PTB. In this study, a total of 254 subjects were analyzed (111 patients with PTB and 143 women at ≥ 38weeks of gestation). Genotype and allele frequency differences between patients and control groups and the Hardy-Weinberg equilibrium were assessed using a Chi-square test. For evaluation indicators, odds ratios (ORs) of 95% confidence intervals (CI) were estimated. In addition, we analyzed the combined genotype frequencies of SNPs of folate-metabolizing genes to measure gene-gene interactions for PTB. Our results showed that the MTR rs1805087 GG (p = 0.031), and TCN2 rs1801198 CG genotype (OR 0.53, 95% CI 0.288-0.980, p = 0.042) were significantly associated with PTB. The MTHFR rs4846049 AA showed a marginal trend toward significance (OR 0.15, 95% CI 0.018-1.205, p = 0.041). In particular, the combined genotypes, including MTHFR rs1537514 CC-MTRR rs1801394 GG, MTHFR rs1537514 CC-TCN2 rs1801198 CG, and MTR rs1805087 AA-TCN2 rs1801198 CG, have significant interactions with PTB (OR 0.49, 95% CI 0.248-0.992, p < 0.05). The polymorphisms of folate metabolic genes may have a genetic association with the development of PTB in Korean women. A larger sample set and functional studies are required to further elucidate our findings.

Essential hypertension in patients exposed to high-arsenic exposed areas in western China: Genetic susceptibility and urinary arsenic metabolism characteristics

ObjectiveTo clarify the urinary arsenic metabolism characteristics in individuals with essential hypertension and to analyze the relationship between lipid metabolism gene polymorphisms and susceptibility to essential hypertension in individuals in high-arsenic areas in western China. MethodsA case-control study was conducted and involved individuals exposed to high arsenic levels (in this study, the arsenic content in the pressurized well water was 0–510.2 μg/L, and that in the mechanical well water was 167 μg/L) in two adjacent high-arsenic areas in Shanxi Province and the Inner Mongolia Autonomous Region, China. A total of 699 samples were collected, including 192 case samples (patients with hypertension) and 507 control samples (no hypertension). Blood pressure measurement data obtained from an epidemiological survey were used to determine whether the subjects had hypertension, and a logistic regression model was used to analyze the association between lipid metabolism gene polymorphisms and hypertension susceptibility. Blood and urine samples were collected based on epidemiological methods, single nucleotide polymorphisms (SNPs) were genotyped using a SNPscan™ multiple SNP typing kit, and urinary arsenic concentrations were determined using the hydride generation atomic fluorescence method (HG-AFS). ResultsADIPOQ/rs266729 was the dominant genetic model [(GC + GG) vs CC = 0.686:1, 95 % CI = 0.478−0.983], and FABP2/rs1799883 was the recessive genetic model [TT vs (CC + TC) = 1.690:1, 95 % CI = 1.014–2.816]. The distribution of the urinary arsenic secondary methylation ratio (SMR) [dimethylated arsenic (DMA)/monomethylated arsenic (MMA)] was different between hypertensive patients and controls. ConclusionADIPOQ/rs266729 and FABP2/rs1799883 polymorphisms affect susceptibility to essential hypertension in individuals exposed to high levels of arsenic; there was a clear difference in the urinary arsenic metabolism pattern between hypertensive patients and controls.

The Effects of Polymorphisms in One-carbon Metabolism Genes on Manifestation of Ichthyosis Vulgaris

BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris. AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris. METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p&lt;0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002). CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.

