TG Haplotype Research Articles

Phenotype-Genotype Correlation Applying a Cocktail Approach and an Exome Chip Analysis Reveals Further Variants Contributing to Variation of Drug Metabolism.

Although great progress has been made in the fine-tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug-metabolizing enzymes.

Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients?

A recently discovered haplotype-CYP2C:TG-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.

Influence of novel CYP2C-haplotype on proton pump inhibitor pharmacokinetics in children.

In this brief report, we provide an analysis of the influence of a novel CYP2C haplotype (CYP2C:TG) on proton pump inhibitor (PPI) pharmacokinetics (PK) in children. The CYP2C:TG haplotype has been proposed to be associated with increased CYP2C19 activity. We sought to determine if this CYP2C:TG haplotype resulted in similar alterations in metabolism for proton pump inhibitors, which are primarily metabolized by CYP2C19. In a cohort of 41 children aged 6-21 participating in a PPI pharmacokinetic study, effects of the CYP2C:TG allele were assessed by fitting two linear regression models for each of the six PK outcomes assessed, the second of which accounted for the presence of the CYP2C:TG allele. The difference in R2 values between the two models was computed to quantify the variability in the outcome that could be accounted for by the CYP2C:TG allele after adjustment for the CYP2C19 genotype. We found the CYP2C:TG haplotype to have no measurable additive impact on CYP2C19-mediated metabolism of PPIs invivo in older children and adolescents. The findings of this study do not support the clinical utility of routine testing for the CYP2C:TG haplotype to guide PPI dose adjustments in children.

Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients

RationaleIn bipolar disorder (BD), immunological factors play a role in the pathogenesis and treatment of the illness. Studies showed the potential link between Abelson Helper Integration Site 1 (AHI1) protein, behavioural changes and innate immunity regulation. An immunomodulatory effect was suggested for lithium, a mood stabilizer used in BD treatment.ObjectivesWe hypothesized that AHI1 may be an important mediator of lithium treatment response. Our study aimed to investigate whether the AHI1 haplotypes and expression associates with lithium treatment response in BD patients. We also examined whether AHI1 expression and lithium treatment correlate with innate inflammatory response genes.ResultsWe genotyped seven AHI1 single nucleotide polymorphisms in 97 euthymic BD patients and found that TG haplotype (rs7739635, rs9494332) was significantly associated with lithium response. We also showed significantly increased AHI1 expression in the blood of lithium responders compared to non-responders and BD patients compared to healthy controls (HC). We analyzed the expression of genes involved in the innate immune response and inflammatory response regulation (TLR4, CASP4, CASP5, NLRP3, IL1A, IL1B, IL6, IL10, IL18) in 21 lithium-treated BD patients, 20 BD patients treated with other mood stabilizer and 19 HC. We found significantly altered expression between BD patients and HC, but not between BD patients treated with different mood stabilizers.ConclusionsOur study suggests the involvement of AHI1 in the lithium mode of action. Moreover, mood-stabilizing treatment associated with the innate immunity-related gene expression in BD patients and only the lithium-treated BD patients showed significantly elevated expression of anti-inflammatory IL10, suggesting lithium’s immunomodulatory potential.

Association of body mass index and PXDNL gene variants with acute primary angle closure in southern Chinese population

This study aimed to evaluate the association of body mass index (BMI) and the weight-related gene, peroxidasin-like (PXDNL), with acute primary angle closure (APAC) and primary angle-closure glaucoma (PACG) in southern Chinese population. Total 4700 study subjects (1024 APAC, 781 PACG, and 2895 control subjects) with complete ophthalmic examinations were enrolled into this study. The association of BMI with APAC, PACG and ocular biometric parameters was evaluated. Three PXDNL missense variants were genotyped by TaqMan assay, and their association with APAC and PACG was also investigated. Multivariable logistic regression analysis showed that BMI and body weight were significantly associated with both APAC and PACG (P < 0.01). Multiple linear regression analysis demonstrated that each 1 kg/m2 increased in BMI was associated with 0.038 mm increase in axial length, 0.018 mm increase in central anterior chamber depth, 0.002 mm increase in lens position, 0.012 mm increase in corneal diameter and 0.014 mm decrease in lens thickness among the APAC subjects (P < 0.001), but not with PACG. Genetic association analysis identified that PXDNL rs11985241–rs16916207 CT haplotype conferred a higher risk to APAC (OR = 1.25, P = 0.004) than the TG haplotype, but not with PACG. The APAC subjects carrying the rs11985241 C or rs16916207 T alleles showed significantly lower weight than those carrying the corresponding protective alleles. In summary, this study revealed that lower BMI could be associated with higher risk of APAC. PXDNL could be a new associated gene for APAC.

Potential Role of Zinc Finger 365 rs10822013 and rs10995190 in Mammographic Density, Sporadic Breast Cancer Risk, and Prognosis.

Despite suggesting many genetic risk markers as the outcome of Genome-wide association studies (GWAS) for breast cancer, replicating the results in different populations has remained the main issue. In this regard, this study assessed the association of two variations in Zinc Finger 365 (ZNF365) in an Iranian population. In a case-control study conducted at Mashhad University of Medical Sciences, Mashhad, Iran, between 2017 and 2020, ZNF365-rs10822013 and rs10995190 were genotyped using Allele-Specific PCR (AS-PCR). Breast density was assessed using mammography images. PHASE software module version 2 and SPSS version 16.0 were used for haplotype and statistical analyses. Quantitative and qualitative variables were compared between groups using independent t tests and Chi square tests, respectively. Binary logistic regression analysis was performed to calculate odds ratios. Multivariate analysis was then undertaken for the baseline variables, with a P<0.05 in the univariate analysis. The survival analysis was performed using the Kaplan-Meier method and the log-rank test. In this survey, 732 females, including 342 breast cancer patients and 390 healthy subjects, were enrolled. rs10822013-T allele (P=0.014), rs10995190-G allele (P=0.003), and TG haplotype (P=0.002) were significantly associated with the increased risk of breast cancer. Moreover, rs10995190-GG genotype (P=0.042) and C-G haplotype (P=0.019) revealed a significant association with better overall survival. However, considered polymorphisms and their haplotypes indicated no association with breast density and clinical features of breast cancer. ZNF365 variants might be a potential risk marker of breast cancer in the Iranian population. The interaction between alleles in haplotypes may modulate the amount of the risk conferred by these variants. Further studies on different ethnic groups can validate these results.

Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity.

A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as "CYP2C:TG," was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N-desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C19*1+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/*2) and poor metabolizers (e.g., CYP2C19*2/*2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C19*1/*17), and ultrarapid metabolizers (i.e., CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C19*17 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapy.

Association of the rs8720 and rs12587 KRAS Gene Variants with Colorectal Cancer in a Mexican Population and Their Analysis In Silico.

Colorectal cancer (CRC) is a major global health challenge and one of the top 10 cancers in Mexico. Lifestyle and genetic factors influence CRC development, prognosis, and therapeutic response; identifying risk factors, such as the genes involved, is critical to understanding its behavior, mechanisms, and prognosis. The association between KRAS gene variants (rs8720 and rs12587) and CRC in the Mexican population was analyzed. We performed in silico analysis and analyzed 310 healthy individuals and 385 CRC patients using TaqMan assays and real-time PCR. The CC and GG genotypes of rs8720 and rs12587 were identified as CRC risk factors (p < 0.05). The CC and TC genotypes of the rs8720 were associated with rectal cancer, age over 50 years, moderately differentiated histology, and advanced cancer stage. TG and GG genotypes of the rs12587 variant were a risk factor in the CRC group, in patients with stage I-II, males, and stage III-IV non-chemotherapy response. The TG haplotype is protected against CRC. The combined CCGG genotype was linked to CRC risk. In silico analysis revealed that the rs12587 and rs8720 variants could influence KRAS gene regulation via miRNAs. In conclusion, rs8720 and rs12587 variants of the KRAS gene were associated with CRC risk and could influence KRAS regulation via miRNAs.

