San Francisco childcare centers' preparedness in the prevention and management of asthma among preschool-aged children.

INTRODUCTION: Asthma is a common health condition for children in childcare. National recommendations for asthma in childcare exist. However, no studies have investigated the extent to which childcare centers adhere to these recommendations. We aimed to assess childcare center adherence to National Asthma Education and Prevention Program (NAEPP) recommendations for asthma care and preparedness and to identify characteristics associated with increased adherence to national asthma recommendations. METHODS: We developed a standardized instrument. Each childcare center received a score of 0 through 7 based on number of recommendations met. We conducted t-tests, chi square tests and linear regression to identify childcare center factors associated with increased asthma preparedness. RESULTS: 36 out of 40 eligible childcare centers (90%) participated. These sites served 1570 children primarily between the ages of 2 to 5 years. On average, centers met 3.8 out of 7 (SD = 1.3) recommendations. Staff familiarity caring for children with asthma (p < 0.001) and the center's asthma prevalence (p = 0.01) was positively associated with the center's asthma preparedness. The 3 areas most in need of improvement related to asthma medications, asthma action plans and asthma policies. None of the managers reported being familiar with the NAEPP recommendations. DISCUSSION: There is room for improvement in the asthma care and preparedness of childcare centers. The 3 areas in which centers performed poorly (appropriate asthma medication management, use of asthma action plans, and presence of appropriate asthma policies) suggest that closer collaboration between clinicians and childcare centers may be a key to improving asthma management for young children.

PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium.

Many common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10(-11)), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10(-9)) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma.

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (OR(combined)  = 0.64, P(combined)  = 2 × 10(-21)) located 962 bp away from rs10484561 (r(2)<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR(adjusted)  = 0.70, P(adjusted)  =  4 × 10(-12); rs10484561:OR(adjusted)  = 1.64, P(adjusted)  = 5 × 10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR(combined)  = 1.36, P(combined)  =  1.4 × 10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Polymorphisms and haplotypes in the cytochrome P450 17A1, prolactin, and catechol-O-methyltransferase genes and non-Hodgkin lymphoma risk.

Expression of prolactin and of prolactin and estrogen receptors in lymphocytes, bone marrow, and lymphoma cell lines suggests that hormonal modulation may influence lymphoma risk. Prolactin and estrogen promote the proliferation and survival of B cells, factors that may increase non-Hodgkin lymphoma risk, and effects of estrogen may be modified by catechol-O-methyltransferase (COMT), an enzyme that alters estrogenic activity. Cytochrome P450 17A1 (CYP17A1), a key enzyme in estrogen biosynthesis, has been associated with increased cancer risk and may affect lymphoma susceptibility. We studied the polymorphisms prolactin (PRL) -1149G>T, CYP17A1 -34T>C, and COMT 108/158Val>Met, and predicted haplotypes among a subset of participants (n = 308 cases, n = 684 controls) in a San Francisco Bay Area population-based non-Hodgkin lymphoma study (n = 1,593 cases, n = 2,515 controls) conducted from 1988 to 1995. Oral contraceptive and other hormone use also was analyzed. Odds ratios (OR) for non-Hodgkin lymphoma and follicular lymphoma were reduced for carriers of the PRL -1149TT genotype [OR, 0.64; 95% confidence interval (95% CI), 0.41-1.0; OR, 0.53; 95% CI, 0.26-1.0, respectively]. Diffuse large-cell lymphoma risk was increased for those with CYP17A1 polymorphisms including CYP17A1 -34CC (OR, 2.0; 95% CI, 1.1-3.5). ORs for all non-Hodgkin lymphoma and follicular lymphoma among women were decreased for COMT IVS1 701A>G [rs737865; variant allele: OR, 0.53; 95% CI, 0.34-0.82; OR, 0.42; 95% CI, 0.23-0.78, respectively]. Compared with never users of oral contraceptives, a 35% reduced risk was observed among oral contraceptive users in the total population. Reduced ORs for all non-Hodgkin lymphoma were observed with use of exogenous estrogens among genotyped women although 95% CIs included unity. These results suggest that PRL, CYP17A1, and COMT may be relevant genetic loci for non-Hodgkin lymphoma and indicate a possible role for prolactin and estrogen in lymphoma pathogenesis.

Polymorphisms in ghrelin and neuropeptide Y genes are associated with non-Hodgkin lymphoma.

We previously reported a positive association among body mass index, single nucleotide polymorphisms (SNP) in the leptin and leptin receptor genes that are involved in body weight regulation, and non-Hodgkin lymphoma (NHL). Polymorphisms in the ghrelin (GHRL) and neuropeptide Y (NPY) genes were examined in the same population-based case-control study of NHL to further explore the role of genes involved in energy homeostasis and obesity in susceptibility to NHL. Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin. NPY is a potent appetite stimulator controlled by ghrelin and leptin and also acts as a mediator of immune function. DNA from 458 cases and 812 controls was genotyped. Among genotyped GHRL SNPs, the variant allele for GHRL -4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74). Another SNP, GHRL 5179A>G, decreased the risk of DLCL (homozygous variant: OR, 0.35; 95% CI, 0.10-1.2). NPY -485T>C, 1258G>A, and 5671C>T were in total linkage disequilibrium (D' = 0.99) and the homozygous variants were associated with an increased risk of NHL in NPY SNPs -485T>C (OR, 1.7; 95% CI, 1.1-2.5), 1258G>A (OR, 1.7; 95% CI, 1.1-2.5), and 5671C>T (OR, 1.9; 95% CI, 1.3-2.8). When stratified by subtype, the variant allele for NPY 1128T>C was positively associated with follicular lymphoma (OR, 2.3; 95% CI, 1.1-4.9) as were homozygous variants for NPY SNPs -485T>C (OR, 2.4; 95% CI, 1.3-4.4), 1258G>A (OR, 2.0; 95% CI, 1.1-3.5), and 5671C>T (OR, 1.8; 95% CI, 1.1-3.0). These results add further support for the hypothesis that SNPs in energy-regulating genes affect risk of NHL.

