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PubMed2006

Xenobiotic-metabolizing genes and small-for-gestational-age births: interaction with maternal smoking.

BACKGROUND: Little is known about the role of xenobiotic-metabolizing gene variants as risk factors for small-for-gestational-age (SGA) births or as modifiers for the effects of exposures such as maternal smoking. METHODS: We conducted 2 joint studies: a case-control design including 493 cases (birth weight below the 10th percentile according to gestational age and sex) and 472 controls (at or above the 10th percentile) and a family-based study (mother, father, and newborn) with approximately 250 case trios and a similar number of control trios. Logistic regression and a log-linear model were used to analyze the association between genetic variants such as CYP1A1*2A, CYP1A1*2B, CYP1A1*4, GSTT1, GSTM1, and XRCC3 and SGA. The interaction between genetic variants and maternal smoking was also studied. RESULTS: The odds ratio (OR) for the association of complete maternal GSTT1 deletion with SGA was 0.63 (95% confidence interval = 0.41-0.97), and that for the complete newborn GSTM1 deletion was 0.74 (0.55-0.98). Newborns with the partial GSTT1 deletion had an OR of 1.40 (1.01-1.95), and newborns homozygous for CYP1A1*2A had an OR of 4.28 (1.02-18.0). These results were coherent with the trio-based results. Significant interactions were observed between maternal smoking in the third trimester and CYP1A1*2A (P = 0.03), XRCC3 (P = 0.03), and newborn GSTT1 (P = 0.01). CONCLUSIONS: Certain genetic variants involved in the metabolism of xenobiotics increase the risk of SGA, as well as modify the effects of maternal smoking by increasing or decreasing its risk.

Adult↗

PubMed2025

Integrative omics of the genetic basis for wheat WUE and drought resilience reveal the function of TaMYB7-A1.

Improving wheat drought resilience and water use efficiency (WUE) is critical for sustaining productivity under increasing water scarcity. Here, we integrate genome-wide association study (GWAS), expression quantitative trait locus (eQTL) mapping, population-transcriptome analysis, and summary-data-based mendelian randomization (SMR), followed by functional validation using indexed EMS mutants and transgenic lines, to systematically identify key WUE regulators. GWAS across water conditions in 228 accessions identifies 73 quantitative trait loci (QTLs) for WUE-traits. Transcriptome profiling of 110 diverse accessions reveals 28 drought-responsive modules. eQTL mapping uncovers 146,966 regulatory variants, including condition-specific hotspots associated with key drought-related pathways. Integrative analysis underscores 85 high-confidence candidate genes, notably TaMYB7-A1. Overexpression of TaMYB7-A1 enhances photosynthesis, WUE, root development, and grain yield under drought condition by activating TaPIP2;2-B1 (water transport), TaRD20-D1 (stomatal regulation), and TaABCB4-B1 (root growth), reflecting reduced water loss and improved physiological resilience. Our study presents a comprehensive regulatory map and robust targets for wheat drought adaptation and resilient cultivar breeding.

Triticum↗

PubMed2006

W4 theory for computational thermochemistry: In pursuit of confident sub-kJ/mol predictions.