Sex-specific association of FABP2 polymorphisms with the risk of obesity in the Tehran Cardio-Metabolic Genetic Study (TCGS)

FABP2 is one of the key genes involved in obesity development across different populations. However, there is no comprehensive report about the FABP2 contribution to obesity incidence among Iranians. Hence, the present study was designed to assess the probable role of FABP2 polymorphisms in obesity incidence in the Tehran Cardio- metabolic Genetic Study (TCGS) representative Iran population. Unrelated adults who had BMI information for at least 3 consecutive phases of the TCGS cohort were included. The control and case groups were defined as individuals who always had long-term persistent normal weight (20 < BMI < 25; n = 1526) and individuals who were long-term persistent obese (30 < BMI < 35; n = 1313), respectively. The logistic regression test was used to assess the possible association between SNPs located in and around the FABP2 gene with obesity. Also, we used Haploview and SHEsis to perform haplotype analysis to detect whether or not this chromosomal region is correlated with obesity. We found a gender-dependent association between the rs10857064 FABP2 and the risk of obesity. The presence of the rs10857064-G allele could significantly increase the risk of obesity only in women, not men (OR = 1.26; 95 % CI: 1.02–1.57; p = 0.03). Through haplotype analysis, we also detected that the TG haplotype containing rs7670862 and rs10857064 could significantly enhance the risk of obesity in women, further supporting the central role of rs10857064 in women’s long-term obesity risk. In the current study, we revealed that rs10857064-G FABP2 can significantly predispose women to develop obesity. It highlights the importance of different genetic variants in both genders, which could help us to distinguish more efficient obesity screening tests and treatments based on gender in the future.

Unveiling the TGF- β1 paradox: Significant implication of TGF- β1 promoter variants and its mRNA and protein expression in atopic dermatitis

BackgroundAtopic Dermatitis (AD) is a chronic inflammatory skin disorder with evidence of lichenification in later stages. There is mounting evidence supporting the role of TGF- β1 in mediating inflammation as well as subsequent tissue remodeling, often resulting in fibrosis. Given the role of genetic variants in the differential expression of TGF-β1 in various diseases, this study seeks to ascertain the role of TGF-β1 promoter variants (rs1800469 and rs1800468) in AD susceptibility, as well as their association with TGF- β1 mRNA expression, TGF- β1 serum levels and skin prick test positivity in Atopic Dermatitis patients. MethodsAn aggregate of 246 subjects including 134 AD cases and 112 matched healthy controls were genotyped for TGF-β1 promoter polymorphisms by PCR-RFLP. TGF- β1 mRNA was quantified by quantitative Real-Time PCR (qRT-PCR), Vitamin-D levels by chemiluminescence, and serum TGF- β1, and total IgE levels were determined by ELISA. In-vivo allergy testing was performed for the evaluation of allergic reactions to house dust mites and food allergens. ResultsA higher frequency of TT genotypes of rs1800469 (OR = 7.7, p = 0.0001) and GA+AA genotypes of rs1800468 (OR-4.4, p < 0.0001) were observed in AD cases than those in controls. Haplotype analysis demonstrated that TG haplotype carriers had an increased risk of AD (p = 0.013). Quantitative analysis revealed a significant upregulation of both mRNA (p = 0.0002) and serum levels (p < 0.0001) of TGF- β1 with a substantial positive correlation between them (Correlation coefficient=0.504; p = 0.01). Moreover, serum TGF-β1 levels were associated with quality of life (p = 0.03), the severity of the disease (p = 0.03), and House dust mite allergy (p = 0.01) whereas TGF-β1 mRNA levels positively correlated with disease severity(p = 0.02). Stratification analysis revealed that the TT genotype of rs1800469 was associated with higher IgE levels (p = 0.01) and eosinophil percentage(p = 0.007) whereas the AA genotype of rs1800468 correlated with elevated serum IgE levels (p = 0.01). Besides, no significant association of genotypes with mRNA and serum expression of TGF-β1 was observed. ConclusionOur study indicates that TGF-β1 promoter SNPs bear a significant risk of AD development. Moreover, upregulation of TGF-β1 mRNA and serum levels and their association with disease severity, quality of life, and HDM allergy suggests its role as a diagnostic/prognostic biomarker that could help in the development of new therapeutic and prevention strategies.

Investigation of Gene Variation Among Non-Alcoholic Fatty Liver Disease Patients in Gaza Strip: A Preliminary Study

The prevalent hepatic presentation of the metabolic syndrome is a non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver illnesses. Patients with NAFLD may develop liver damage depending on their genetic heritage. In this preliminary study, our main aim was to detect the genetic association of p85α (Met326Ile), PNPLA3 (C&gt;G), IL28B275 (A&gt;G), and IL28B860 (C&gt;T) single nucleotide polymorphisms (SNPs) with steatosis and NASH in patients from Gaza Strip. We performed an SNP analysis by RFLP-PCR in 33 cases of steatosis and 28 cases of non-alcoholic steatohepatitis (NASH), in addition to 29 age- and sex-matched controls. We found that only the mutant T allele of IL28B860 was significantly associated with an increased risk of steatosis (P = 0.04). The other studied alleles and genotypes were not significantly associated with increased or decreased risk of steatosis, NASH, or combined steatosis or NASH groups. Among all of the studied variables (age, sex, diabetes, and BMI), only BMI was significantly associated with an increased risk of steatosis as well as NASH. A linkage disequilibrium analysis showed that the association between the two SNPs of IL28B860 and IL28B275 was significant. Having the TG haplotype increased the risk of steatosis by 2.97 fold and the risk of combined steatosis or NASH by 2.44 fold. This haplotype increased the risk of NASH, but the effect was not significant.

Distribution of a novel CYP2C haplotype in Native American populations.

The CYP2C19 gene, located in the CYP2C cluster, encodes the major drug metabolism enzyme CYP2C19. This gene is highly polymorphic and no-function (CYP2C19*2 and CYP2C19*3), reduced function (CYP2C19*9) and increased function (CYP2C19*17) star alleles (haplotypes) are commonly used to predict CYP2C19 metabolic phenotypes. CYP2C19*17 and the genotype-predicted rapid (RM) and ultrarapid (UM) CYP2C19 metabolic phenotypes are absent or rare in several Native American populations. However, discordance between genotype-predicted and pharmacokinetically determined CYP2C19 phenotypes in Native American cohorts have been reported. Recently, a haplotype defined by rs2860840T and rs11188059G alleles in the CYP2C cluster has been shown to encode increased rate of metabolism of the CYP2C19 substrate escitalopram, to a similar extent as CYP2C19*17. We investigated the distribution of the CYP2C:TG haplotype and explored its potential impact on CYP2C19 metabolic activity in Native American populations. The study cohorts included individuals from the One Thousand Genomes Project AMR superpopulation (1KG_AMR), the Human Genome Diversity Project (HGDP), and from indigenous populations living in Brazil (Kaingang and Guarani). The frequency range of the CYP2C:TG haplotype in the study cohorts, 0.469 to 0.598, is considerably higher than in all 1KG superpopulations (range: 0.014-to 0.340). We suggest that the high frequency of the CYP2C:TG haplotype might contribute to the reported discordance between CYP2C19-predicted and pharmacokinetically verified CYP2C19 metabolic phenotypes in Native American cohorts. However, functional studies involving genotypic correlations with pharmacokinetic parameters are warranted to ascertain the importance of the CYP2C:TG haplotype.

