RESUMEN
The zinc (Zn) transporter ZnT2 (SLC30A2) is expressed in specialized secretory cells including breast, pancreas and prostate, and imports Zn into mitochondria and vesicles. Mutations in SLC30A2 substantially reduce milk Zn concentration ([Zn]) and cause severe Zn deficiency in exclusively breastfed infants. Recent studies show that ZnT2-null mice have low milk [Zn], in addition to profound defects in mammary gland function during lactation. Here, we used breast milk [Zn] to identify novel non-synonymous ZnT2 variants in a population of lactating women. We also asked whether specific variants induce disturbances in intracellular Zn management or cause cellular dysfunction in mammary epithelial cells. Healthy, breastfeeding women were stratified into quartiles by milk [Zn] and exonic sequencing of SLC30A2 was performed. We found that 36% of women tested carried non-synonymous ZnT2 variants, all of whom had milk Zn levels that were distinctly above or below those in women without variants. We identified 12 novel heterozygous variants. Two variants (D(103)E and T(288)S) were identified with high frequency (9 and 16%, respectively) and expression of T(288)S was associated with a known hallmark of breast dysfunction (elevated milk sodium/potassium ratio). Select variants (A(28)D, K(66)N, Q(71)H, D(103)E, A(105)P, Q(137)H, T(288)S and T(312)K) were characterized in vitro. Compared with wild-type ZnT2, these variants were inappropriately localized, and most resulted in either 'loss-of-function' or 'gain-of-function', and altered sub-cellular Zn pools, Zn secretion, and cell cycle check-points. Our study indicates that SLC30A2 variants are common in this population, dysregulate Zn management and can lead to breast cell dysfunction. This suggests that genetic variation in ZnT2 could be an important modifier of infant growth/development and reproductive health/disease. Importantly, milk [Zn] level may serve as a bio-reporter of breast function during lactation.
Asunto(s)
Proteínas de Transporte de Catión/genética , Células Epiteliales/fisiología , Lactancia/genética , Glándulas Mamarias Humanas/fisiopatología , Leche Humana/química , Zinc/metabolismo , Animales , Lactancia Materna , Puntos de Control del Ciclo Celular/genética , Línea Celular , Análisis Mutacional de ADN , Exoma , Femenino , Humanos , Ratones , Mutación , Análisis de Secuencia de ADN , Zinc/análisisRESUMEN
The tobacco-specific nitrosamine NNK is a potent carcinogen found in tobacco smoke and implicated in the development of lung cancer. The major route of NNK metabolism is carbonyl reduction by AKR1C1, AKR1C2, CBR1, and 11ß-HSD1 to form NNAL. This study investigated the potential role of variants in this pathway on lung cancer risk by examining 53 tag-SNPs representing the common variations in AKR1C1, AKR1C2, CBR1, and HSD11B1 in 456 lung cancer cases and 807 controls. One SNP in CBR1 (rs2835267) was significantly associated with overall risk of lung cancer, but did not pass multiple testing adjustment (OR: 0.76 95% CI: 0.58-0.99, P = 0.048, FDR P = 0.20). After stratification and multiple testing correction, three SNPs showed significance. One SNP (rs2835267) in CBR1 showed a significant decreased risk for smokers with a high pack-years (OR: 0.3595% CI: 0.17-0.69, P = 0.018) and in SCC (OR: 0.4895% CI: 0.29-0.76, P = 0.018). Another SNP located in CBR1 (rs3787728) also showed a significant decreased risk in SCC (OR: 0.4695% CI: 0.26-0.80, P = 0.024) and small cell carcinoma (only in current smokers) (OR: 0.06895% CI: 0.01-0.42, P = 0.028). The HSD11B1 SNP (rs4844880) showed a significant increased risk for adenocarcinoma within former smokers (OR: 3.9495% CI: 1.68-9.22, P = 0.011). Haplotype analysis found significance with six haplotypes and lung cancer risk. These findings indicate that select variants in genes in the carbonyl reduction pathway of NNK may alter the risk of lung cancer.
