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1.
medRxiv ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39108521

RESUMO

Background: Maternal obesity is a health concern that may predispose newborns to a high risk of medical problems later in life. To understand the transgenerational effect of maternal obesity, we conducted a multi-omics study, using DNA methylation and gene expression in the CD34+/CD38-/Lin- umbilical cord blood hematopoietic stem cells (uHSCs) and metabolomics of the cord blood, all from a multi-ethnic cohort (n=72) from Kapiolani Medical Center for Women and Children in Honolulu, Hawaii (collected between 2016 and 2018). Results: Differential methylation (DM) analysis unveiled a global hypermethylation pattern in the maternal pre-pregnancy obese group (BH adjusted p<0.05), after adjusting for major clinical confounders. Comprehensive functional analysis showed hypermethylation in promoters of genes involved in cell cycle, protein synthesis, immune signaling, and lipid metabolism. Utilizing Shannon entropy on uHSCs methylation, we discerned notably higher quiescence of uHSCs impacted by maternal obesity. Additionally, the integration of multi-omics data-including methylation, gene expression, and metabolomics-provided further evidence of dysfunctions in adipogenesis, erythropoietin production, cell differentiation, and DNA repair, aligning with the findings at the epigenetic level. Furthermore, the CpG sites associated with maternal obesity from these pathways also predicted highly accurately (average AUC = 0.8687) between cancer vs. normal tissues in 14 cancer types in The Cancer Genome Atlas (TCGA). Conclusions: This study revealed the significant correlation between pre-pregnancy maternal obesity and multi-omics level molecular changes in the uHSCs of offspring, particularly in DNA methylation. Moreover, these maternal obesity epigenetic markers in uHSCs may predispose offspring to higher cancer risks.

2.
Am J Hum Genet ; 111(3): 456-472, 2024 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-38367619

RESUMO

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10-8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10-4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.


Assuntos
MicroRNAs , Fumantes , Humanos , Nicotina , Epigênese Genética/genética , Epigenoma , Estudos de Coortes , Estudos Prospectivos , Estudo de Associação Genômica Ampla , Metilação de DNA/genética , Ilhas de CpG/genética , Receptores de Peptídeos/genética , Receptores Acoplados a Proteínas G/genética
3.
Front Cell Dev Biol ; 10: 1015665, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36684450

RESUMO

The 90 kDa ribosomal S6 kinases (RSKs) are serine threonine kinases comprising four isoforms. The isoforms can have overlapping functions in regulation of migration, invasion, proliferation, survival, and transcription in various cancer types. However, isoform specific differences in RSK1 versus RSK2 functions in gene regulation are not yet defined. Here, we delineate ribosomal S6 kinases isoform-specific transcriptional gene regulation by comparing transcription programs in RSK1 and RSK2 knockout cells using microarray analysis. Microarray analysis revealed significantly different mRNA expression patterns between RSK1 knockout and RSK2 knockout cell lines. Importantly some of these functions have not been previously recognized. Our analysis revealed RSK1 has specific roles in cell adhesion, cell cycle regulation and DNA replication and repair pathways, while RSK2 has specific roles in the immune response and interferon signaling pathways. We further validated that the identified gene sets significantly correlated with mRNA datasets from cancer patients. We examined the functional significance of the identified transcriptional programs using cell assays. In alignment with the microarray analysis, we found that RSK1 modulates the mRNA and protein expression of Fibronectin1, affecting cell adhesion and CDK2, affecting S-phase arrest in the cell cycle, and impairing DNA replication and repair. Under similar conditions, RSK2 showed increased ISG15 transcriptional expression, affecting the immune response pathway and cytokine expression. Collectively, our findings revealed the occurrence of RSK1 and RSK2 specific transcriptional regulation, defining separate functions of these closely related isoforms.

4.
JGH Open ; 5(12): 1363-1372, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34950780

RESUMO

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). METHODS: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. RESULTS: In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. CONCLUSIONS: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.