AGT, ACE, AGTR1, UMOD AND ADIPOQ GENES POLYMORPHISMS INTERACTIONS IN PREHYPERTENSION

Abstract Objective: Prehypertension (PHT) is recognized as a cardio-renal risk factor, and associated with progression to hypertension (HT). Studies of the genetic background of PHT have not been fully elucidated and the results suggested a possible role of genes involved in the etiopathogenesis of HT. The lack of data has prompted this study to hypothesize that hypertension and metabolic syndrome-related AGT rs2004776, ACE rs1799752, AGTR1 rs5186, UMOD rs13333226, ADIPOQ rs266729 and rs17300539 gene polymorphisms are more commonly found in subjects with PHT, than in subjects with optimal and normal blood pressure (BP). Design and method: A total of 601 subjects were included in this cross-sectional, observational study; 319 with high normal BP (PHT, 120–139/80–89 mmHg), ages 20–45, and 282 individuals with normal and optimal BP as a control group (NT). Results: The results indicated that the AGT, ACE, AGTR1, UMOD, and ADIPOQ gene polymorphisms were not found more frequently in PHT subjects than in NT. A significant difference was found in the number of rs266729 ADIPOQ heterozygous carriers; there were less carriers in the PHT group (35.1%) than in the NT group (44.7%), P &lt; 0.03. The significance of the heterozygous model (CG vs GG/CC) of rs266729 ADIPOQ polymorphism in PHT in terms of reduced risk was observed (OR 0.66; 95% CI 0.47–0.92; P = 0.01). PHT was significantly associated with following haplotypes: hIAGCA ACE:UMOD:ADIPOQ_rs17300539:ADIPOQ_rs266729:AGTR1 (OR 1.56; 95%CI 1.08–2.24; P = 0.02), hIAGC ACE:UMOD:ADIPOQ_rs17300539:ADIPOQ_rs266729 (OR 1.45; 95%CI 1.07–1.96; P = 0.02), hIAG ACE:UMOD:ADIPOQ_rs17300539 (OR 1.30; 95%CI 1.00–1.68; P = 0.05), hAGC UMOD:ADIPOQ_rs17300539:ADIPOQ_rs266729 (OR 1.37; 95%CI 1.07–1.77; P = 0.01) and hAG UMOD:ADIPOQ_rs17300539 (OR 1.42; 95%CI 1.07–1.90; P = 0.02). Results emphasized two significant models of gene-gene-other determinants interactions with PHT, one model included creatinine, total cholesterol, alpha-1-microglobulin, ADIPOQ rs17300539 and UMOD rs13333228; and the second model includes ADIPOQ rs17300539, AGT rs2004776, cardiovascular risk, sex, BMI, and the gene-gene interaction AGTR1:ADIPOQ_rs266729:UMOD:ACE. Conclusions: The finding of five significantly related gene-gene interactions, as well as the discovery of their haplotypes that increase the PHT risk, and the finding of two gene-gene-other determinants interactions models, confirmed the good selection of genes, particularly UMOD and ADIPOQ, involved in various biological pathways responsible for controlling BP.

Genetic polymorphisms of metabolic enzyme genes associated with leukocyte mitochondrial DNA copy number in PAHs exposure workers.

BackgroundPolycyclic aromatic hydrocarbons (PAHs) exposure had been reported to be a risk factor of mtDNAcn in our early study. However, the effect of metabolic enzymes' genetic polymorphisms on mtDNAcn in PAHs‐Exposure workers has not been fully evaluated.AimThe aim of the study was to explore the effect of metabolic enzymes' genetic polymorphisms on mtDNAcn in PAHs‐Exposure.Methods and ResultsWe investigated the effects of metabolic enzymes' genetic polymorphisms on mtDNAcn among 544 coke oven workers and 238 office staffs. The mtDNAcn of peripheral blood leukocytes was measured using the Real‐time quantitative polymerase chain reaction (PCR) method. PCR and restriction fragment length was used to detect five polymorphisms in GSTT1, GSTM1, GSTP1 rs1695, CYP2E1 rs6413432, and CYP2E1 rs3813867. The mtDNAcn in peripheral blood leukocytes was significantly lower in the exposure group than that in the control group (p < .001). The 1‐OHPYR had an increasing trend with the genotypes AA→AG → GG of GSTP1 rs1695 in the control group. Generalized linear model indicated that the influencing factors of mtDNAcn were PAHs‐exposure [β (95% CI) = −0.420 (−0.469, −0.372), p < .001], male [β (95% CI) = −0.058 (−0.103, −0.012), p = .013], and AA genotype for GSTP1 rs1695 [β (95% CI) = −0.051 (−0.095, −0.008), p = .020].ConclusionThe individuals carrying the AA genotype of GSTP1 rs1695 may have a lower mtDNAcn due to their weaker detoxification of PAHs.

The presence of polymorphisms in genes controlling neurotransmitter metabolism and disease prognosis in patients with prostate cancer: a possible link with schizophrenia.

Polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time (PSADT) corresponding to unfavorable and favorable disease prognosis respectively. The ‘unfavorable prognosis’ group (40 cases) was defined by PSADT ≤ 2 months, whereas patients in the ‘favorable prognosis’ group (67 cases) had PSADT ≥ 30 months. The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated: a) the STin2 VNTR in the serotonin transporter SLC6A4 gene; b) the 30-bp VNTR in the monoamine oxidase A MAOA gene; c) the Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene; d) the promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene.The STin2 12R/10R variant of the SLC6A4 gene (OR = 2.278; 95% CI = 0.953–5.444) and the -521T/T homozygosity of the DRD4 gene (OR = 1.579; 95% CI = 0.663–3.761) tended to be overrepresented in PC patients with unfavorable disease prognosis. These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients. These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia.

Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction. Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients. The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013). This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.

Discovery of breast cancer risk genes and establishment of a prediction model based on estrogen metabolism regulation

BackgroundMultiple common variants identified by genome-wide association studies have shown limited evidence of the risk of breast cancer in Chinese individuals. In this study, we aimed to uncover the relationship between estrogen levels and the genetic polymorphism of estrogen metabolism-related enzymes in breast cancer (BC) and establish a risk prediction model composed of estrogen-metabolizing enzyme genes and GWAS-identified breast cancer-related genes based on a polygenic risk score.MethodsUnrelated BC patients and healthy subjects were recruited for analysis of estrogen levels and single nucleotide polymorphisms (SNPs) in genes encoding estrogen metabolism-related enzymes. The polygenic risk score (PRS) was used to explore the combined effect of multiple genes, which was calculated using a Bayesian approach. An independent sample t-test was used to evaluate the differences between PRS scores of BC and healthy subjects. The discriminatory accuracy of the models was compared using the area under the receiver operating characteristic (ROC) curve.ResultsThe estrogen homeostasis profile was disturbed in BC patients, with parent estrogens (E1, E2) and carcinogenic catechol estrogens (2/4-OHE1, 2-OHE2, 4-OHE2) significantly accumulating in the serum of BC patients. We then established a PRS model to evaluate the role of SNPs in multiple genes. PRS model 1 (M1) was established from SNPs in 6 GWAS-identified high risk genes. On the basis of M1, we added SNPs from 7 estrogen metabolism enzyme genes to establish PRS model 2 (M2). The independent sample t-test results showed that there was no difference between BC and healthy subjects in M1 (P = 0.17); however, there was a significant difference between BC and healthy subjects in M2 (P = 4.9*10− 5). The ROC curve results showed that the accuracy of M2 (AUC = 62.18%) in breast cancer risk identification was better than that of M1 (AUC = 54.56%).ConclusionEstrogen and related metabolic enzyme gene polymorphisms are closely related to BC. The model constructed by adding estrogen metabolic enzyme gene SNPs has a good predictive ability for breast cancer risk, and the accuracy is greatly improved compared with that of the PRS model that only includes GWAS-identified gene SNPs.

Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk.

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

Role of Metabolic Risk Factors, Family History, and Genetic Polymorphisms (PPARγ and TCF7L2) on Type 2 Diabetes Mellitus Risk in an Asian Indian Population

Introduction: Women with family history of diabetes (FHD) are at significantly increased risk of developing gestational diabetes mellitus which may eventually lead to type 2 diabetes mellitus (T2DM) in later life. Objective: This study investigates the role of FHD on metabolic markers and gene polymorphisms and hence on T2DM susceptibility in nondiabetic pregnant women and the subsequent risks in their newborns. Materials and Methods: The present study was conducted on 200 healthy (nondiabetic and normotensive) adult Asian Indian women, including 100 with and 100 without FHD, living in and around Kolkata, India. During the gestational period, they were studied twice and followed up till delivery. During delivery, both mothers’ venous blood and cord blood were collected to estimate serum CRP, glucose, and lipid profiles of the respective mothers and their newborns. Genotyping of PPARγ and TCF7L2 polymorphisms was done from these blood samples. Results: A comparison of the metabolic variables among the subjects with and without FHD revealed significant differences among them. We also found close relationship between mothers and their newborn babies in terms of both PPARγ (rs1801282) C/G and TCF7L2 (rs7903146) C/T polymorphisms. More specifically, genotyping results for mothers with FHD and their newborn babies showed high concordance in inheritance of alleles: (i) for PPARγ via the risk allele G (74.0%) which is carried over to the newborn babies (64.5%) and (ii) for TCF7L2 via the risk allele T (73.0%) which is carried over to the newborn babies (68.5%). Conclusion: This study leads to the conclusion that Asian Indian women population based in Kolkata, India, are ethnically and genetically predisposed to the risk factors of diabetes through FHD, which is reflected in their gestational phase, and it has a significant implication on their birth outcomes.