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1.
Clin Infect Dis ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33031500

RESUMO

BACKGROUND: Remdesivir is efficacious for severe COVID-19 in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. METHODS: Reported data span March 21 to June 16, 2020 for hospitalized pregnant women with PCR-confirmed SARS-CoV-2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200mg on Day 1, followed by 100mg for Days 2-10, given intravenously). RESULTS: Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day=1; range 0-3). At baseline, 40% of pregnant women (median gestational age 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By Day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to pregnancy and underlying disease; most laboratory abnormalities were Grades 1 or 2. There was one maternal death attributed to underlying disease and no neonatal deaths. CONCLUSIONS: Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate use remdesivir, recovery rates were high, with a low rate of serious adverse events.

3.
Clin Infect Dis ; 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32706859

RESUMO

BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe COVID-19 using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard-of-care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed SARS-CoV-2 infection, were hospitalized, had oxygen saturation 94% or lower on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard-of-care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio 2.03: 95% confidence interval 1.34-3.08, p<0.001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (adjusted odds ratio 0.38, 95% confidence interval: 0.22-0.68, p=0.001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19.

4.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

5.
J Natl Cancer Inst ; 109(8)2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29117387

RESUMO

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 22 , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino
6.
Nat Commun ; 7: 10979, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052111

RESUMO

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.


Assuntos
Afro-Americanos , Epigênese Genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Padrões de Herança , Neoplasias da Próstata/genética , Acetilação , Atlas como Assunto , Linhagem Celular Tumoral , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia
7.
Cancer Epidemiol Biomarkers Prev ; 25(5): 815-22, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26941364

RESUMO

BACKGROUND: The incidence of acute lymphoblastic leukemia (ALL) is nearly 20% higher among Hispanics than non-Hispanic Whites. Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes. However, variants identified only account for <10% of the genetic risk of ALL. METHODS: We applied pathway-based analyses to genome-wide association study (GWAS) data from the California Childhood Leukemia Study to determine whether different biologic pathways were overrepresented in childhood ALL and major ALL subtypes. Furthermore, we applied causal inference and data reduction methods to prioritize candidate genes within each identified overrepresented pathway, while accounting for correlation among SNPs. RESULTS: Pathway analysis results indicate that different ALL subtypes may involve distinct biologic mechanisms. Focal adhesion is a shared mechanism across the different disease subtypes. For ALL, the top five overrepresented Kyoto Encyclopedia of Genes and Genomes pathways include axon guidance, protein digestion and absorption, melanogenesis, leukocyte transendothelial migration, and focal adhesion (PFDR < 0.05). Notably, these pathways are connected to downstream MAPK or Wnt signaling pathways which have been linked to B-cell malignancies. Several candidate genes for ALL, such as COL6A6 and COL5A1, were identified through targeted maximum likelihood estimation. CONCLUSIONS: This is the first study to show distinct biologic pathways are overrepresented in different ALL subtypes using pathway-based approaches, and identified potential gene candidates using causal inference methods. IMPACT: The findings demonstrate that newly developed bioinformatics tools and causal inference methods can provide insights to furthering our understanding of the pathogenesis of leukemia. Cancer Epidemiol Biomarkers Prev; 25(5); 815-22. ©2016 AACR.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos de Casos e Controles , Genótipo , Humanos , Pessoa de Meia-Idade
8.
J Natl Cancer Inst ; 108(7)2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26823525

RESUMO

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Estados Unidos/epidemiologia
9.
Ann Epidemiol ; 26(2): 141-145, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26795698

RESUMO

PURPOSE: The purpose of the study was to examine whether birth characteristics affect the risk of rhabdomyosarcoma (RMS) in children and adolescents younger than 19 years. METHODS: A total of 722 RMS cases diagnosed at the age of 0-19 years during 1988-2011 were identified from the California Cancer Registry and matched by birth date, sex, and race to 2,888 controls using California birth records. Conditional logistic regression was used to estimate the risk of RMS associated with birth weight, gestational age, and size for gestational age. RESULTS: High birth weight (odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.78-1.29) and large for gestational age (LGA; OR: 0.94, 95% CI: 0.72-1.23) were not associated with RMS risk overall. Among non-Hispanic whites, the ORs were 1.33 for high birth weight (95% CI: 0.94-1.89) and 1.17 for LGA (95% CI: 0.78-1.75); no indications of association were observed for other racial or ethnic groups (P interaction <.10). Compared with normal gestational age, preterm (<37 weeks) and post-term (>40 weeks) babies had 16%-18% lower risks of RMS overall, after adjusting for birth weight. CONCLUSIONS: In the largest study to date, there was an indication of association between high birth weight, LGA, and increased RMS risk among non-Hispanic white children and adolescents, but not in other racial or ethnic groups.


Assuntos
Peso ao Nascer , Desenvolvimento Fetal , Idade Gestacional , Rabdomiossarcoma/epidemiologia , Adolescente , California/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Rabdomiossarcoma/etnologia , Adulto Jovem
10.
Hum Mol Genet ; 24(19): 5603-18, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26162851

RESUMO

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Mapeamento Cromossômico/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Anotação de Sequência Molecular , Neoplasias da Próstata/etnologia , Locos de Características Quantitativas
11.
Cancer Causes Control ; 26(4): 609-19, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25761407

RESUMO

BACKGROUND: Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections). METHODS: Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term. RESULTS: Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed. CONCLUSIONS: Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas de Ligação a DNA/genética , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Alelos , California , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Lactente , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia
12.
J Urol ; 192(3): 730-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24747091

RESUMO

PURPOSE: To our knowledge the reasons for the high rates of prostate cancer in black American men are unknown. Genetic and lifestyle factors have been implicated. Better understanding of prostate cancer rates in West African men would help clarify why black American men have such high rates since the groups share genetic ancestry and yet have different lifestyles and screening practices. To estimate the prostate cancer burden in West African men we performed a population based screening study with biopsy confirmation in Ghana. MATERIALS AND METHODS: We randomly selected 1,037 healthy men 50 to 74 years old from Accra, Ghana for prostate cancer screening with prostate specific antigen testing and digital rectal examination. Men with a positive screen result (positive digital rectal examination or prostate specific antigen greater than 2.5 ng/ml) underwent transrectal ultrasound guided biopsies. RESULTS: Of the 1,037 men 154 (14.9%) had a positive digital rectal examination and 272 (26.2%) had prostate specific antigen greater than 2.5 ng/ml, including 166 with prostate specific antigen greater than 4.0 ng/ml. A total of 352 men (33.9%) had a positive screen by prostate specific antigen or digital rectal examination and 307 (87%) underwent biopsy. Of these men 73 were confirmed to have prostate cancer, yielding a 7.0% screen detected prostate cancer prevalence (65 patients), including 5.8% with prostate specific antigen greater than 4.0 ng/ml. CONCLUSIONS: In this relatively unscreened population in Africa the screen detected prostate cancer prevalence is high, suggesting a possible role of genetics in prostate cancer etiology and the disparity in prostate cancer risk between black and white American men. Further studies are needed to confirm the high prostate cancer burden in African men and the role of genetics in prostate cancer etiology.


Assuntos
Grupo com Ancestrais do Continente Africano , Neoplasias da Próstata/epidemiologia , Afro-Americanos , Idoso , Gana , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Antígeno Prostático Específico
13.
Am J Hematol ; 89(7): 721-5, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24753091

RESUMO

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL.


Assuntos
Hispano-Americanos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etnologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores Etários , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Hispano-Americanos/estatística & dados numéricos , Humanos , Incidência , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Estados Unidos/epidemiologia
14.
Blood ; 123(16): 2497-503, 2014 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-24518758

RESUMO

Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.


Assuntos
Genes MHC Classe I/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores KIR/fisiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Antígenos HLA-B/genética , Haplótipos , Humanos , Ligantes , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores KIR/genética
15.
Front Oncol ; 3: 300, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24377085

RESUMO

The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL), is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2-5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (MHC), an approximately 7.6 Mb region that is well-known for its high-density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA). First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C) and class II (HLA-DR, HLA-DQ, and HLA-DP) molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk.

17.
PLoS One ; 8(8): e72557, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23991122

RESUMO

The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.


Assuntos
Leucemia de Células B/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino
18.
Cancer Causes Control ; 24(10): 1789-95, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23836053

RESUMO

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case-control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10(-9) to 0.004) and NHWs (p values of 2.2 × 10(-6) to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53-1.99 and 1.37-1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (>50 chromosomes; ORs of 2.21-3.22 and 1.67-2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p < 1 × 10(-5)), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas de Ligação a DNA/genética , Hispano-Americanos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , California , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Fatores de Transcrição/metabolismo
20.
Cancer Epidemiol Biomarkers Prev ; 22(6): 1088-94, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23576692

RESUMO

BACKGROUND: A role for folate in cancer etiology has long been suspected because of folate's function as a cofactor in DNA methylation and maintenance of DNA synthesis. Previous case-control studies examining the association between risk of childhood acute lymphoblastic leukemia (ALL) and mothers' self-reported folate intake and supplementation have been inconclusive. MATERIALS AND METHODS: We used a quantitative microbiologic assay to measure newborn folate concentrations in archived dried bloodspots collected at birth from 313 incident ALL cases, 44 incident acute myeloid leukemia (AML) cases, and 405 matched population-based controls. RESULTS: Overall, we found no difference in hemoglobin-normalized newborn folate concentrations (HbFol, nmol/g) between ALL cases and controls (2.76 vs. 2.77, P = 0.97) or between AML cases and controls (2.93 vs. 2.76, P = 0.32). Null results persisted after stratification by both birth period (1982-94, 1995-98, and 1999-2002) to account for the start of folate fortification of grain products in the United States, and by self-reported maternal prepregnancy supplement use. Similarly, no association was observed for major ALL subgroups. CONCLUSIONS: Our results do not support an association between birth folate concentrations and risk of childhood AML or major ALL subgroups. IMPACT: However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development.


Assuntos
Ácido Fólico/sangue , Leucemia Mieloide Aguda/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Suplementos Nutricionais , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/sangue , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Prognóstico , Fatores de Tempo
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