5.
Clin Epigenetics ; 13(1): 188, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635168

RESUMO

BACKGROUND: Racial/ethnic disparities in health reflect a combination of genetic and environmental causes, and DNA methylation may be an important mediator. We compared in an exploratory manner the blood DNA methylome of Japanese Americans (JPA) versus European Americans (EUA). METHODS: Genome-wide buffy coat DNA methylation was profiled among healthy Multiethnic Cohort participant women who were Japanese (JPA; n = 30) or European (EUA; n = 28) Americans aged 60-65. Differentially methylated CpGs by race/ethnicity (DM-CpGs) were identified by linear regression (Bonferroni-corrected P < 0.1) and analyzed in relation to corresponding gene expression, a priori selected single nucleotide polymorphisms (SNPs), and blood biomarkers of inflammation and metabolism using Pearson or Spearman correlations (FDR < 0.1). RESULTS: We identified 174 DM-CpGs with the majority of hypermethylated in JPA compared to EUA (n = 133), often in promoter regions (n = 48). Half (51%) of the genes corresponding to the DM-CpGs were involved in liver function and liver disease, and the methylation in nine genes was significantly correlated with gene expression for DM-CpGs. A total of 156 DM-CpGs were associated with rs7489665 (SH2B1). Methylation of DM-CpGs was correlated with blood levels of the cytokine MIP1B (n = 146). We confirmed some of the DM-CpGs in the TCGA adjacent non-tumor liver tissue of Asians versus EUA. CONCLUSION: We found a number of differentially methylated CpGs in blood DNA between JPA and EUA women with a potential link to liver disease, specific SNPs, and systemic inflammation. These findings may support further research on the role of DNA methylation in mediating some of the higher risk of liver disease among JPA.


Assuntos
Povo Asiático/etnologia , Metilação de DNA/genética , Etnicidade/genética , População Branca/etnologia , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/sangue , Idoso , Povo Asiático/estatística & dados numéricos , Estudos de Coortes , Metilação de DNA/fisiologia , Etnicidade/estatística & dados numéricos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Estados Unidos/etnologia , População Branca/estatística & dados numéricos
6.
Sci Rep ; 11(1): 7484, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33820921

RESUMO

Long non-coding RNAs (lncRNAs) have important biological functions, but their involvement in ovarian cancer remains elusive. We analyzed high-throughput data to identify lncRNAs associated with ovarian cancer outcomes. Our search led to the discovery of lncRNA TOPORS Antisense RNA 1 (TOPORS-AS1). Patients with high TOPORS-AS1 expression had favorable overall survival compared to low expression. This association was replicated in our study and confirmed by meta-analysis. In vitro experiments demonstrated that overexpressing TOPORS-AS1 in ovarian cancer cells suppressed cell proliferation and inhibited aggressive cell behaviors, including migration, invasion, and colony formation. Analysis of tumor cell transcriptomes indicated TOPORS-AS1's influence on the Wnt/ß-catenin signaling. Additional experiments revealed that TOPORS-AS1 increased the phosphorylation of ß-catenin and suppressed the expression of CTNNB1, disrupting the Wnt/ß-catenin pathway. Our experiments further discovered that vitamin D receptor (VDR) upregulated TOPORS-AS1 expression and that inhibition of ß-catenin by TOPORS-AS1 required a RNA binding protein, hnRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1). Taken together, these findings suggest that TOPORS-AS1 may behave like a tumor suppressor in ovarian cancer through interrupting the Wnt/ß-catenin signaling and that VDR upregulates the expression of TOPORS-AS1. Assessing TOPORS-AS1 expression in ovarian cancer may help predict disease prognosis and develop treatment strategy.


Assuntos
Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Receptores de Calcitriol/metabolismo , Regulação para Cima/genética , Via de Sinalização Wnt , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos Biológicos , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , RNA Longo não Codificante/metabolismo , Análise de Sobrevida , Transcriptoma/genética , Ensaio Tumoral de Célula-Tronco , Via de Sinalização Wnt/genética , beta Catenina/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-33553649

RESUMO

Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.

8.
Asian Pac J Cancer Prev ; 21(10): 3019-3026, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112562

RESUMO

OBJECTIVE: Certain microRNAs (miR) have been previously described to be dysregulated in cancers and can be detected in blood samples. Studies examining the utility of miRs for colon cancer screening have primarily been performed in ethnically homogeneous groups of patients, thus the performance of miRs in multiethnic populations is unknown. METHODS: Four miRs were selected that were shown to be aberrantly expressed in the blood or stool of patients with colorectal cancer (CRC) of various ethnicities. In this study, the ability of these miRs to discern early stage CRC was determined in a previously untested multiethnic population of 73 CRC cases and 18 controls. RESULTS: The ratios of non-vesicular to extracellular vesicular levels of miR's -21, -29a, and -92a were statistically and quantitatively related to CRC stage compared to controls. CONCLUSION: Serum levels of miR-21, miR-29a and miR-92a were able to significantly detect early stage CRC in a multiethnic and previously untested population.
.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Etnicidade/genética , MicroRNAs/genética , Idoso , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Havaí/epidemiologia , Humanos , Japão/epidemiologia , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico
9.
Hum Mol Genet ; 29(13): 2275-2284, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32491157

RESUMO

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping in a large number of self-reported Native Hawaiians (N = 3693) a functionally important, Polynesian-specific variant in the CREBRF gene, rs373863828. We found the derived allele was significantly associated with several adiposity traits with large effects (e.g. ~ 1.28 kg/m2 per allele in body mass index as the most significant; P = 7.5 × 10-5), consistent with the original findings in Samoans. Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at the entire CREBRF locus could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of internally constructed Polynesian reference individuals were available; this would increase sample size and improve the statistical evidence of associations. Taken together, our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Obesidade/genética , Proteínas Supressoras de Tumor/genética , Adiposidade/genética , Alelos , Índice de Massa Corporal , Feminino , Genética Populacional , Genótipo , Humanos , Masculino , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Obesidade/epidemiologia , Obesidade/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
11.
Clin Rheumatol ; 39(8): 2387-2392, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32107664

RESUMO

Gout is a metabolic disorder and one of the most common arthritic conditions. Hyperuricemia is the hallmark of developing gout and mostly caused by uric acid underexcretion. Gout disproportionately affects people of specific races and ethnicities. Filipinos are the second-largest Asian population in the USA and reported to have a higher prevalence of gout and hyperuricemia than non-Filipino counterparts and Filipinos residing in the Philippines. The genetic polymorphism rs2231142 G>T in the ABCG2 has been strongly associated with hyperuricemia and gout across multiple populations. However, the prevalence of this variant in Filipinos is unknown. Therefore, assessing the prevalence of this variant may provide insights on the high prevalence of hyperuricemia and gout in Filipinos. A total of 190 DNA samples from pregnant females who self-identified as a Filipino from the Hawaii Biorepository Bank were genotyped for rs2231142 G>T in the ABCG2. The prevalence of the gout risk allele (T) (46%) was significantly higher in Filipinos than in samples of Caucasians (12%, p < 0.001), Han Chinese (29%, p = 0.014), and African Americans (3%, p < 0.001). Similarly, the prevalence of the gout-risk genotype (TT) (21%) was significantly higher in Filipinos than in samples of Caucasians (1%, p < 0.001), Han Chinese (9%, p = 0.002), and African Americans (0.1%, p < 0.001). Though there were no gout cases in this cohort, these findings are suggestive of a genetic basis to the high prevalence of hyperuricemia and gout in Filipinos. This might also explain the reported reduced urinary uric acid excretion in Filipinos compared with Caucasians. Key Points • The Filipinos have the highest prevalence of the gout-associated risk allele (T) of the rs2231142 G>T in ABCG2. • The high prevalence of the risk allele (T) of the rs2231142 G>T in ABCG2 may partly explain the reduced urinary urate excretion and early-onset gout in Filipinos. • The high prevalence of the risk allele (T) of the rs2231142 G > T in ABCG2 may predispose Filipinos to hyperuricemia and gout when acculturated to high-purine diet.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Predisposição Genética para Doença , Gota/genética , Proteínas de Neoplasias/genética , Ácido Úrico/sangue , Adolescente , Adulto , Negro ou Afro-Americano/genética , Alelos , Povo Asiático/genética , Feminino , Gota/sangue , Gota/etnologia , Havaí , Humanos , Hiperuricemia/etnologia , Polimorfismo de Nucleotídeo Único , Gravidez , Prevalência , População Branca/genética , Adulto Jovem
12.
FEBS Open Bio ; 9(7): 1270-1280, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102318