Dva ko-nasleđena SNPs gena telomeraza reverzne transkriptaze (TERT) koja se dovode u vezu sa pacijentima od raka pluća u Iraku

Background: The telomerase reverse transcriptase (TERT) gene is essential polymorphic loci linked to most malignant tumors. This study assessed the association between the TERT gene and non-small cell lung carcinoma (NSCLC) in Iraq. Methods: Genomic DNA samples were extracted from a total of 200 samples of blood. Four specific PCR fragments were designed to amplify four high-frequency rs2735940, rs2736098, rs2736100, and rs10069690 SNPs within the TERT gene. Single-strand conformation polymorphism (SSCP) followed by sequencing reactions were used for genotyping and validating the amplified fragments. Results: Individuals with the genotype rs2735940: A/G were at a significantly greater risk of developing NSCLC (P=0.0299; OD 2.3158; Cl95% 1.0853 to 4.9414). Individuals with the genotype rs2736098: C/T were also significantly associated with the increased likelihood of developing NSCLC (P=0.0363; OD 2.1583; Cl95% 1.0503 to 4.4351). Linkage disequilibrium analysis showed that both SNPs showed a very high level of patient coinheritance. The LD plot showed that allele T of rs2736098 had collaborated with allele G of rs2735940 to generate TG haplotype in patients. According to our findings, both TERTrs2735940: A/G and TERT-rs2736098: C/T SNPs were found to be significant associations with the elevated risk of NSCLC. Both SNPs showed the highest values of co-inheritance in patients. This co-inheritance is mainly represented by alleles rs2735940: A and rs2736098: C. Both pathogenic T and G alleles have generated TG haplotype that is only available in patients' samples. Conclusion: This study suggests employing the haplotype TG as a promising biomarker for the early diagnosis of NSCLC. These findings need further validation by largescale investigation with a larger size of samples in the study population.

Evaluating the Role of BglI rs739837 and TaqI rs731236 Polymorphisms in Vitamin D Receptor with SARS-CoV-2 Variants Mortality Rate.

A lack of vitamin D is a potential risk factor for coronavirus disease (COVID-19). Variants in the Vitamin D Receptor (VDR) gene, such as BglI rs739837 and TaqI rs731236, are associated with various viral infection progressions. This study aimed to evaluate the relationship between the BglI rs739837 and TaqI rs731236 polymorphisms and the mortality rate of COVID-19 based on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. The genotyping of BglI rs739837 and TaqI rs731236 genotypes was analyzed using the polymerase chain reaction-restriction fragment length polymorphism in 1734 improved and 1450 deceased patients positive for SARS-CoV-2. In this study, the rate of COVID-19 mortality was correlated with TaqI rs731236 TC and CC in the α variant and with TaqI rs731236 CC in the Delta variant, whereas no relationship was found in the Omicron BA.5 variant. In addition, the rate of COVID-19 mortality was associated with BglI rs739837 GT and TT in the Omicron BA.5 variant, while there was no association between BglI rs739837 and COVID-19 mortality in the α and Delta variants. The TG haplotype was more common in all SARS-CoV-2 variants, while the CT haplotype was associated with COVID-19 mortality in the Delta and Omicron BA.5 variants. In conclusion, this study indicated that the impacts of BglI rs739837 and TaqI rs731236 polymorphisms were related to SARS-CoV-2 variants. However, further research is still needed to approve our findings.

Exploring the association between Th17 pathway gene polymorphisms and pulmonary tuberculosis.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis (MTB), and this study aimed to explore the association of Th17 pathway gene polymorphisms with pulmonary tuberculosis (PTB) susceptibility in a Chinese population. A total of 10 single nucleotide polymorphisms in Th17 pathway genes (IL-17A gene rs2275913, rs3748067, rs8193036, rs3819024, IL-17F gene rs7741835, rs763780, IL-21 gene rs907715, rs2055979, IL-23R gene rs11805303, and rs7518660) were genotyped in 456 PTB patients and 466 controls using SNPscan technique. The IL-23R rs11805303 CC genotype, C allele frequencies were significantly lower in PTB patients than in controls, and the rs11805303 variant was significantly associated with the reduced risk of PTB in a recessive model. There were no significant associations between IL-17A, IL-17F, and IL-21 gene variations and PTB risk. In IL-17A gene, rs2275913, rs3748067, and rs3819024 variants were associated with drug resistance in PTB patients. In IL-17F gene, rs7741835 variant affected drug resistance, and rs763780 variant was associated with hypoproteinemia in PTB patients. In addition, the lower frequencies of the TT genotype, T allele of rs2055979 were found in PTB patients with drug-induced liver injury. Haplotype analysis showed that IL-23R CG haplotype frequency was significantly lower in PTB patients than in controls, while the TG haplotype frequency was higher. In conclusion, IL-23R rs11805303 polymorphism may contribute to the genetic underpinnings of PTB in the Chinese population, and the IL-17A, IL-17F, and IL-21 genetic variations are associated with several clinical manifestations of PTB patients.

Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population.

Sertraline is a commonly used SSRI antidepressant drug, metabolized by CYP2C19 and CYP2B6, that exhibits a substantial interindividual variation in clinical response, of which only a part can be attributed to known genetic variants. In the current study we have examined the role of a newly discovered ultrarapid CYP2C:TG haplotype and CYP2B6 variants in order to identify the possible missing heritability for such variation in sertraline response in a large patient population (n = 840). Compared to the reference group (CYP2C19*1/*1, n = 160), sertraline exposure was increased by 128% in CYP2C19 PMs (n = 29, p < 0.001) but decreased by about 20% in CYP2C19 ultrarapid metabolizers (Ums) (homozygous carriers of CYP2C19*17 and/or CYP2C:TG haplotype) with the diplotypes CYP2C19*17/*17, CYP2C:TG/TG, or CYP2C19*17/CYP2C:TG (n = 135, p < 0.003, p = 0.022, p < 0.003, respectively). Interestingly, in patients carrying the increased function CYP2B6*4 allele, and also carrying the CYP2C19*17 and CYP2C:TG alleles (n = 10), sertraline exposure was 35.4% lower compared to the reference group, whereas in subjects being poor metabolizers (PM) in both the CYP2C19 and CYP2B6 gene, the sertraline concentrations were raised by 189%. In summary, the CYP2C19 variants including the CYP2C:TG haplotype had a significant impact on sertraline metabolism, as well as the CYP2B6*4, *6, and *9 alleles. Knowing the CYP2B6 and CYP2C19 genotype, including the CYP2C:TG haplotype status, can prospectively be useful to clinicians in making more appropriate sertraline dosing decisions

Prevalence of risk alleles in the lysyl oxidase-like 1 gene in pseudoexfoliation glaucoma patients in India.

Purpose:The purpose of this study was to genotype two previously identified SNPs (rs1048661:R141L, and rs3825942:G153D) in the lysyl oxidase-like 1 (LOXL1) gene and determine their association with pseudoexfoliation glaucoma (XFG) in patients from Pune, India.Methods:All subjects underwent detailed phenotyping, and DNA extraction was performed on blood samples by using standardized techniques. Exon 1 of the LOXL1 gene containing the SNPs (rs3825942:G153D; rs1048661:R141L) were Sanger sequenced, and the results were analyzed using sequence analysis software SeqScape 2.1.1.Results:Data were analyzed from 71 patients with XFG and 81 disease-negative, age-matched controls. There was a strong association between the G allele of rs3825942 and XFG with an odds ratio of 10.2 (CI: 3.92–26.6; P < 0.001). The G allele of rs1048661 also showed an increase in risk relative to the T allele (OR = 1.49; CI: 0.88–2.51; P = 0.13), but this was not significant. Haplotype combination frequencies were estimated for rs1048661 and rs3825942; the GG haplotype was associated with a significant increase in risk (OR = 3.91; CI: 2.27–6.73; P < 0.001). Both the GA and TG haplotypes were associated with decreased XFG risk, although the latter was not significant (GA: OR = 0.08; CI: 0.03–0.21; P < 0.001; TG: OR = 0.67; CI: 0.40–1.13; P = 0.13).Conclusion:The risk G allele in rs3852942 (G153D) is strongly associated with the development of XFG in the Western Indian population. Genetic screening strategies to identify LOXL1 risk alleles in the population can assist in case definition and early diagnosis, targeting precious resources to high-risk patients.