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Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Nitrosaminas/farmacología , Polimorfismo de Nucleótido Simple , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Peak heart rate (HRpeak) is a common tool used in exercise prescription for groups in which maximal exercise intensity is contraindicated; however, the application of this method in normobaric hypoxia is unknown. Therefore, this study investigated the response of HRpeak and the application of predictive HRpeak equations to prescribe exercise intensity in acute normobaric hypoxia. Results were used to examine whether age-derived HRpeak predictive equations are valid in hypoxic conditions. METHODS: Fifteen untrained (eight men) volunteers (age 22 ± 2 years; peak rate of oxygen consumption 46.3 ± 7.0 ml kg(-1) min(-1)) completed incremental cycle ergometer tests (randomised order) to measure HRpeak at sea-level (SL (ambient inspiratory oxygen fraction (FIO2) 0.209)) and four normobaric hypoxic conditions FIO2: 0.185, 0.165, 0.142, 0.125 (≈1,000-4,000 m). RESULTS: HRpeak was similar across all conditions (SL, 182 ± 13; 0.185, 178 ± 11; 0.165, 177 ± 9; 0.142, 178 ± 9; 0.125, 175 ± 10 b min(-1)) despite a reduction in oxygen saturation with increasing hypoxia (SL, 95 ± 5; 0.185, 95 ± 2; 0.165, 92 ± 2; 0.142, 88 ± 3; 0.125, 82 ± 4 %; P ≤ 0.05). The HRpeak was overestimated by all equations compared to the measured value (P < 0.05). Four equations overestimated HRpeak in all conditions (P < 0.01); two in four conditions (0.185, 0.165, 0.142, 0.125; P < 0.01); and two in three conditions (0.165, 0.142, 0.125; P < 0.01). CONCLUSION: The overestimation of HRpeak by commonly used age-derived predictive equations in normobaric hypoxic conditions suggests that despite possible contraindications researchers should directly measure HRpeak whenever possible if it is to be used to prescribe exercise intensities.
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Altitud , Prueba de Esfuerzo/normas , Frecuencia Cardíaca , Hipoxia/fisiopatología , Interpretación Estadística de Datos , Ejercicio Físico , Femenino , Humanos , Masculino , Consumo de Oxígeno , Valores de Referencia , Adulto JovenRESUMEN
UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR = 0.28, 95% CI = 0.110.69) and for the distal colon (OR = 0.32, 95% CI = 0.120.91)], and that the C-T-G haplotype in the 3' region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.105.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI = 1.215.04) and in females (OR = 3.08, 95% CI = 1.088.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.
Asunto(s)
Neoplasias Colorrectales/genética , Interacción Gen-Ambiente , Glucuronosiltransferasa/genética , Polimorfismo de Nucleótido Simple , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios de Casos y Controles , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 4 , Neoplasias Colorrectales/metabolismo , Femenino , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Factores de RiesgoRESUMEN
PURPOSE: This study investigated the response of the ventilatory threshold (VT) to acute normobaric hypoxia and compared the agreement between software-based algorithms which use automatic detection to identify the VT. Results were used to examine whether the VT can be used as a physiological parameter to prescribe and monitor exercise intensity in hypoxic exercise training programs. METHODS: Fourteen untrained individuals (7 women, 7 men; age 22 ± 2 years, [Formula: see text]O2peak 46 ± 7 mL kg(-1) min(-1)) completed five identical graded exercise tests (randomized order) on a cycle ergometer to measure VT at sea-level (SL) and in response to four normobaric hypoxic conditions (FIO2: 0.185, 0.165, 0.142, 0.125) equivalent to 1,000, 2,000, 3,000 and 4,000 m. Data were analyzed using a one-way analysis of variance (ANOVA) with repeated measures. RESULTS: The VT was similar across all conditions (SL = 1.98 ± 0.46, 1,000 m = 2.03 ± 0.61, 2,000 m = 2.27 ± 0.62, 3,000 m = 1.84 ± 0.50, 4,000 m = 2.29 ± 0.58 L min(-1)) for all algorithms used despite a reduction in arterial oxygen saturation at 3,000 (P ≤ 0.01) and 4,000 m (P ≤ 0.01) compared with SL values. CONCLUSION: The VT appears to be a suitable physiological parameter for exercise prescription in normobaric hypoxia up to an altitude of 4,000 m.