RESUMO

The WW and C2 domain containing 1 (WWC1) gene encodes a protein named WWC1 (or KIBRA), which is involved in the Hippo signaling pathway. WWC1 is often lost in triple-negative breast cancer and has been shown to suppress tumor metastasis. In this study, 470 breast cancer patients were recruited and WWC1 expression in the tumor samples was measured with quantitative reverse transcriptase PCR. Associations of WWC1 expression with breast cancer survival were analyzed using the Cox proportional hazards regression model and Kaplan-Meier survival analysis. The relationship between WWC1 expression and methylation was evaluated in a dataset from The Cancer Genome Atlas. Using our microarray data on gene expression and the Ingenuity Pathway Analysis, we predicted the WWC1-associated signaling pathways in breast cancer. Our results showed that low expression of WWC1 was significantly associated with advanced-stage diseases, high-grade tumors, and estrogen receptor- or progesterone receptor-negative status. Compared to those with high expression, patients with low WWC1 had higher risk of breast cancer relapse [hazard ratio (HR) = 2.06, 95% confidence interval (CI): 1.26-3.37] and higher risk of death (HR = 2.76, 95% CI: 1.51-5.03). The association with relapse-free survival remained significant after adjustment for disease stage, tumor grade, and hormone receptor status and was replicated in a public dataset. Analysis of high-throughput gene expression data indicated that WWC1 was involved in the Hippo signaling pathway. Online data also suggested that DNA methylation was inversely associated with WWC1 expression. The study confirmed that low WWC1 expression was associated with aggressive breast cancer and poor survival outcomes.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/mortalidade , Metilação de DNA/genética , Bases de Dados Genéticas , Intervalo Livre de Doença , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Estimativa de Kaplan-Meier , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Prognóstico , Modelos de Riscos Proporcionais , Transdução de Sinais , Transcriptoma/genética
13.
Cancer Res ; 79(7): 1696-1704, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30760520

RESUMO

Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). Positron emission tomography/computed tomography (PET/CT) has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by the tissue uptake of the radiopharmaceutical 18F-fluorocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent 18F-fluorocholine PET/CT, followed by tumor resection and gene expression profiling. Over- and underexpressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low 18F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by FDR based on phenotype permutation. Associations with overall survival were analyzed by univariate and multivariate proportional hazards regression. Ten gene sets related to HCC were significantly associated with high tumor 18F-fluorocholine uptake at FDR q < 0.05, including those from three different clinical molecular classification systems and two prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for 18F-fluorocholine was associated with favorable characteristics based on these signatures with lower mortality based on survival analysis (HR 0.36; 95% confidence interval, 0.14-0.95). Tumors demonstrating high 18F-fluorocholine uptake were also enriched for genes involved in oxidative phosphorylation, fatty acid metabolism, peroxisome, bile acid metabolism, xenobiotic metabolism, and adipogenesis. These results provide a pathobiological framework to further evaluate 18F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC. SIGNIFICANCE: A pathobiological framework for HCC brings together multiple prognostically relevant gene signatures via convergence with 18F-fluorocholine PET/CT imaging phenotype.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Colina/análogos & derivados , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Transcriptoma , Idoso , Carcinoma Hepatocelular/diagnóstico por imagem , Colina/administração & dosagem , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
14.
Clin Epigenetics ; 10(1): 110, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30139389