Development of a Tool to Evaluate Asthma Preparedness and Management in Child-Care Centers.

Introduction: Asthma is a common condition affecting many children in child-care centers. The National Asthma Education and Prevention Program offers recommendations about creating an asthma-friendly child-care setting. However, no studies have investigated the extent to which child-care centers adhere to these recommendations. This study describes the development of a novel instrument to determine the ability of child-care centers to meet national recommendations for asthma. Methods: The Preparing for Asthma in Child Care (PACC) Instrument was developed using information from existing recommendations and standards, the peer-reviewed literature, site visits, and expert interviews. The survey questions were pilot-tested at 36 child-care centers throughout San Francisco. Results: The instrument is composed of 43 items across seven domains: smoking exposure, presence of a medical consultant and policies, management of ventilation and triggers, access to medication, presence of asthma action plans, staff training, and encouragement of physical activity. Discussion: The PACC Instrument is an evidence-based and comprehensive tool designed to identify areas to target to improve asthma care for children in child-care centers.

Chemokine polymorphisms and lymphoma: a pooled analysis.

Polymorphisms in chemokine genes have been associated with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) but are understudied in non-HIV-related NHL. Associations of NHL and NHL subtypes with polymorphisms and haplotypes in CCR5, CCR2, CCL5, CXCL12, and CX(3)CR(1) were explored in a pooled analysis of three case-control studies (San Francisco Bay Area, California; United Kingdom; total: cases N = 1610, controls N = 1992). Adjusted unconditional logistic regression was used to estimate relative risks among HIV-negative non-Hispanic Caucasians. The CCR5 Delta32 deletion reduced the risk of NHL (odds ratio = 0.56, 95% confidence interval = 0.38-0.83) in men but not women with similar effects observed for diffuse large-cell and follicular lymphoma (FL). NHL risk also was reduced in men with the CCR2/CCR5 haplotype characterized by the CCR5 Delta32 deletion. The CCL5 -403A allele conferred reduced risks of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma. Results should be interpreted conservatively. Continued investigation is warranted to confirm these findings.

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma.

We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL; N = 189 cases, 592 controls) with validation in another 456 FL cases and 2,785 controls (combined allelic P = 4.7 x 10(-11)). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1).

A functional TNFRSF5 gene variant is associated with risk of lymphoma.

CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in humoral and cellular immunity. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFRSF5 and TNFSF5 encoding the CD40 and CD154 proteins, respectively, influence lymphoma risk, particularly a functional TNFRSF5 SNP (-1C>T, rs1883832) associated with reduced B-cell CD40 expression. TNFRSF5 and TNFSF5 SNPs were examined in a population-based case-control study of non-Hodgkin lymphoma (376 cases/801 controls with DNA), and compelling findings were followed up in 2 independent populations. Pooled analyses of all 3 case-control studies (total N = 1776 non-Hodgkin lymphoma cases, N = 2482 controls) revealed an increased risk of follicular lymphoma (FL) associated with the TNFRSF5 -1TT genotype (odds ratio = 1.6; 95% confidence interval, 1.1-2.4). In addition, among women, an inverse association was found between the variant A allele for a TNFSF5 6809G>A SNP and FL risk (OR = .61; 95% CI, 0.36-0.98). In genotype-phenotype studies, significantly reduced circulating soluble CD40 was observed in TNFRSF5 -1TT compared with -1CC carriers. Further, dendritic cells from those with -1TT versus -1CC genotypes exhibited lower CD40 cell surface expression. These results suggest that the TNFRSF5 -1C>T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings.

Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. CONCLUSIONS/SIGNIFICANCE: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation.

Polymorphisms in cytochrome P450 17A1 and risk of non-Hodgkin lymphoma.

Broad cross-talk exists between the endocrine and immune systems. Estrogen receptor expression in lymphocytes suggests that hormonal modulation may influence lymphoma risk. Analysis of genetic polymorphisms that affect oestrogen production, such as cytochrome P450 17A1 (CYP17A1) -34T>C, may provide insight into oestrogen's role in lymphomagenesis. CYP17A1-34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non-Hodgkin lymphoma (NHL) population-based case-control study. The CYP17A1-34CC genotype was positively associated with NHL [odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.02-2.03], particularly diffuse large B-cell lymphoma (OR = 1.76, CI 1.14-2.71). Associations of CYP17A1 polymorphisms with increased risk of NHL suggest a role for oestrogen in lymphomagenesis.

Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma.

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL.