A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium.

There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.

A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians.

The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >or= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P(adj) = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.

A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk.

Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2) , pancreatic cancer risk was 47% higher (95%CI:23-75%) among obese (BMI ≥ 30 kg/m(2) ) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI ≥ 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2) ). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2) ) and not obese at baseline (BMI < 30 kg/m(2) ), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI ≥ 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.

Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure-response relationship.

BACKGROUND: Fine particulate matter exposure from both ambient air pollution and secondhand cigarette smoke has been associated with larger risks of cardiovascular mortality than would be expected on the basis of linear extrapolations of the relative risks from active smoking. This study directly assessed the shape of the exposure-response relationship between cardiovascular mortality and fine particulates from cigarette smoke and ambient air pollution. METHODS AND RESULTS: Prospective cohort data for >1 million adults were collected by the American Cancer Society as part of the Cancer Prevention Study II in 1982. Cox proportional hazards regression models that included variables for increments of cigarette smoking and variables to control for education, marital status, body mass, alcohol consumption, occupational exposures, and diet were used to describe the mortality experience of the cohort. Adjusted relative risks of mortality were plotted against estimated average daily dose of fine particulate matter from cigarette smoke along with comparison estimates for secondhand cigarette smoke and air pollution. There were substantially increased cardiovascular mortality risks at very low levels of active cigarette smoking and smaller but significant excess risks even at the much lower exposure levels associated with secondhand cigarette smoke and ambient air pollution. CONCLUSIONS: Relatively low levels of fine particulate exposure from either air pollution or secondhand cigarette smoke are sufficient to induce adverse biological responses increasing the risk of cardiovascular disease mortality. The exposure-response relationship between cardiovascular disease mortality and fine particulate matter is relatively steep at low levels of exposure and flattens out at higher exposures.

SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer.

Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.

Body mass index and risk of suicide among one million US adults.

BACKGROUND: Body mass index (BMI) has been linked with both increased and decreased risk of suicide attempts and deaths. METHODS: In a prospective cohort study of 1.1 million adults, participants reported their anthropometric and other characteristics in 1982. Participants were followed for cause-specific mortality through 2004. RESULTS: A total of 2231 participants died of suicide during 21.6 million person-years of follow-up. Compared with a BMI of 18.5-22.9 kg/m(2), adjusted hazard ratios for completed suicide were 0.99 (95% confidence interval = 0.72-1.37), 0.78 (0.69-0.88), 0.73 (0.65-0.82), 0.72 (0.62-0.83), 0.77 (0.65-0.92), and 0.55 (0.36-0.83) for BMI values <18.5, 23.0-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9, and >or=35.0 kg/m(2), respectively. The relationship was consistent among men and women and across geographic regions, but was limited to married individuals (test for interaction, P = 0.009). CONCLUSIONS: The risk of death from suicide is inversely related to BMI in middle-aged and older adults.

Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort.

INTRODUCTION: Vitamin D status measured during adulthood has been inversely associated with breast cancer risk in some, but not all, studies. Vitamin D has been hypothesized to prevent breast cancer through genomic and non-genomic actions in cell-cycle regulation. METHODS: A subset (n = 21,965) of female participants from the prospective Cancer Prevention Study-II (CPS-II) Nutrition Cohort provided a blood sample from 1998-2001 and were followed through 2005. We measured serum 25-hydroxyvitamin D (25(OH)D) in 516 verified incident cases and 516 controls, matched on birth date (+/- 6 months), date of blood draw (+/- 6 months) and race. Information on medical history, risk factors and lifestyle was available from repeated questionnaires. We computed multi-variable odds ratios (OR) and 95% confidence intervals (95% CI) for the association between 25(OH)D quintile and breast cancer risk using unconditional logistic regression, controlling for matching factors and additional confounders. RESULTS: We observed no association between 25(OH)D and breast cancer (OR = 1.09, 95% CI 0.70-1.68, P = 0.60) for the top vs bottom quintile. Using a priori cut-points, the OR was 0.86 (95% CI 0.59-1.26), for > or =75 vs <50 nmol/L. Results were not different when the first two years of follow-up were excluded, or in analyses stratified by season, latitude, BMI, postmenopausal hormone use, or by tumor grade or estrogen receptor status. CONCLUSIONS: These results do not support an association between adulthood serum 25(OH)D and postmenopausal breast cancer. We cannot rule out an association with 25(OH)D status earlier in life.

Suicide among US veterans: A prospective study of 500,000 middle-aged and elderly men.

Expert opinion is divided about whether US military veterans, the vast majority of whom are middle-aged or older, are at increased risk of suicide. To assess the risk of suicide associated with veteran status, the authors conducted a prospective cohort study of 499,356 male participants in the Cancer Prevention Study II. Participants reported their veteran status and other characteristics in 1982 and were followed for mortality through 2004. The relative risk of mortality from suicide according to veteran status at baseline was estimated by using Cox proportional hazards models. During follow-up, 1,248 veterans and 614 nonveterans died by suicide. In age-adjusted analyses, the risk of suicide did not differ by veteran status. Additional adjustment for several sociodemographic, behavioral, and clinical factors had little effect on hazard ratios. The authors concluded that the risk of death from suicide among middle-aged and older US males is independent of veteran status and suggest that policies to prevent veteran suicide should focus on factors that may heighten suicide risk rather than on veteran status per se.

Comparing methods for accounting for seasonal variability in a biomarker when only a single sample is available: insights from simulations based on serum 25-hydroxyvitamin d.

In biomarker-disease association studies, the long-term average level of a biomarker is often considered the optimal measure of exposure. Long-term average levels may not be accurately measured from a single sample, however, because of systematic temporal variation. For example, serum 25-hydroxyvitamin D (25(OH)D) concentrations may fluctuate because of seasonal variation in sun exposure. Association studies of 25(OH)D and cancer risk have used different strategies to minimize bias from such seasonal variation, including adjusting for date of sample collection (DOSC), often after matching on DOSC, and/or using season-specific cutpoints to assign subjects to exposure categories. To evaluate and understand the impact of such strategies on potential bias, the authors simulated a population in which 25(OH)D levels varied between individuals and by season, and disease risk was determined by long-term average 25(OH)D. Ignoring temporal variation resulted in bias toward the null. When cutpoints that did not account for DOSC were used, adjustment for DOSC sometimes resulted in bias away from the null. Using season- or month-specific cutpoints reduced bias toward the null and did not cause bias away from the null. To avoid potential bias away from the null, using season- or month-specific cutpoints may be preferable to adjusting for DOSC.

Dietary intake of omega-6 and omega-3 fatty acids and risk of colorectal cancer in a prospective cohort of U.S. men and women.

BACKGROUND: omega-6 and omega-3 polyunsaturated fatty acids intakes may play opposing roles in inflammation-driven colorectal carcinogenesis. We examined the relationship of these polyunsaturated fatty acids and the ratio of their intake with colorectal cancer risk in a large U.S. prospective cohort. DESIGN: Participants in the Cancer Prevention Study-II Nutrition Cohort completed a detailed questionnaire on diet, medical history, and lifestyle in 1999. Between 1999 and 2005, 869 incident colorectal cancer cases (452 men and 417 women) were identified among 99,080 participants (43,108 men and 55,972 women). Multivariate-adjusted rate ratios were calculated using Cox proportional hazards models. RESULTS: The ratio of total omega-6 to total omega-3 intake was not associated with colorectal cancer risk in either sex. Contrary to our initial hypothesis, total omega-6 intake was inversely related to colorectal cancer risk in men [multivariate relative risk (95% confidence interval) for highest to lowest quartile, 0.81 (0.61-1.07); P(trend) = 0.07], and alpha-linolenic acid, the primary contributor to total omega-3 intake, was associated with increased risk in women for quartiles 2 through 4 versus the lowest quartile [relative risk (95% confidence interval), 1.50 (1.12-2.01), 1.40 (1.04-1.87), and 1.38 (1.02-1.85), respectively; P(trend) = 0.13]. In women, total omega-6 and marine omega-3 intake appeared to be associated with higher and lower risk, respectively, but associations were attenuated with adjustment for other risk factors. CONCLUSIONS: The ratio of omega-6 to omega-3 intake was not related to colorectal cancer risk in this cohort, which may be due to unexpected findings for the individual components. Differential associations by sex warrant further investigation.

Vitamin D receptor polymorphisms and breast cancer risk: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

BACKGROUND: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability. METHODS: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression. RESULTS: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1.16; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.10; 95% CI, 0.98-1.24). No association was noted between rs1544410 (BsmI) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). CONCLUSIONS: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status.

Use of blood-pressure-lowering medication and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

OBJECTIVES: To examine the association between use of anti-hypertensive drugs and prostate cancer incidence among 48,389 men in the Cancer Prevention Study II Nutrition Cohort. METHODS: Proportional hazards models were used to calculate rate ratios (RR) for use of Beta-Blockers (BBs), Calcium Channel Blockers (CCBs), and ACE Inhibitors (ACE) and incident prostate cancer in time-dependent analyses. RESULTS: During follow-up from 1997 to 2005, we identified 3,031 cases of incident prostate cancer. Anti-hypertensive use was associated with slightly decreased risk of all (RR = 0.90, 95% CI 0.83-0.98) and organ-confined low-grade prostate cancer (RR = 0.89, 95% CI 0.81-0.99), but was not statistically significantly associated with aggressive-fatal prostate cancer (RR = 0.93, 95% CI 0.79-1.10). BB and ACE inhibitor treatment was associated with an approximately 10% lower risk for all prostate cancer in models adjusted for age and race. These associations were attenuated and lost statistical significance when adjusted for history of heart disease. No trend with duration of use was detected. CONCLUSIONS: These results do not support the hypothesis that anti-hypertensive medication is strongly associated with risk of prostate cancer. Confounding by concurrent illness may explain inverse associations seen in other studies.

Family history of various cancers and pancreatic cancer mortality in a large cohort.

A family history of pancreatic cancer is associated with increased risk of pancreatic cancer, but uncertainty remains about the magnitude of this association, whether it varies by age or smoking and whether a family history of other cancers may also be associated with increased risk. We examined family history of 14 cancers and pancreatic cancer mortality among ~1.1 million men and women in Cancer Prevention Study-II (CPS-II). CPS-II participants completed a questionnaire at enrollment in 1982. During follow-up through 2006, there were 7,306 pancreatic cancer deaths. A family history of pancreatic cancer in a parent or sibling was associated with pancreatic cancer mortality [multivariable adjusted rate ratio (RR) = 1.66, 95% confidence interval (CI) 1.43-1.94]. This association was stronger among participants aged under 60 (RR = 2.89, 95% CI 1.67-5.02) than among participants aged 60 or older (RR = 1.61, 95% CI 1.37-1.88). Weaker associations were observed for family history of stomach cancer (RR = 1.23, 95% CI 1.11-1.37), liver cancer (RR = 1.25, 95% CI 1.10-1.43), and colorectal cancer (RR = 1.12, 95% CI 1.01-1.23). Results from this large prospective study indicate family history of pancreatic cancer is associated with a moderate increase in risk of pancreatic cancer, and also identify associations with the family history of certain other cancers which may be useful in generating hypotheses about shared risk factors.

Ambient air pollution and brain cancer mortality.

OBJECTIVE: Growing evidence that ultrafine particles in ambient air can cause brain lesions in animals led us to investigate whether particulate components of air pollution may be associated with brain cancer risk in humans. Air pollution has been associated with respiratory disorders and cardiovascular morbidity and mortality, but associations between air pollutants and brain cancer have not been investigated in adults. METHODS: The analyses included 1,284 deaths due to brain cancer from the Cancer Prevention Study-II, an ongoing prospective mortality study of adults in the United States and Puerto Rico conducted by the American Cancer Society. Air pollution data from national databases for metropolitan areas were combined with residential history and vital status data to estimate exposure to particulate and gaseous air pollution. RESULTS: We found no elevated risk for estimated measures of air pollutants, an unanticipated reduction in risk was found between gaseous air pollutants and brain cancer mortality. CONCLUSION: The findings do not provide evidence of increased risk of brain cancer mortality due to air pollutants.

Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).

BACKGROUND: Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). METHODS: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. RESULTS: Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. CONCLUSION: Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

Extended follow-up and spatial analysis of the American Cancer Society study linking particulate air pollution and mortality.