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related death. While cigarette smoking is the primary cause of this malignancy, risk differs across racial/ethnic groups. For the same number of cigarettes smoked, Native Hawaiians compared to whites are at greater risk and Japanese Americans are at lower risk of developing lung cancer. DNA methylation of specific CpG sites (e.g., in AHRR and F2RL3) is the most common blood epigenetic modification associated with smoking status. However, the influence of internal smoking dose, measured by urinary nicotine equivalents (NE), on DNA methylation in current smokers has not been investigated, nor has a study evaluated whether for the same smoking dose, circulating leukocyte DNA methylation patterns differ by race. METHODS: We conducted an epigenome-wide association study (EWAS) of NE in 612 smokers from three racial/ethnic groups: whites (n = 204), Native Hawaiians (n = 205), and Japanese Americans (n = 203). Genome-wide DNA methylation profiling of blood leukocyte DNA was measured using the Illumina 450K BeadChip array. Average ß value, the ratio of signal from a methylated probe relative to the sum of the methylated and unmethylated probes at that CpG, was the dependent variables in linear regression models adjusting for age, sex, race (for pan-ethnic analysis), and estimated cell-type distribution. RESULTS: We found that NE was significantly associated with six differentially methylated CpG sites (Bonferroni corrected p < 1.48 × 10-7): four in or near the FOXK2, PBX1, FNDC7, and FUBP3 genes and two in non-annotated genetic regions. Higher levels of NE were associated with increasing methylation beta-valuesin all six sites. For all six CpG sites, the association was only observed in Native Hawaiians, suggesting that the influence of smoking dose on DNA methylation patterns is heterogeneous across race/ethnicity (p interactions < 8.8 × 10-8). We found two additional CpG sites associated with NE in only Native Hawaiians. CONCLUSIONS: In conclusion, internal smoking dose was associated with increased DNA methylation in circulating leukocytes at specific sites in Native Hawaiian smokers but not in white or Japanese American smokers.


Assuntos
Asiático/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Fumar/genética , População Branca/genética , Adulto , Idoso , Ilhas de CpG , Epigênese Genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/urina , Análise de Sequência de DNA , Fumar/etnologia , Fumar/urina , Estados Unidos/etnologia
15.
Chem Res Toxicol ; 31(3): 168-175, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29460622

RESUMO

At similar smoking levels, African American's lung cancer risk is as much as twice that of whites. We hypothesized that racial/ethnic differences in UDP-glucuronosyltransferase (UGT)-catalyzed glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a detoxication pathway for the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) may contribute to this variable risk. UGT2B10 catalyzes NNAL- N-glucuronidation, and a UGT2B10 splice variant is common among African Americans. Smokers from two independent studies were genotyped for this variant (rs116294140) and an Asp67Tyr variant (rs61750900), and urinary NNAL and NNAL-glucuronide concentrations were quantified. In the first, no significant differences in NNAL- N-glucuronidation between African Americans ( n = 257) and whites ( n = 354) or between homozygous carriers of UGT2B10 variants (genetic score 2) and noncarriers (score 0) were detected. However, total NNAL glucuronidation by score 2 compared to score 0 smokers was lower (68.9 vs 71.2%, p < 0.0001). For NNAL- N-glucuronide to be more precisely quantified in a second study, a sensitive high-resolution LC-MS/MS-based method, which separated NNAL, NNAL- O-glucuronide, and NNAL- N-glucuronide prior to analysis, was developed. In this study, the excretion of total NNAL (free plus glucuronides) by African American ( n = 52) and white ( n = 54) smokers was not different; however, total NNAL glucuronidation by African Americans (64.0%) was slightly less than by whites (68.3%, p = 0.05). The mean NNAL- N-glucuronidation by African Americans was much lower than for whites (14 vs 24.9%, p < 0.00001), but the NNAL- O-glucuronidation was greater (50.0 vs 43.3%, p = 0.013). UGT2B10 genotype influenced NNAL- N-glucuronidation; the geometric mean percentage N-glucuronidation was 22.5% for smokers with genetic score 0 ( n = 57) and 11.2% for score 2 ( n = 11). In summary, the high prevalence of a UGT2B10 splice variant among African Americans results in lower NNAL- N-glucuronidation but only a small decrease in total NNAL glucuronidation. Therefore, despite the significant contribution of UGT2B10 to NNAL- N-glucuronidation, the UGT2B10 genotype does not play a large role in NNAL detoxication. Any decrease in N-glucuronidation was accompanied by a parallel increase in O-glucuronidation.


Assuntos
Negro ou Afro-Americano/genética , Genótipo , Glucuronídeos/urina , Glucuronosiltransferase/genética , Nitrosaminas/urina , Fumar Tabaco/genética , Fumar Tabaco/urina , Feminino , Humanos , Masculino , Isoformas de Proteínas/genética , Fumantes
16.
Artigo em Inglês | MEDLINE | ID: mdl-29376136

RESUMO

Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular sub-classes of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC. Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis. Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival. Conclusion: Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.

17.
J Gerontol A Biol Sci Med Sci ; 73(11): 1459-1464, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-29300832

RESUMO

Longevity is a polygenic trait in which genetic predisposition is particularly important. We hypothesized that among genes differentially expressed in response to caloric restriction, several may be candidate longevity genes. We tested 459 single-nucleotide polymorphisms (SNPs) in 47 genes differentially expressed in calorically restricted mice and 12 other genes for association with longevity. Subjects were American men of Japanese ancestry, 440 aged ≥95 years and 374 with an average life span. Based on a dominant model of inheritance, an association with longevity at the p < .05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 18. After correction for multiple testing, four genes retained significance, namely, MAP3K5 (p = .00004), SIRT7 (p = .00004), SIRT5 (p = .0007), and PIK3R1 (p = .01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. MAP3K5 and FLT1 haplotypes were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7, and SIRT5 in human longevity.


Assuntos
Longevidade/genética , Polimorfismo de Nucleotídeo Único , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Classe Ia de Fosfatidilinositol 3-Quinase , Frequência do Gene , Haplótipos , Humanos , Japão , Desequilíbrio de Ligação , MAP Quinase Quinase Quinase 5/genética , Masculino , Fosfatidilinositol 3-Quinases/genética , Sirtuínas/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
18.
Cancer Epidemiol Biomarkers Prev ; 26(7): 1034-1042, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28292921

RESUMO

Background: 1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk.Methods: We measured the levels of BD metabolites, 1- and 2-(N-acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism.Results: We found that mean urinary MHBMA concentrations differed significantly by ethnicity (P = 4.0 × 10-25). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by GSTT1 gene copy number (P < 0.0001); conditional on GSTT1, no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups (P = 3.3 × 10-4), but were not affected by GSTT1 copy number (P = 0.226).Conclusions:GSTT1 gene deletion has a strong effect on urinary MHBMA levels, and therefore BD metabolism, in smokers.Impact: Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained by GSTT1 genotype. Cancer Epidemiol Biomarkers Prev; 26(7); 1034-42. ©2017 AACR.


Assuntos
Butadienos/metabolismo , Carcinógenos/metabolismo , Glutationa Transferase/genética , Neoplasias Pulmonares/genética , Fumantes/estatística & dados numéricos , Fumar/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/metabolismo , Acetilcisteína/urina , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Asiático/estatística & dados numéricos , Biomarcadores/urina , Feminino , Deleção de Genes , Dosagem de Genes , Estudo de Associação Genômica Ampla , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/urina , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/efeitos adversos , Fumar/urina , População Branca/estatística & dados numéricos
19.
Sci Rep ; 6: 37446, 2016 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-27981970

RESUMO

Polarization of macrophages is regulated through complex signaling networks. Correlating miRNA and mRNA expression over time after macrophage polarization has not yet been investigated. We used paired RNA-Seq and miRNA-Seq experiments to measure the mRNA and miRNA expression in bone marrow-derived macrophages over a time-series of 8 hours. Bioinformatics analysis identified 31 differentially expressed miRNAs between M1 and M2 polarized macrophages. The top 4 M1 miRNAs (miR-155-3p, miR-155-5p, miR-147-3p and miR-9-5p) and top 4 M2 miRNAs (miR-27a-5p, let-7c-1-3p, miR-23a-5p and miR-23b-5p) were validated by qPCR. Interestingly, M1 specific miRNAs could be categorized to early- and late-response groups, in which three new miRNAs miR-1931, miR-3473e and miR-5128 were validated as early-response miRNAs. M1 polarization led to the enrichment of genes involved in immune responses and signal transduction, whereas M2 polarization enriched genes involved in cell cycle and metabolic processes. C2H2 zinc-finger family members are key targets of DE miRNAs. The integrative analysis between miRNAs and mRNAs demonstrates the regulations of miRNAs on nearly four thousand differentially expressed genes and most of the biological pathways enriched in macrophage polarization. In summary, this study elucidates the expression profiles of miRNAs and their potential targetomes during macrophage polarization.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Macrófagos/metabolismo , MicroRNAs/genética , RNA Mensageiro/genética , Animais , Biologia Computacional/métodos , Fêmur/citologia , Fêmur/imunologia , Fêmur/metabolismo , Perfilação da Expressão Gênica , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/imunologia , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Cultura Primária de Células , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Tíbia/citologia , Tíbia/imunologia , Tíbia/metabolismo
20.
BioData Min ; 9: 24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27478503

RESUMO

BACKGROUND: Technological advances enable the cost-effective acquisition of Multi-Modal Data Sets (MMDS) composed of measurements for multiple, high-dimensional data types obtained from a common set of bio-samples. The joint analysis of the data matrices associated with the different data types of a MMDS should provide a more focused view of the biology underlying complex diseases such as cancer that would not be apparent from the analysis of a single data type alone. As multi-modal data rapidly accumulate in research laboratories and public databases such as The Cancer Genome Atlas (TCGA), the translation of such data into clinically actionable knowledge has been slowed by the lack of computational tools capable of analyzing MMDSs. Here, we describe the Joint Analysis of Many Matrices by ITeration (JAMMIT) algorithm that jointly analyzes the data matrices of a MMDS using sparse matrix approximations of rank-1. METHODS: The JAMMIT algorithm jointly approximates an arbitrary number of data matrices by rank-1 outer-products composed of "sparse" left-singular vectors (eigen-arrays) that are unique to each matrix and a right-singular vector (eigen-signal) that is common to all the matrices. The non-zero coefficients of the eigen-arrays identify small subsets of variables for each data type (i.e., signatures) that in aggregate, or individually, best explain a dominant eigen-signal defined on the columns of the data matrices. The approximation is specified by a single "sparsity" parameter that is selected based on false discovery rate estimated by permutation testing. Multiple signals of interest in a given MDDS are sequentially detected and modeled by iterating JAMMIT on "residual" data matrices that result from a given sparse approximation. RESULTS: We show that JAMMIT outperforms other joint analysis algorithms in the detection of multiple signatures embedded in simulated MDDS. On real multimodal data for ovarian and liver cancer we show that JAMMIT identified multi-modal signatures that were clinically informative and enriched for cancer-related biology. CONCLUSIONS: Sparse matrix approximations of rank-1 provide a simple yet effective means of jointly reducing multiple, big data types to a small subset of variables that characterize important clinical and/or biological attributes of the bio-samples from which the data were acquired.

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