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1.
Artigo em Inglês | MEDLINE | ID: mdl-31181608

RESUMO

Acute leukemia is the most common pediatric malignancy. Some studies suggest early-life exposures to air pollution increase risk of childhood leukemia. Therefore, we explored the association between maternal residential proximity to major roadways and risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Information on cases with acute leukemia (n = 2030) was obtained for the period 1995-2011 from the Texas Cancer Registry. Birth certificate controls were frequency matched (10:1) on birth year (n = 20,300). Three residential proximity measures were assessed: (1) distance to nearest major roadway, (2) residence within 500 meters of a major roadway, and (3) roadway density. Multivariate logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI). Mothers who lived ≤500 meters to a major roadway were not more likely to have a child who developed ALL (OR = 1.03; 95% CI: 0.91-1.16) or AML (OR = 0.84; 95% CI: 0.64-1.11). Mothers who lived in areas characterized by high roadway density were not more likely to have children who developed ALL (OR = 1.06, 95% CI: 0.93-1.20) or AML (OR = 0.83, 95% CI: 0.61-1.13). Our results do not support the hypothesis that maternal proximity to major roadways is strongly associated with childhood acute leukemia. Future assessments evaluating the role of early-life exposure to environmental factors on acute leukemia risk should explore novel methods for directly measuring exposures during relevant periods of development.

2.
Birth Defects Res ; 111(13): 932-937, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31102501

RESUMO

BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias. METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n = 36 and n = 9, respectively) and controls (n = 45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias. RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p > .05). CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.

3.
Clin Infect Dis ; 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-31102440

RESUMO

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30875870

RESUMO

Objective: Investigate whether residential prenatal exposure to heavy metal hazardous air pollutants (HMHAPs) is associated with an increased risk of hypospadias. Methods: Data on non-syndromic hypospadias cases (n = 8981) and control patients delivered in Texas were obtained from the Texas Birth Defects Registry and matched 1:10 by birth year. Average exposure concentrations of HMHAPs were obtained from the 2005 U.S. Environmental Protection Agency National-Scale Air Toxics Assessment and categorized into quintiles. Odds ratios and 95% confidence intervals were estimated. STROBE reporting guidelines were followed. Results: We observed associations between hypospadias and prenatal HMHAP exposure. Manganese demonstrated significant increased risk of hypospadias at the medium, medium-high and high exposure quintiles; lead in the medium-high and high exposure quintiles. Cadmium, mercury and nickel demonstrated a significant inverted "U-shaped" association for exposures with significant associations in the medium and medium-high quintiles but not in the medium-low and high quintiles. Arsenic and chromium demonstrated a significant bivalent association for risk of hypospadias in a lower quintile as well as a higher quintile with non-significant intermediate quintiles. Conclusions: Using data from one of the world's largest active surveillance birth defects registries, we identified significant associations between hypospadias and HMHAP exposures. These results should be used in counseling for maternal demographic risk factors as well as avoidance of heavy metals and their sources.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/efeitos adversos , Hipospadia/epidemiologia , Exposição Materna/efeitos adversos , Metais Pesados/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Adulto , Feminino , Substâncias Perigosas/efeitos adversos , Humanos , Hipospadia/induzido quimicamente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores de Risco , Texas/epidemiologia , Adulto Jovem
5.
Birth Defects Res ; 111(7): 345-352, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694020

RESUMO

BACKGROUND: With the increasing birth prevalence of hypospadias, there is growing concern for pollutant exposure interfering with normal penile development. We assess the association between hypospadias and hormonally active hazardous air pollutants (HAHAPs) through a nationwide database of hazardous air pollutants and the Texas Birth Defects Registry (TBDR). METHODS: Using the TBDR, we identified 8,981 nonsyndromic isolated hypospadias cases from 1999 to 2008. Birth certificate controls were matched for birth year at a 10:1 ratio to cases. Estimated HAHAP concentrations from the 2005 U.S. EPA National-Scale Air Toxics Assessment were used to assign exposure based on maternal residence at birth. Exposure levels were categorized as quintiles based on the distribution in controls. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each increasing exposure category of selected HAHAPs. RESULTS: Of the 10 HAHAPs studied, seven were significantly associated with hypospadias risk. The HAHAP that was most strongly associated with hypospadias was phenol, which was associated with risk in all groups except the high exposure group. Cumulative HAHAP exposure demonstrated a modest increase in hypospadias risk (OR 1.15, 95% CI: 1.07-1.24, p < 0.001) in the medium and medium-high quintiles. CONCLUSIONS: While maternal exposure to some HAHAPs was significantly associated with the risk of hypospadias in male offspring, the effects were modest, and no dose-response effects were observed. Future work should employ biomarkers of exposure to better delineate the relationship.