In an attempt to improve on our earlier W3 theory [A. D. Boese et al., J. Chem. Phys. 120, 4129 (2004)] we consider such refinements as more accurate estimates for the contribution of connected quadruple excitations (T4), inclusion of connected quintuple excitations (T5), diagonal Born-Oppenheimer corrections (DBOC), and improved basis set extrapolation procedures. Revised experimental data for validation purposes were obtained from the latest version of the Active Thermochemical Tables thermochemical network. The recent CCSDT(Q) method offers a cost-effective way of estimating T4, but is insufficient by itself if the molecule exhibits some nondynamical correlation. The latter considerably slows down basis set convergence for T4, and anomalous basis set convergence in highly polar systems makes two-point extrapolation procedures unusable. However, we found that the CCSDTQ-CCSDT(Q) difference converges quite rapidly with the basis set, and that the formula 1.10[CCSDT(Q)cc-pVTZ+CCSDTQcc-pVDZ-CCSDT(Q)cc-pVDZ] offers a very reliable as well as fairly cost-effective estimate of the basis set limit T4 contribution. The T5 contribution converges very rapidly with the basis set, and even a simple double-zeta basis set appears to be adequate. The largest T5 contribution found in the present work is on the order of 0.5 kcal/mol (for ozone). DBOCs are significant at the 0.1 kcal/mol level in hydride systems. Post-CCSD(T) contributions to the core-valence correlation energy are only significant at that level in systems with severe nondynamical correlation effects. Based on the accumulated experience, a new computational thermochemistry protocol for first- and second-row main-group systems, to be known as W4 theory, is proposed. Its computational cost is not insurmountably higher than that of the earlier W3 theory, while performance is markedly superior. Our W4 atomization energies for a number of key species are in excellent agreement (better than 0.1 kcal/mol on average, 95% confidence intervals narrower than 1 kJ/mol) with the latest experimental data obtained from Active Thermochemical Tables. Lower-cost variants are proposed: the sequence W1-->W2.2-->W3.2-->W4lite-->W4 is proposed as a converging hierarchy of computational thermochemistry methods. A simple a priori estimate for the importance of post-CCSD(T) correlation contributions (and hence a pessimistic estimate for the error in a W2-type calculation) is proposed.

Journal Article↗

PubMed2025

Semiparametric efficient estimation of small genetic effects in large-scale population cohorts.

Population genetics seeks to quantify DNA variant associations with traits or diseases, as well as interactions among variants and with environmental factors. Computing millions of estimates in large cohorts in which small effect sizes and tight confidence intervals are expected, necessitates minimizing model-misspecification bias to increase power and control false discoveries. We present TarGene, a unified statistical workflow for the semi-parametric efficient and double robust estimation of genetic effects including $ k $-point interactions among categorical variables in the presence of confounding and weak population dependence. $ k $-point interactions, or Average Interaction Effects (AIEs), are a direct generalization of the usual average treatment effect (ATE). We estimate genetic effects with cross-validated and/or weighted versions of Targeted Minimum Loss-based Estimators (TMLE) and One-Step Estimators (OSE). The effect of dependence among data units on variance estimates is corrected by using sieve plateau variance estimators based on genetic relatedness across the units. We present extensive realistic simulations to demonstrate power, coverage, and control of type I error. Our motivating application is the targeted estimation of genetic effects on trait, including two-point and higher-order gene-gene and gene-environment interactions, in large-scale genomic databases such as UK Biobank and All of Us. All cross-validated and/or weighted TMLE and OSE for the AIE $ k $-point interaction, as well as ATEs, conditional ATEs and functions thereof, are implemented in the general purpose Julia package TMLE.jl. For high-throughput applications in population genomics, we provide the open-source Nextflow pipeline and software TarGene which integrates seamlessly with modern high-performance and cloud computing platforms.

Humans↗

PubMed2004

Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck.

p73, a novel p53 homolog, has some p53-like activity and plays an important role in modulating cell-cycle control, apoptosis and cell growth. p73 regulates differentiation of head and neck squamous epithelium, and changes in p73 may lead to the development of squamous cell carcinoma of the head and neck (SCCHN). Two linked non-coding exon 2 polymorphisms (designated as G4C14-to-A4T14) were identified recently but their functional relevance is unknown. We hypothesized that this p73 polymorphism plays a role in the etiology of SCCHN. Therefore, in this hospital-based case-control study of 708 patients newly diagnosed with SCCHN and 1229 cancer-free controls, we evaluated the association between the p73 AT variant allele and risk of SCCHN. The controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status, and all subjects were non-Hispanic whites. Our results showed that the frequencies of variant AT allele and genotypes were more common in the cases than in the controls (P = 0.029 and P = 0.009, respectively). Compared with the GC/GC genotype, the variant genotypes (GC/AT + AT/AT) were associated with a statistically significantly increased risk for SCCHN [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.10-1.60]. Further stratification analyses by age, sex, smoking and alcohol status and by cancer sites within the head and neck region indicated that this significantly increased risk was more pronounced in younger (< or =50 years) individuals (adjusted OR = 1.70; 95% CI, 1.19-2.43), women (1.61; 1.09-2.37), current smokers (1.77; 1.25-2.51) and patients with oral cancer (1.54; 1.15-2.07). Our results suggest that this p73 polymorphism may be a risk marker for genetic susceptibility to SCCHN.