Omeprazole Treatment Failure in Gastroesophageal Reflux Disease and Genetic Variation at the CYP2C Locus.

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19–82) and GerdQ score of 11 (5–17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

Contribution of -1031T/C and -376G/A tumor necrosis factor alpha polymorphisms and haplotypes to preeclampsia risk in Tunisia (North Africa)

Preeclampsia is a gestational disorder characterized by hypertension and proteinuria. Excessive release of pro-inflammatory cytokines, particularly tumour necrosis factor-alpha, has been demonstrated to contribute to endothelial activation and poor trophoblast invasion in placental development, resulting in preeclampsia's clinical symptoms. Genetic polymorphisms of tumour necrosis factor-alpha can regulate its production and may play an important role in the pathogenesis of this disease. This study aimed to evaluate the association of five tumour necrosis factor-alpha gene promoter single nucleotide polymorphisms, or their haplotype combinations, with preeclampsia prevalence. This case-control study was conducted on 300 women with preeclampsia and 300 age-matched women with normal pregnancy from Tunisian hospitals. Genotyping of tumour necrosis factor-alpha −1031 T/C, −376 G/A, −308 G/A, −238 G/A, and +489 G/A SNPs was performed on DNA extracted from blood samples using PCR-restriction fragment-length polymorphism analysis. Statistical analysis was performed using the chi-square test. P < 0.01 were considered statistically significant to take into consideration the multiple comparisons. A significantly higher frequency of the minor allele -1031C (p < 0.001) was observed in preeclampsia cases compared to controls. Notably, the -1031C and -376A (CA) haplotype, which correlates with a higher production of TNF-α protein, had a higher incidence in women with preeclampsia (p = 0.0005). Conversely, the TG haplotype had a low frequency in preeclampsia cases compared to controls (p = 0.002) which suggests that it is associated with a reduced incidence of preeclampsia. These results suggest that tumour necrosis factor-alpha polymorphisms, in particular the -1031C/A, and the haplotype CA, contribute to an increased risk of preeclampsia in Tunisian women.

Associations of Polymorphisms Localized in the 3'UTR Regions of the KRAS, NRAS, MAPK1 Genes with Laryngeal Squamous Cell Carcinoma.

Background: Genetic variations, localized in the 3′ untranslated region (UTR) in mitogen-activated protein kinase (MAPK) pathway-related genes, may alter the transcription and impact the pathogenesis of laryngeal squamous cell carcinoma (LSCC). The present study investigated the associations of single-nucleotide polymorphisms (SNP), localized in the 3′UTR) of the KRAS, NRAS, and MAPK1 genes with LSCC risk and clinicopathological features. Methods: Genomic DNA and clinical data were collected from 327 adult men with LSCC. The control group was formed from 333 healthy men. Genotyping of the SNPs was performed using TaqMan SNP genotyping assays. Five KRAS, NRAS, and MAPK1 polymorphisms were analyzed. All studied genotypes were in Hardy–Weinberg equilibrium and had the same allele distribution as the 1000 Genomes project Phase 3 dataset for the European population. Results: Significant associations of the studied SNPs with reduced LSCC risk were observed between NRAS rs14804 major genotype CC. Significant associations of the studied SNPs with clinicopathologic variables were also observed between NRAS rs14804 minor T allele and advanced tumor stage and positive lymph node status. SNP of MAPK1 rs9340 was associated with distant metastasis. Moreover, haplotype analysis of two KRAS SNPs rs712 and rs7973450 revealed that TG haplotype was associated with positive lymph node status in LSCC patients. Conclusions: According to the present study, 3′UTR SNP in the NRAS and MAPK1 genes may contribute to the identifications of patients at higher risk of LSCC lymph node and distant metastasis development.