We conducted an extended follow-up and spatial analysis of the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) cohort in order to further examine associations between long-term exposure to particulate air pollution and mortality in large U.S. cities. The current study sought to clarify outstanding scientific issues that arose from our earlier HEI-sponsored Reanalysis of the original ACS study data (the Particle Epidemiology Reanalysis Project). Specifically, we examined (1) how ecologic covariates at the community and neighborhood levels might confound and modify the air pollution-mortality association; (2) how spatial autocorrelation and multiple levels of data (e.g., individual and neighborhood) can be taken into account within the random effects Cox model; (3) how using land-use regression to refine measurements of air pollution exposure to the within-city (or intra-urban) scale might affect the size and significance of health effects in the Los Angeles and New York City regions; and (4) what exposure time windows may be most critical to the air pollution-mortality association. The 18 years of follow-up (extended from 7 years in the original study [Pope et al. 1995]) included vital status data for the CPS-II cohort (approximately 1.2 million participants) with multiple cause-of-death codes through December 31, 2000 and more recent exposure data from air pollution monitoring sites for the metropolitan areas. In the Nationwide Analysis, the influence of ecologic covariate data (such as education attainment, housing characteristics, and level of income; data obtained from the 1980 U.S. Census; see Ecologic Covariates sidebar on page 14) on the air pollution-mortality association were examined at the Zip Code area (ZCA) scale, the metropolitan statistical area (MSA) scale, and by the difference between each ZCA value and the MSA value (DIFF). In contrast to previous analyses that did not directly include ecologic covariates at the ZCA scale, risk estimates increased when ecologic covariates were included at all scales. The ecologic covariates exerted their greatest effect on mortality from ischemic heart disease (IHD), which was also the health outcome most strongly related with exposure to PM2.5 (particles 2.5 microm or smaller in aerodynamic diameter), sulfate (SO4(2-)), and sulfur dioxide (SO2), and the only outcome significantly associated with exposure to nitrogen dioxide (NO2). When ecologic covariates were simultaneously included at both the MSA and DIFF levels, the hazard ratio (HR) for mortality from IHD associated with PM2.5 exposure (average concentration for 1999-2000) increased by 7.5% and that associated with SO4(2-) exposure (average concentration for 1990) increased by 12.8%. The two covariates found to exert the greatest confounding influence on the PM2.5-mortality association were the percentage of the population with a grade 12 education and the median household income. Also in the Nationwide Analysis, complex spatial patterns in the CPS-II data were explored with an extended random effects Cox model (see Glossary of Statistical Terms at end of report) that is capable of clustering up to two geographic levels of data. Using this model tended to increase the HR estimate for exposure to air pollution and also to inflate the uncertainty in the estimates. Including ecologic covariates decreased the variance of the results at both the MSA and ZCA scales; the largest decrease was in residual variation based on models in which the MSA and DIFF levels of data were included together, which suggests that partitioning the ecologic covariates into between-MSA and within-MSA values more completely captures the sources of variation in the relationship between air pollution, ecologic covariates, and mortality. Intra-Urban Analyses were conducted for the New York City and Los Angeles regions. The results of the Los Angeles spatial analysis, where we found high exposure contrasts within the Los Angeles region, showed that air pollution-mortality risks were nearly 3 times greater than those reported from earlier analyses. This suggests that chronic health effects associated with intra-urban gradients in exposure to PM2.5 may be even larger between ZCAs within an MSA than the associations between MSAs that have been previously reported. However, in the New York City spatial analysis, where we found very little exposure contrast between ZCAs within the New York region, mortality from all causes, cardiopulmonary disease (CPD), and lung cancer was not elevated. A positive association was seen for PM2.5 exposure and IHD, which provides evidence of a specific association with a cause of death that has high biologic plausibility. These results were robust when analyses controlled (1) the 44 individual-level covariates (from the ACS enrollment questionnaire in 1982; see 44 Individual-Level Covariates sidebar on page 22) and (2) spatial clustering using the random effects Cox model. Effects were mildly lower when unemployment at the ZCA scale was included. To examine whether there is a critical exposure time window that is primarily responsible for the increased mortality associated with ambient air pollution, we constructed individual time-dependent exposure profiles for particulate and gaseous air pollutants (PM2.5 and SO2) for a subset of the ACS CPS-II participants for whom residence histories were available. The relevance of the three exposure time windows we considered was gauged using the magnitude of the relative risk (HR) of mortality as well as the Akaike information criterion (AIC), which measures the goodness of fit of the model to the data. For PM2.5, no one exposure time window stood out as demonstrating the greatest HR; nor was there any clear pattern of a trend in HR going from recent to more distant windows or vice versa. Differences in AIC values among the three exposure time windows were also small. The HRs for mortality associated with exposure to SO2 were highest in the most recent time window (1 to 5 years), although none of these HRs were significantly elevated. Identifying critical exposure time windows remains a challenge that warrants further work with other relevant data sets. This study provides additional support toward developing cost-effective air quality management policies and strategies. The epidemiologic results reported here are consistent with those from other population-based studies, which collectively have strongly supported the hypothesis that long-term exposure to PM2.5 increases mortality in the general population. Future research using the extended Cox-Poisson random effects methods, advanced geostatistical modeling techniques, and newer exposure assessment techniques will provide additional insight.

Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women.

The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (> or =5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 x 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer.

A common 8q24 variant in prostate and breast cancer from a large nested case-control study.

Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 x 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an OR(AC) = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an OR(AA) = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result.