Adolescent↗

PubMed2004

Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming.

With the increase in life expectancy, death from cardiovascular disease has risen greatly. There is increasing evidence that inflammation plays an important role in cardiovascular disease. We postulate that the development of cardiovascular disease in old age is a late consequence of evolutionary programming for a pro-inflammatory response to resist infections in early age. In 311 women, aged 85 yr old, the production of the pro- and anti-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined in lipopolysaccharide-stimulated whole blood samples and studied prospectively in association with cardiovascular mortality. High TNF-alpha was a risk factor for death from cardiovascular disease (relative risk [RR] = 1.56; 95% confidence interval [CI]: 1-2.40), whereas high IL-10 was protective (RR = 0.58; 95% CI: 0.40-0.85). A genetic variant of the IL-10 gene promoter, which is associated with lower IL-10 production, was found to predispose to a 2.8-fold higher cardiovascular mortality risk (95% CI: 1.17-6.60). Reproductive success, which was studied as a measure of evolutionary programming because it trades off with early survival by pro-inflammatory resistance genes, was negatively associated with an increasing production of TNF-alpha (RR = 0.77; 95% CI: 0.68-0.88), while a positive association with IL-10 was found (RR = 1.22; 95% CI: 1.05-1.41). We suggest that cardiovascular mortality is a late consequence of evolutionary programming for a pro-inflammatory response.

Adult↗

PubMed2004

Genetic predisposition to wheeze following respiratory syncytial virus bronchiolitis.

BACKGROUND: The nature of the association between severe respiratory syncytial virus (RSV) bronchiolitis and subsequent wheezing remains unknown. In a previous study, we showed that genetic variation in the IL-8-promoter region is associated with susceptibility to severe bronchiolitis. OBJECTIVE: The purpose of this study was to assess the association between wheezing post-bronchiolitis and the genetic variant of IL-8 gene. METHODS: We collected data from 134 children who had suffered from bronchiolitis, enrolled in our previous study. The occurrence of wheezing post-bronchiolitis was recorded from a questionnaire sent by post. The association between the genotype and wheezing phenotype was assessed by family-based and case-control approaches. RESULTS: Family-based association showed that the IL-8 variant was transmitted significantly more often than expected in the children who wheezed after the episode of bronchiolitis (transmission=56%, P=0.02). This effect was not observed in the group of children who had bronchiolitis but did not go on to wheeze. Moreover, the variant was significantly more frequent in post-bronchiolitis wheezers compared with the general population (odds ratio=1.6, 95% confidence interval 1.0-2.6). CONCLUSION: These preliminary results suggest that there is a genetic predisposition to wheeze following severe RSV bronchiolitis.

Alleles↗

PubMed1995

Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk.

Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals with protein C deficiency are at risk for thrombophlebitis, deep-vein thrombosis, and pulmonary embolism. Genetic analysis of a number of randomly chosen healthy individuals revealed three polymorphisms, C/T at -654, A/G at -641, and A/T at -476, in the protein C promoter region. To investigate whether these genetic variations associate with the plasma protein C level, we determined the genotype for the three polymorphisms and measured plasma protein C levels in 240 individuals not deficient in protein C. The mean protein C level of these individuals was 103%. Interestingly, individuals with the homozygous CGT genotype (n = 40) had a mean protein C level of 94%, whereas individuals with a homozygous TAA genotype (n = 28) had a mean protein C level of 116%. This difference in mean protein C levels between the CGT and TAA groups (P < .001) could not be explained by environmental factors known to influence protein C levels in the normal population. Plasma factor II and factor X levels did not differ between the two groups, which makes a difference in liver function an unlikely cause. Finally, we tested whether the genotype associated with lower protein C levels is associated with higher thrombotic risks. This analysis showed that compared with the genetic variant associated with higher protein C levels (TT/AA/AA), the genetic variant associated with lower protein C levels (CC/GG/TT genotype) is indeed a risk factor for thrombosis (OR, 1.6; 95% confidence interval, 1.0 to 2.5).

Aged↗

PubMed1999

Association of polymorphisms in the beta2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus.

To assess the role of polymorphisms in the beta2-adrenergic receptor gene in the development of obesity and obesity-related metabolic disorders, we analysed Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms in 400 non-obese subjects (body mass index < 27 kg/m2) and 108 obese subjects (body mass index> or =27 kg/m2). The Gln27Glu substitution was twice as common in obese subjects as in non-obese subjects (0.14 vs 0.07, p = 0.001, odds ratio 2.14, 95 % confidence interval 1.35-3.41). The frequency of the Glu27 allele was also higher in patients with Type II (non-insulin-dependent) diabetes mellitus than nondiabetic subjects (0.14 vs 0.07, p = 0.001, odds ratio 2.13, 95% confidence interval 1.34-3.41). Analysis of variance of multiple variables showed an association between 2-h post-load glucose concentrations and body mass index but not with the Glu27 variant, suggesting that the association with diabetes could be secondary to obesity. Obese subjects carrying the variant allele had higher concentrations of serum triglyceride than obese subjects homozygous for the wild type allele (2.68+/-1.90 vs 1.18+/-1.15 mmol/l, p = 0.02). Conversely, the frequency of Gly16 homozygotes was lower in obese women when compared with non-obese women (11% vs 28%, p = 0.01, odds ratio 0.30, 95% confidence interval 0.12-0.75), although the association was not present in male subjects. Thr164Ile substitution was not detected in the subjects of this study. These observations suggest that the amino-terminal polymorphisms of the beta2-adrenergic receptor gene could be involved in the molecular pathogenesis of obesity and hypertriglyceridaemia, and thereby the development of Type II diabetes mellitus.

Amino Acid Substitution↗

PubMed1997

Susceptibility to lung cancer in light smokers associated with CYP1A1 polymorphisms in Mexican- and African-Americans.

The gene-environment associations between potential carcinogenic agents modified by polymorphisms in the cytochrome P450 1A1 (CYP1A1) gene and lung cancer risk were assessed in a hospital-based case-control study composed of African- and Mexican-Americans. The study involved 171 cases and 295 controls identified from the greater Houston and San Antonio metropolitan areas. Both the exon 7 and MspI polymorphisms were analyzed by RFLP of PCR-amplified DNA, and in addition, the African-American-specific polymorphism was assayed for subjects who reported that they were African-American. Logistic regression analysis was performed to assess the association between each of the CYP1A1 polymorphisms and lung cancer, adjusting for the matching variables (age, sex, ethnicity) and other potential risk factors. Interactions between pack-years smoked, CYP1A1 genotypes, and case status were also evaluated. The variant allele frequencies did not differ by case status, but the distributions of genotypes were strikingly different by ethnicity. In addition, both the exon 7 and MspI polymorphisms, but not the African-American-specific polymorphism, were modified by the amount of cigarette consumption measured in pack-years. An approximate 2-fold increase in lung cancer risk among individuals with one or more of the variant alleles was observed among light smokers (defined as having smoked < or = 30 pack-years). The respective risk ratios for the exon 7 and MspI polymorphisms were 2.26 (95% confidence interval, 0.82-6.26) and 2.03 (95% confidence interval, 1.03-4.01) at low smoking dose. No such increase in risk was found among heavy smokers (> 30 pack-years). This phenomenon at low smoking dose was also observed when the two common polymorphisms were combined, which resulted in was a progressive increase in risk with an increasing number of variant alleles. These results indicate that at low smoking levels, the MspI and exon 7 CYP1A1 genetic polymorphisms confer susceptibility to lung cancer.

Adult↗

PubMed2003

Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men.

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.

Aged↗

PubMed1999

Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.

CONTEXT: Genetic testing for cancer predisposition is evolving from purely research applications to affecting clinical management. OBJECTIVE: To determine how often genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) can be definitively interpreted and used to guide clinical management. DESIGN: Case-series study conducted in 1996 to 1998 in which a complete sequence analysis of hMSH2 and hMLH1 coding sequence and flanking intronic regions was performed. Mutations were categorized as protein truncating and missense. In the case of missense alterations, additional analyses were performed in an effort to assess pathogenicity. SETTING AND PARTICIPANTS: Families were identified by self-referral or health care provider referral to a cancer genetics program. Participants and kindreds were classified into 1 of 4 categories: (1) Amsterdam criteria for HNPCC, (2) modified Amsterdam criteria for HNPCC, (3) young age at onset, or (4) HNPCC-variant. In addition, each proband was classified according to the Bethesda guidelines for identification of individuals with HNPCC. MAIN OUTCOME MEASURE: Alterations of hMSH2 and hMLH1 genes. RESULTS: Twenty-seven alterations of hMSH2 and hMLH1 were found in 24 of 70 families (34.3%). Of these, deleterious mutations that could be used with confidence in clinical management were identified in 25.7% (18/70) of families. The rates of definitive results for families fulfilling Amsterdam criteria, modified Amsterdam criteria, young age at onset, HNPCC-variant, and Bethesda guidelines were 27 (39.3%), 13 (18.2%), 12 (16.7%), 11 (15.8%), and 21 (30.4%), respectively. The prevalence of missense mutations, genetic heterogeneity of the syndrome, and limited availability of validated functional assays present a challenge in the interpretation of genetic test results of HNPCC families. CONCLUSIONS: The identification of pathogenic mutations in a significant subset of families for whom the results may have marked clinical importance makes genetic testing an important option for HNPCC and HNPCC-like kindreds. However, for the majority of individuals in whom sequence analysis of hMSH2 and hMLH1 does not give a definitive result, intensive follow-up is still warranted.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Evolutionary analysis of variants of hepatitis C virus found in South-East Asia: comparison with classifications based upon sequence similarity.

Variants of hepatitis C virus (HCV) have been classified by nucleotide sequence comparisons in different regions of the genome. Many investigators have defined the ranges of sequence similarity values or evolutionary distances corresponding to divisions of HCV into types, subtypes and isolates. Using these criteria, novel variants of HCV from Vietnam, Thailand and Indonesia have been classified as types 7, 8, 9, 10 and 11, many of which can be further subdivided into between two to four subtypes. In this study, this distance-based method of virus classification was compared with phylogenetic analysis and statistical measures to establish the confidence of the groupings. Using bootstrap resampling of phylogenetic trees in several subgenomic regions (core, E1, NS5) and with complete genomic sequences, we found that one set of novel HCV variants ('types 7, 8, 9 and 11') consistently grouped together into a single clade that also contained type 6a, while 'type 10a' grouped with type 3. In contrast, no robust higher-order groupings were observed between any of the other five previously described HCV genotypes (types 1-5). In each subgenomic region, the distribution of pairwise distances between members of the type 6 clade were consistently bi-modal and therefore provided no justification for classification of these variants into the three proposed categories (type, subtype, isolate). Based on these results, we propose that a more useful classification would regard all these variants as subtypes of type 6 or type 3, even though the level of sequence diversity within the clade was greater than observed for other genotypes. Classification by phylogenetic relatedness rules out simple sequence similarity measurements as a method for assigning HCV genotypes, but provides a more appropriate description of the evolutionary and epidemiological history of a virus.

Asia, Southeastern↗

PubMed1994

The use of polymerase chain reaction to determine fetal RhD status.

OBJECTIVE: Our purpose was (1) to establish the accuracy of a deoxyribonucleic acid amplification method in determination of RhD status in adult blood samples, including weak D variants (previously referred to as Du) and a D mosaic, and (2) to apply the method to determine fetal RhD status in alloimmunized pregnancies. STUDY DESIGN: Twenty-five adult blood samples, including five weak D variants and one D mosaic, were analyzed with a polymerase chain reaction to determine RhD type. The method was then applied to amniotic fluid samples obtained by amniocentesis from three RhD-negative women with known RhD sensitization. RESULTS: RhD type determined by polymerase chain reaction for all adult blood samples agreed with serologic typing results. All weak D variants and the D mosaic gave results consistent with RhD positivity. Fetal RhD status was determined in each of the three alloimmunized pregnancies, and obstetric management decisions were made on the basis of these results. CONCLUSIONS: This polymerase chain reaction method allows rapid and accurate determinations of fetal RhD status by amniocentesis. Fetal blood sampling or serial amniocenteses may be avoided when the fetus is RhD negative, and plans for surveillance and intervention can be confidently made if the fetus is RhD positive. However, before the widespread use of this assay, its sensitivity and specificity must be established. Because weak D variants and a D mosaic demonstrated RhD-positive status by polymerase chain reaction, the method described is applicable to these RhD variants.

Adult↗

PubMed2002

The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk.

The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is involved in the nucleotide excision repair of DNA lesions induced by many tobacco and environmental carcinogens. In order to study the functional impact of the common polymorphisms in XPD exon 10 (G > A, Asp312Asn) and exon 23 (A > C, Lys751Gln), we have genotyped 185 Swedish lung cancer cases (97 smokers and 88 never-smokers) and 162 matched population controls (83 smokers and 79 never-smokers). Presence of one or two variant alleles was associated with increased risk for lung cancer among never-smokers only, in particular younger (<70 years) never-smokers [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.1-6.5 for exon 10; OR = 3.2, 95% CI = 1.3-8.0 for exon 23, adjusted for age, gender and environmental tobacco smoke]. Aromatic DNA adduct level (AL) in peripheral lymphocytes was found to be similar between cases and controls, but significantly increased by current or recent smoking. Overall, there was a significant trend for increasing AL with increasing number of variant alleles in exon 10 (P = 0.02) or in exon 23 (P = 0.001). In addition, subjects with the combined exon 10 AA and exon 23 CC genotype showed a significantly higher AL compared with all those with any of the other genotypes (P = 0.02). We conclude that the XPD variant alleles may be associated with reduced repair of aromatic DNA adducts in general and increased lung cancer risk among never-smokers.

Adenocarcinoma↗

PubMed2001

Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1.

Human microsomal epoxide hydrolase (mEH) catalyzes a key step in the biotransformation of benzo[a]pyrene that yields the highly mutagenic (+)-anti-7,8-diol-9,10 epoxide (BPDE). Two polymorphisms have been described in the coding region of the mEH gene (EPHX1) that produce two protein variants: 113Tyr-->113His (exon 3) and 139His-->139Arg (exon 4). We performed a case-control study among Northwestern Mediterranean Caucasians to investigate a possible association between these EPHX1 variants and lung cancer risk. Both EPHX1 polymorphisms were analyzed in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=187). The results showed a significantly decreased risk for the rare homozygous 113His/113His (adjusted odds ratio (OR): 0.44, 95% confidence interval (CI): 0.27-0.71) and 139Arg/139Arg (adjusted OR: 0.55, 95% CI: 0.33-0.91) compared with the major wild-types 113Tyr/113Tyr and 139His/139His, respectively, as the references. Thereafter, we analyzed the EPHX1 variants in combination with three glutathione S-transferase polymorphic genes (GSTM1, GSTT1, and GSTP1) and we found a significant overepresentation of cancer patients with a combination of exon 3 113Tyr/113Tyr EPHX1 and exon 5 105Ile/105Ile GSTP1 (adjusted OR: 2.34, 95% CI: 1.21-4.52). The polymorphic site within the exon 5 of GSTP1 results in a Ile-->Val substitution, and the isoleucine GSTpi isoform has been found in vitro to be less active than the valine isoform towards the conjugation of BPDE. The 113 Tyr/Tyr EPHX1 encodes for a high-activity mEH. Our results agree with these observations in vitro and suggest that a genetically determined combination of a high-activity mEH and a low-activity GSTpi may increase lung cancer risk among smokers.

Adult↗

PubMed2004

p53 codon 72 polymorphic variants, loss of allele-specific transcription, and human papilloma virus 16 and/or 18 E6 messenger RNA expression in squamous cell carcinomas of the head and neck.

A polymorphism at codon 72 of the human tumor suppressor p53 determines translation into either arginine or proline. Yet, the impact of this amino acid variability on the risk to develop malignant tumors, particularly carcinomas associated with human papilloma virus (HPV) infections, remains unresolved because of contradictory results. To address a potential correlation between the different genotypes and the manifestation of squamous cell carcinomas of the head and neck (SCCHN), we determined the p53 codon 72 in 193 healthy subjects and 122 unselected SCCHN with known HPV status. Furthermore, loss of allele-specific transcription was analyzed in p53 codon 72 heterozygous (Arg/Pro) SCCHN and correlated with HPV 16 and/or 18 E6 transcript expression. We found a moderately increased risk (odds ratio, 1.86; 95% confidence interval, 1.0-3.3) for individuals with germ line heterozygosity to develop SCC of the pharynx. On the other hand, p53 codon 72 polymorphic variants, most notably the Arg/Arg genotype, showed no association with the presence of HPV 16 and/or 18 E6 transcript. Moreover, there was no evidence for HPV-driven selection in SCCHN with allele-specific loss of transcription. Our data suggest that the p53 codon 72 polymorphism has a minor impact on the development of SCCHN.

Adult↗

PubMed2026

Genetic variants in IGF2BP family genes are associated with glioma risk in Chinese children.

BACKGROUND: Glioma is a highly prevalent malignant tumor of the central nervous system in children and is driven by complex genetic and environmental factors. IGF2BP family genes (IGF2BP1, IGF2BP2, and IGF2BP3) encode critical RNA epigenetic "readers" that participate in posttranscriptional gene regulation and modulate various cellular processes. However, the contributions of these gene variants to glioma risk remain unclear. METHODS: A multicenter case-control study was conducted, enrolling 360 patients with glioma and 547 cancer-free controls. Genotyping of 11 potentially functional polymorphisms within IGF2BP family genes was performed using the TaqMan assay. Unconditional logistic regression models were employed to estimate odds ratios and 95% confidence intervals. Furthermore, expression quantitative trait loci (eQTL) and The Cancer Genome Atlas (TCGA) clinical database analyses were conducted to investigate the potential regulatory mechanisms and clinical significance of the identified variants. RESULTS: We found that the IGF2BP1 rs2270575 polymorphism was significantly associated with a decreased risk of glioma. Conversely, the IGF2BP2 rs17289925 and rs7646419 polymorphisms were linked to increased glioma risk. Stratification and cumulative effect analyses revealed that harboring multiple risk genotypes of IGF2BP1 or IGF2BP2 substantially increased glioma susceptibility. This cumulative risk was especially notable among males, younger children (< 60 months), and patients diagnosed with early-stage (I + II) tumors. Additionally, eQTL and TCGA analyses revealed that the rs2270575 and rs7646419 alleles correlated significantly with altered mRNA expression levels of CALCOCO2 and AC099661.1 (ENSG00000286086), respectively, which further correlated with favorable molecular subtypes (IDH mutation status) and WHO tumor grades. CONCLUSION: Genetic polymorphisms within IGF2BP family genes significantly modulate pediatric glioma susceptibility and have cumulative, subtype-specific, and age-dependent effects; thus, these genes may serve as promising noninvasive biomarkers for early risk stratification of childhood glioma.

Adolescent↗