Asunto(s)
Altitud , Ejercicio Físico , Hipoxia/fisiopatología , Ventilación Pulmonar , Femenino , Humanos , Masculino , Consumo de Oxígeno , Adulto JovenRESUMEN
OBJECTIVE: Ascent to high altitude leads to a reduction in ambient pressure and a subsequent fall in available oxygen. The resulting hypoxia can lead to elevated pulmonary artery (PA) pressure, capillary stress, and an increase in interstitial fluid. This fluid can be assessed on lung ultrasound (LUS) by the presence of B-lines. We undertook a chamber and field study to assess the impact of high-intensity exercise in hypoxia on the development of pulmonary interstitial edema in healthy lowlanders. METHODS: Thirteen volunteers completed a high-intensity intermittent exercise (HIIE) test at sea level, in acute normobaric hypoxia (12% O2, approximately 4090 m equivalent altitude), and in hypobaric hypoxia during a field study at 4090 m after 6 days of acclimatization. Pulmonary interstitial edema was assessed by the evaluation of LUS B-lines. RESULTS: After HIIE, no increase in B-lines was seen in normoxia, and a small increase was seen in acute normobaric hypoxia (2 ± 2; P < .05). During the field study at 4090 m, 12 participants (92%) demonstrated 7 ± 4 B-lines at rest, which increased to 17 ± 5 immediately after the exercise test (P < .001). An increase was evident in all participants. There was a reciprocal fall in peripheral arterial oxygen saturations (Spo2) after exercise from 88% ± 4% to 80% ± 8% (P < .01). B-lines and Spo2 in all participants returned to baseline levels within 4 hours. CONCLUSIONS: HIIE led to an increase in B-lines at altitude after subacute exposure but not during acute exposure at equivalent simulated altitude. This may indicate pulmonary interstitial edema.
Asunto(s)
Mal de Altura/fisiopatología , Ejercicio Físico/fisiología , Hipoxia/fisiopatología , Edema Pulmonar/fisiopatología , Adulto , Altitud , Prueba de Esfuerzo , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Edema Pulmonar/diagnóstico por imagen , Perfil de Impacto de Enfermedad , UltrasonografíaRESUMEN
Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC.
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Neoplasias Colorrectales/epidemiología , Ácido Fólico/administración & dosificación , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Dieta , Suplementos Dietéticos , Femenino , Ácido Fólico/metabolismo , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Pennsylvania/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.
Asunto(s)
Monkeypox virus , Profilinas , Simulación del Acoplamiento Molecular , Benzamidas , Antivirales/farmacologíaRESUMEN
BACKGROUND: Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS: To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS: A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS: The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.
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Neoplasias Colorrectales/genética , Variaciones en el Número de Copia de ADN , Eliminación de Gen , Glucuronosiltransferasa/genética , Fase II de la Desintoxicación Metabólica/genética , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias del Colon/genética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Carne/efectos adversos , Productos de la Carne/efectos adversos , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Pennsylvania/epidemiología , Neoplasias del Recto/genética , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Población Blanca/genéticaRESUMEN
BACKGROUND: Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). METHODS: Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. RESULTS: Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)]. CONCLUSION: This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
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Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/etiología , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Chaperonas Moleculares/genética , Oportunidad Relativa , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
BACKGROUND: Previously we performed a linkage scan of 638 African American affected sibling pairs (ASP) with type 2 diabetes (T2D) enriched for end-stage renal disease (ESRD). Ordered subset linkage analysis (OSA) revealed a linkage peak on chromosome 7p in the subset of families with earlier age of T2D diagnosis. METHODS: We fine mapped this region by genotyping 11 additional polymorphic markers in the same ASP and investigated a total of 68 single nucleotide polymorphisms (SNPs) in functional candidate genes (GCK1, IL6, IGFBP1 and IGFBP3) for association with age of T2D diagnosis, age of ESRD diagnosis, duration of T2D to onset of ESRD, body mass index (BMI) in African American cases and T2D-ESRD in an African American case-control cohort. OSA of fine mapping markers supported linkage at 28 cM on 7p (near D7S3051) in early-onset T2D families (max. LOD = 3.61, P = 0.002). SNPs in candidate genes and 70 ancestry-informative markers (AIMs) were evaluated in 577 African American T2D-ESRD cases and 596 African American controls. RESULTS: The most significant association was observed between ESRD age of diagnosis and SNP rs730497, located in intron 1 of the GCK1 gene (recessive T2D age-adjusted P = 0.0006). Nominal associations were observed with GCK1 SNPs and T2D age of diagnosis (BMI-adjusted P = 0.014 to 0.032). Also, one IGFBP1 and four IGFBP3 SNPs showed nominal genotypic association with T2D-ESRD (P = 0.002-0.049). After correcting for multiple tests, only rs730497 remanined significant. CONCLUSION: Variant rs730947 in the GCK1 gene appears to play a role in early ESRD onset in African Americans.