6.
Int J Cancer ; 144(1): 110-116, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30204240

RESUMO

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.


Assuntos
Infecções por HIV/metabolismo , Infecções por Herpesviridae/metabolismo , Interleucina-6/metabolismo , Sarcoma de Kaposi/metabolismo , Carga Viral , Adolescente , Criança , Pré-Escolar , Doenças Endêmicas , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/fisiologia , Humanos , Lactente , Malaui/epidemiologia , Masculino , Projetos Piloto , Estudos Prospectivos , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/virologia , Ativação Viral/fisiologia
7.
Infect Agent Cancer ; 13: 33, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455728

RESUMO

Background: Endemic Kaposi sarcoma (KS) was first described in African children over fifty years ago, but has recently been overshadowed by HIV-related disease. We aimed to evaluate the similarities and differences between endemic HIV-negative and epidemic HIV-positive pediatric KS in a KS-associated herpesvirus-endemic region of Africa. Methods: We describe clinical characteristics of 20 HIV-negative children with endemic KS over a six-year period and compare findings with a historical control-an HIV-related pediatric KS cohort from Lilongwe, Malawi. Results: The HIV-negative endemic KS cohort was 70% male with a median age of 9.3 years. Lymph node involvement was present in 50%, hyperpigmented skin lesions in 45%, and woody edema in 40%. One patient (5%) presented with oral KS involvement and no patients presented initially with visceral KS. Significant anemia (hemoglobin < 8 g/dL) and thrombocytopenia (platelet count < 100 × 109/L) were found at time of original KS diagnosis in 45 and 40% respectively. In both HIV-negative and HIV-positive cohorts, lymphadenopathy was the most common presentation, prototypical skin lesions were often absent, severe cytopenias were a common clinical feature, and treatment outcomes were similar. Patients with endemic KS demonstrated less frequent oral involvement (5% versus 29%, P = 0.03) and a lower proportion of patients with visceral involvement (0% versus 16%, P = 0.06). Conclusions: These data suggest clinical overlap between epidemiological variants. Treatment protocols for pediatric KS in sub-Saharan Africa should be devised to include both endemic HIV-negative and epidemic HIV-related disease to better define the clinical and biological comparison.

8.
Ann Epidemiol ; 28(8): 521-528, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29724524

RESUMO

PURPOSE: Potential roles of inherited and environmental risk factors in pathogenesis of Langerhans cell histiocytosis (LCH), a myeloid neoplastic disorder, are undefined. We therefore evaluated the role of parental and perinatal factors on the risk of this childhood cancer. METHODS: Information on LCH cases (n = 162) for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on year of birth at a ratio of 10:1 for the same period. Variables evaluated included parental age, race/ethnicity, size for gestational age, and birth order. Logistic regression was used to generate an adjusted odds ratio (aOR) and 95% confidence interval (CI) testing the association between each factor and LCH. RESULTS: Few perinatal or parental factors were associated with LCH risk, with the exception of race/ethnicity. Mothers of Hispanic ethnicity were more likely to have children who developed LCH compared to non-Hispanic whites (aOR: 1.51; 95% CI: 1.02-2.25). This risk increased when both parents were Hispanic (aOR: 1.80; 95% CI: 1.13-2.87). Non-Hispanic black mothers were suggested as less likely to give birth to offspring who developed LCH compared to non-Hispanic whites (aOR: 0.50; 95% CI: 0.24-1.02). CONCLUSIONS: LCH is characterized by somatic mutations in MAPK pathway genes in myeloid precursors. Increased risk for LCH in children of Hispanic parents suggests potential impact of inherited factors on LCH pathogenesis.

9.
J Neurooncol ; 139(1): 69-75, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29663170

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~ 5-10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across racial/ethnic groups in pediatric populations. Therefore, we sought to estimate differences in MPNST incidence by race/ethnicity among all ages in the United States. METHODS: Incidence data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). We estimated incidence rates among all ages, and among those diagnosed < 25 and ≥ 25 years. RESULTS: MPNST cases were abstracted from SEER-18 (n = 1047). Among all age groups, Blacks experienced an elevated incidence of MPNSTs compared to Whites (IRRBlacks = 1.26, 95% CI 1.04-1.50). Asian and Latinos/as experienced lower incidences compared to Whites (IRRAsians = 0.78, 95% CI 0.61-0.99; IRRLatinos/as = 0.84, 95% CI 0.69-1.02). In subgroup analyses, no statistically significant associations with MPNSTs were identified among cases diagnosed < 25 years of age, whereas the associations observed among all age groups were prominent among those diagnosed ≥ 25 years of age. CONCLUSIONS: Incidence rates of MPNSTs were highest in Blacks compared to Whites and other minority groups. This study suggests specific patterns exist in terms of race/ethnicity and age at diagnosis of MPNSTs.

10.
Cancer Epidemiol ; 54: 90-94, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29684801

RESUMO

BACKGROUND: Racial predilection to pediatric cancer exists; however optic pathway glioma (OPG) risk differences by race/ethnicity are undefined. We estimated differences in OPG incidence across racial/ethnic groups in a multi-state cancer surveillance registry in the United States. METHODS: OPG data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rates and rate ratios (IRR) with 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). RESULTS: Data on 709 OPG cases ages 0-19 were abstracted from SEER-18. Minority children experienced lower age-adjusted OPG incidence rates compared to White children (IRRBlack = 0.38, 95% CI: 0.28-0.50; IRRAsian = 0.41, 95% CI: 0.29-0.58; and IRRLatino/a = 0.39, 95% CI: 0.32-0.48). In subgroup analyses among the highest risk age categories (0-4, 5-9), minority children experienced lower incidence rates compared to White children. Specific patterns for Latinos/as also emerged. Latino/a children ages 0-4 experienced the lowest incidence rates of all racial/ethnic groups compared to Whites (0.24 per 100,000 person-years versus 0.66 per 100,000 person-years, respectively), whereas among those ages 5-9, Black and Asian children experienced the lowest incidence rates (0.08 per 100,000 person-years each). CONCLUSIONS: Incidence of OPGs was highest among White children. This study represents one of the largest to assess differences in OPG susceptibility by race/ethnicity. These findings may inform future studies that seek to evaluate modifying factors for this pediatric tumor including tumorigenesis, treatment, outcome, and long-term late effects.

11.
Blood ; 132(1): 89-100, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29632024

RESUMO

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

13.
PLoS One ; 12(8): e0180488, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28817678

RESUMO

We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70-3.14, p = 1.7×10-8 and rs7089424, RR = 2.22, 95% CI = 1.64-3.01, p = 5.2×10-8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63-3.02, p = 9.63×10-8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57-2.88, p = 2.81×10-7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group.


Assuntos
Proteínas de Ligação a DNA/genética , Exoma , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Guatemala , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Texas
14.
Neuro Oncol ; 19(10): 1372-1379, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444219

RESUMO

Background: Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Methods: Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. Results: The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P < 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders. Conclusions: We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.


Assuntos
Neoplasias Cerebelares/terapia , Cisplatino/uso terapêutico , Metilação de DNA/fisiologia , Meduloblastoma/terapia , Quinases Ativadas por p21/metabolismo , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Perda Auditiva/induzido quimicamente , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adulto Jovem , Quinases Ativadas por p21/genética
15.
Pediatr Blood Cancer ; 64(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27896915

RESUMO

BACKGROUND: Lymphoma is one of the most common pediatric malignancies; however, there are few well-established risk factors. Therefore, we investigated if maternal and perinatal characteristics influenced the risk of childhood lymphoma. PROCEDURE: Information on cases (n = 374) diagnosed with lymphoma and born in Texas for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were randomly selected at a ratio of 10 controls per 1 case for the same period of 1995-2011. Unconditional logistic regression was used to generate unadjusted (OR) and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the following histologic subtypes: Hodgkin (HL), Burkitt (BL), and non-BL non-HLs (non-BL NHLs). RESULTS: Overall, our findings indicate specific maternal and perinatal characteristics influence childhood lymphoma risk. Mexico-born mothers were more likely to have offspring who developed BL compared to mothers born in the United States (U.S.; aOR: 2.15; 95% CI: 1.06-4.36). Further, mothers who resided at time of delivery in a county on the U.S.-Mexico border were more likely to give birth to offspring who developed non-BL NHL (aOR: 1.72; 95% CI: 1.11-2.67) compared to mothers not living on the U.S.-Mexico border at time of infant birth. Last, infants born large-for-gestational-age experienced a twofold increase in BL risk (aOR: 2.00; 95% CI: 1.10-3.65). CONCLUSIONS: In this population-based assessment, we confirmed previously reported risk predictors of childhood lymphoma, including sex of infant, while highlighting novel risk factors that warrant assessment in future studies.


Assuntos
Doença de Hodgkin/epidemiologia , Linfoma não Hodgkin/epidemiologia , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , México/epidemiologia , Fatores de Risco , Texas/epidemiologia , Estados Unidos/epidemiologia
16.
Cancer Epidemiol ; 45: 47-57, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27701053

RESUMO

BACKGROUND: MicroRNAs, small non-coding RNAs involved in gene regulation, are implicated in lymphomagenesis. We evaluated whether genetic variations in microRNA coding regions, binding sites, or biogenesis genes (collectively referred to as miRNA-SNPs) were associated with risk of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), and serum levels of four lymphoma-related microRNAs. METHODS: Twenty-five miRNA-SNPs were genotyped in 180 AIDS-NHL cases and 529 HIV-infected matched controls from the Multicenter AIDS Cohort Study (MACS), and real-time polymerase chain reaction was used to quantify serum microRNA levels. Adjusted odds ratios (ORs) estimated using conditional logistic regression evaluated associations between miRNA-SNPs and AIDS-NHL risk. A semi-Bayes shrinkage approach was employed to reduce likelihood of false-positive associations. Adjusted mean ratios (MR) calculated using linear regression assessed associations between miRNA-SNPs and serum microRNA levels. RESULTS: DDX20 rs197412, a non-synonymous miRNA biogenesis gene SNP, was associated with AIDS-NHL risk (OR=1.34 per minor allele; 95% CI: 1.02-1.75), and higher miRNA-222 serum levels nearing statistical significance (MR=1.21 per minor allele; 95% CI: 0.98-1.49). MiRNA-196a2 rs11614913 was associated with decreased central nervous system (CNS) AIDS-NHL (CT vs. CC OR=0.52; 95% CI: 0.27-0.99). The minor allele of HIF1A rs2057482, which creates a miRNA-196a2 binding site, was associated with systemic AIDS-NHL risk (OR=1.73 per minor allele; 95% CI: 1.12-2.67), and decreased CNS AIDS-NHL risk (OR=0.49 per minor allele; 95% CI: 0.25-0.94). CONCLUSIONS: This study suggests that a few miRNA-SNPs are associated with AIDS-NHL risk and may modulate miRNA expression. These results support a role for miRNA in AIDS-NHL and may highlight pathways to be targeted for risk stratification or therapeutics.


Assuntos
Predisposição Genética para Doença , Linfoma Relacionado a AIDS/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Cancer ; 122(23): 3697-3704, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27529658

RESUMO

BACKGROUND: Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility. METHODS: The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used. RESULTS: Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10-6 ): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10-5 ]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10-5 ]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10-4 ]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10-4 ; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10-5 ). CONCLUSIONS: In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.


Assuntos
Linfócitos B/patologia , Exoma/genética , Predisposição Genética para Doença/genética , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
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