Asunto(s)
Población Negra/genética , Cromosomas Humanos Par 7/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/etiología , Ligamiento Genético/genética , Fallo Renal Crónico/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Edad de Inicio , Índice de Masa Corporal , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Nefropatías Diabéticas/etnología , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Quinasas del Centro Germinal , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Interleucina-6/genética , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/etnología , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Factores de RiesgoRESUMEN
UDP-glucuronosyltransferases (UGTs) are enzymes involved in the metabolism of steroid hormones, carcinogens, cancer chemotherapy agents, and addictive agents from cigarettes. Because the UGT2B family of genes has been linked to hormonal regulation in human cell lines in vitro, we hypothesized that there may be sex-related differences in the expression and activity of these genes in human tissues. To evaluate whether there are sex differences in UGT2B expression and activity, we examined 103 normal human liver specimens for UGT2B expression by real-time polymerase chain reaction and in vitro glucuronidation activities in human liver microsomes (HLM). Men exhibited an approximately 4-fold higher level of expression of UGT2B17 than women (p = 0.007). Consistent with the increased expression of UGT2B17 in men, HLM from men also had a higher level of glucuronidation activity than HLM from women against three UGT2B17 substrates: 3-fold higher for 17-dihydroexemestane (p = 0.002); 3-fold higher for 3-hydroxycotinine (p < 0.001); and 1.5-fold higher for suberoylanilide hydroxamic acid (p = 0.014). When we stratified by UGT2B17 gene deletion genotype, similar patterns were observed for all three substrates, with HLM from men with the UGT2B17 (+/+) or (+/0) genotypes exhibiting significantly higher levels of glucuronidation activity against all three substrates compared with HLM from women. These data suggest that men have a higher amount of UGT2B17 glucuronidation activity then women. This sex difference in UGT2B17 gene expression and corresponding protein activity could potentially result in different levels of carcinogen detoxification or drug elimination in men versus women.
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Glucuronosiltransferasa/genética , Caracteres Sexuales , Femenino , Regulación Enzimológica de la Expresión Génica , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Humanos , Masculino , Microsomas Hepáticos/enzimología , Antígenos de Histocompatibilidad Menor , ARN Mensajero/análisisRESUMEN
Microsomal epoxide hydrolase (EPHX1) biotransforms epoxide derivatives of pharmaceuticals, including metabolites of certain antiepileptic medications, such as phenytoin and carbamazepine, and many environmental epoxides, such as those derived from butadiene, benzene, and carcinogenic polyaromatic hydrocarbons. We previously identified a far upstream promoter region, designated E1-b, in the EPHX1 gene that directs expression of an alternatively spliced EPHX1 mRNA transcript in human tissues. In this investigation, we characterized the structural features and expression character of the E1-b promoter region. Results of quantitative real-time polymerase chain reaction analyses demonstrated that the E1-b variant transcript is preferentially and broadly expressed in most tissues, such that it accounts for the majority of total EPHX1 transcript in vivo. Comparative genomic sequence comparisons indicated that the human EPHX1 E1-b gene regulatory region is primate-specific. Direct sequencing and genotyping approaches in 450 individuals demonstrated that the E1-b promoter region harbors a series of transposable element cassettes, including a polymorphic double Alu insertion. Results of reporter assays conducted in several human cell lines demonstrated that the inclusion of the Alu(+/+) insertion significantly decreases basal transcriptional activities. Furthermore, using haplotype block analyses, we determined that the E1-b polymorphic promoter region was not in linkage disequilibrium with two previously identified nonsynonomous single nucleotide polymorphisms (SNPs) in the coding region or with functional SNPs previously identified in the proximal promoter region of the gene. These results demonstrate that the upstream E1-b promoter is the major regulator of EPHX1 expression in human tissues and that polymorphism in this region may contribute an interindividual risk determinant to xenobiotic-induced toxicities.
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Epóxido Hidrolasas/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Polimorfismo Genético/fisiología , Regiones Promotoras Genéticas/fisiología , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Epóxido Hidrolasas/biosíntesis , Epóxido Hidrolasas/metabolismo , Variación Genética/fisiología , Humanos , Macaca mulatta , Pan troglodytes , Transcripción GenéticaRESUMEN
The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted P(a) = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.
Asunto(s)
Negro o Afroamericano/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/genética , Receptor alfa de Estrógeno/genética , Fallo Renal Crónico/genética , Población Blanca/genética , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Exones/genética , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in approximately 10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.
Asunto(s)
Adenocarcinoma/enzimología , Adenocarcinoma/genética , Glucuronosiltransferasa/genética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Nitrosaminas/orina , Piridinas/orina , Adenocarcinoma/epidemiología , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Estudios Transversales , Femenino , Florida/epidemiología , Eliminación de Gen , Genotipo , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiología , Masculino , New York/epidemiología , Fenotipo , Riesgo , Fumar/epidemiologíaRESUMEN
Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. Low levels of serum bilirubin, an endogenous antioxidant, have been associated with increased risk for Crohn's disease (CD). Therefore, the aim of this study was to examine whether total serum bilirubin levels are associated with ulcerative colitis (UC). We identified a retrospective case-control population (n = 6,649) from a single tertiary care center, Penn State Hershey Medical Center (PSU) and a validation cohort (n = 1,996) from Virginia Commonwealth University Medical Center (VCU). Cases were age- and sex-matched to controls (PSU: CD n = 254, UC n = 187; VCU: CD n = 233, UC n = 124). Total serum bilirubin levels were obtained from de-identified medical records and segregated into quartiles. Logistic regression analysis was performed on each quartile of total serum bilirubin compared to the last quartile (highest bilirubin levels) to determine the association of total serum bilirubin with UC. Similar to CD patients, UC patients demonstrated reduced levels of total serum bilirubin compared to controls at PSU and VCU. The lowest quartile of total serum bilirubin was independently associated with UC for the PSU (OR: 1.98 [95% CI: 1.09-3.63]) and VCU cohorts (OR: 6.07 [95% CI: 3.01-12.75]). Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. Therapeutics that reduce oxidative stress may be beneficial for these patients.
Asunto(s)
Bilirrubina/sangre , Colitis Ulcerosa/sangre , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: Epidemiologic evidence indicates that greater intakes of vitamin D may decrease the risk of colorectal cancer. Variants in the vitamin D receptor (VDR) gene have the potential to modify associations between vitamin D intake and colorectal cancer. METHODS: Associations between intakes of vitamin D and colorectal cancer were studied in a large case-control study conducted in central and northeastern Pennsylvania including 1,012 cases with histologically confirmed colorectal cancer and 1,080 population-based controls. Associations between 35 tagSNPs encompassing the VDR gene and risk for colorectal cancer as well as gene-diet associations were also assessed among a subset of the population (770 controls, 710 cases). RESULTS: No significant trends were observed between vitamin D intake and colorectal cancer risk. After adjustment for multiple comparisons, none of the SNPs or haplotypes within the VDR gene were associated with colorectal cancer. There were also no interactions between dietary factors and variants in the entire VDR gene. CONCLUSIONS: Overall, results from this study suggest that vitamin D intake and variants in the VDR gene have little effect on risk for colorectal cancer. IMPACT: Increasing vitamin D intake from the diet may not result in decreasing the incidence of colorectal cancer.
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Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Polimorfismo Genético , Vigilancia de la Población , Receptores de Calcitriol/genética , Vitamina D/administración & dosificación , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Receptores de Calcitriol/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Vitaminas/administración & dosificaciónRESUMEN
The aim was to assess the effect of high altitude on the development of new immune memory (induction) using a contact sensitization model of in vivo immunity. We hypothesized that high-altitude exposure would impair induction of the in vivo immune response to a novel antigen, diphenylcyclopropenone (DPCP). DPCP was applied (sensitization) to the lower back of 27 rested controls at sea level and to ten rested mountaineers 28 hours after passive ascent to 3777 m. After sensitization, mountaineers avoided strenuous exercise for a further 24 hours, after which they completed alpine activities for 11-18 days. Exactly 4 weeks after sensitization, the strength of immune memory induction was quantified in rested mountaineers and controls at sea level, by measuring the response to a low, dose-series DPCP challenge, read at 48 hours as skin measures of edema (skinfold thickness) and redness (erythema). Compared with control responses, skinfold thickness and erythema were reduced in the mountaineers (skinfold thickness,-52%, p=0.01, d=0.86; erythema, -36%, p=0.02, d=0.77). These changes in skinfold thickness and erythema were related to arterial oxygen saturation (r=0.7, p=0.04), but not cortisol (r<0.1, p>0.79), at sensitization. In conclusion, this is the first study to show, using a contact sensitization model of in vivo immunity, that high altitude exposure impairs the development of new immunity in humans.
Asunto(s)
Altitud , Ciclopropanos/inmunología , Dermatitis por Contacto/inmunología , Haptenos/inmunología , Montañismo/fisiología , Aciltransferasas/efectos de los fármacos , Aciltransferasas/inmunología , Administración Cutánea , Adulto , Biomarcadores/sangre , Estudios Transversales , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacología , Dermatitis por Contacto/sangre , Proteínas de Drosophila/efectos de los fármacos , Proteínas de Drosophila/inmunología , Eritema/inducido químicamente , Eritema/inmunología , Femenino , Haptenos/administración & dosificación , Haptenos/farmacología , Humanos , Masculino , Oxígeno/sangreRESUMEN
BACKGROUND: The formation of bulky DNA adducts caused by diol epoxide derivatives of polycyclic aromatic hydrocarbons has been associated with tobacco-induced cancers, and inefficient repair of such adducts by the nucleotide excision repair (NER) system has been linked to increased risk of tobacco-induced lung and head and neck (H&N) cancers. The human excision repair cross-complementation group 1 (ERCC1) protein is essential for a functional NER system and genetic variation in ERCC1 may contribute to impaired DNA repair capacity and increased lung and H&N cancer risk. METHODS: In order to comprehensively capture common genetic variation in the ERCC1 gene, Caucasian data from the International HapMap project was used to assess linkage disequilibrium and choose four tagSNPs (rs1319052, rs3212955, rs3212948, and rs735482) in the ERCC1 gene to genotype 452 lung cancer cases, 175 H&N cancer cases, and 790 healthy controls. Haplotypes were estimated using expectation maximization (EM) algorithm, and haplotype association with cancer was investigated using Haplo.stats software adjusting for known covariates. RESULTS: The genotype and haplotype frequencies matched previous estimates from Caucasians. There was no significant difference in the prevalence of rs1319052, rs3212955, rs3212948, and rs735482 when comparing lung or H&N cancer cases with controls (p-values>0.05). Similarly, there was no association between ERCC1 haplotypes and lung or H&N cancer susceptibility in this Caucasian population (p-values>0.05). No associations were found when stratifying lung cancer cases by histology, sex, smoking status, or smoking intensity. CONCLUSIONS: This study suggests that ERCC1 polymorphisms and haplotypes do not play a role in lung and H&N cancer susceptibility in Caucasians.