Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have ...favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy CCRT) or a part of the cycle (sequential estrogen plus progestin therapy SEPRT). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study.
Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided.
HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval CI = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant.
This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.
GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of ...inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10(-4)) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.
Objectives: Since the 1970s incidence rates for esophageal and gastric cardia adenocarcinomas have risen substantially, particularly among white males in the United States. Reasons for the increase ...of these tumor types are not well understood. We sought to determine the role of smoking, alcohol use, and body size characteristics in the etiology of esophageal, gastric cardia, and distal gastric adenocarcinomas. Materials and methods: A population-based case-control study that included Whites, African-Americans, Latinos and Asian-Americans diagnosed with incident esophageal (n = 222), gastric cardia (n = 277), and distal gastric adenocarcinomas (n = 443), and 1356 control subjects was conducted in Los Angeles County. Unconditional logistic regression was used to calculate odds ratios (ORs), as an estimate of the relative risk, and corresponding 95% confidence intervals (CIs) for the three tumor types of interest. Results: After adjustment for age, gender, race, birthplace, and education, current cigarette smoking was a significant risk factor for all tumor types; the association was strongest for esophageal adenocarcinomas (OR = 2.80, 95% CI = 1.8-4.3), intermediate for gastric cardia adenocarcinomas (OR = 2.12, 95% CI = 1.5-3.1), and weaker for distal gastric adenocarcinomas (OR = 1.50, 95% CI = 1.1-2.1). For esophageal adenocarcinomas only, cigarette smoking had a long-lasting deleterious effect, even 20 years after smoking cessation. Alcohol use was not associated with an increased risk of these tumor types. Risks of esophageal and gastric cardia adenocarcinomas also increased statistically significantly in a dose-dependent manner with increasing body mass index measured at ages 20 and 40 years and recently. The positive associations with smoking and body mass index were generally consistent when evaluated separately for Whites, non-Whites, males, and females. Conclusions: Cigarette smoking and high body mass index are significant, independent risk factors for esophageal and gastric cardia adenocarcinomas. Studies designed to understand the mechanisms whereby smoking and high body mass influence these tumor types are needed.
Studies have provided evidence of an inverse association between atopic allergic conditions (AACs) and invasive colorectal cancer (CRC) incidence and mortality in predominantly white populations. We ...examined the association between AACs (asthma, hay fever, or allergy) and CRC among white, African-American, Native Hawaiian, Japanese-American, and Latino men and women in the Multiethnic Cohort Study within Hawaii and Los Angeles, California. The prospective analysis included 4,834 incident CRC cases and 1,363 CRC-related deaths ascertained between 1993 and 2010. We examined associations by ethnicity, location, stage, and potential effect modification by CRC risk factors. AACs were associated with a reduced risk of CRC incidence among both men and women (relative risk (RR) = 0.86, 95% confidence interval (CI): 0.80, 0.92). The reduction in risk was noted in all populations except Latinos and was significant in whites (RR = 0.85, 95% CI: 0.73, 0.98), African Americans (RR = 0.81, 95% CI: 0.70, 0.95), Native Hawaiians (RR = 0.72, 95% CI: 0.54, 0.96), and Japanese Americans (RR = 0.87, 95% CI: 0.78, 0.98). Individuals with AACs also had a 20% reduction in CRC-related mortality (P = 0.001). These findings provide evidence for the potential protective role of the reactive immune system in colorectal cancer.
Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk ...variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio OR >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (Pheterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in ...Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos.
Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894).
No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10(-5) and stage II: OR = 1.58; P = 3.05 × 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10(-25) and OR = 1.07; P = 1.02 × 10(-16) for Japanese and Latinos, respectively).
Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos.
Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of ...unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.
Few data exist on the extent to which the differences in breast cancer risk between "racial-ethnic" groups in the United States (US) are "explained" by differences in their distribution of risk ...factors. We have determined this for African-American (AA), native Hawaiian (NH), Japanese-American (JA), Latina-US-born (L-US), Latina-non-US-born (L-NUS), and white (W) women using prospective incidence data on 88,712 postmenopausal women recruited in 1993-1996. We identified 1,757 incident breast cancer cases through 1999 among these women (1,116 cases after excluding women with a simple hysterectomy or missing risk factor data). Data were available on seven "known" risk factors: ages at menarche and first birth; parity; age at and type of menopause; weight; hormone replacement therapy use; and alcohol consumption. The relative risks (RRs) of breast cancer (with the RR in Ws set to 1.0) for the groups were as follows: W = 1.0; AA = 0.78; NH = 1.33; JA = 0.99; L-US = 0.77; and L-NUS = 0.60. After adjustment for the risk factors, the RRs were as follows: W = 1.0; AA = 0.98; NH = 1.65; JA = 1.11; L-US = 0.95; and L-NUSB = 0.84. The slightly greater risk of the JAs compared with the Ws is in sharp contrast to the very low breast cancer rates that were observed in "traditional" Japanese women and in early Japanese migrants. The adjusted RR of NHs is 65% greater than that of Ws, and that of migrant Latinas is 16% lower than that of Ws. Elucidating the causes of the high rates in NHs is now a major focus of our efforts.
Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease ...susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.
Reports and discusses the result of a study to examine the risk of dying from acute myocardial infarction (AMI) and other heart disease (OHD) among African American (AA), native Hawaiian (NH), ...Japanese-American (JA), Latino and white men and women initially free from cardiovascular disease followed prospectively between 1993-1996 and 2003 in the Multiethnic Cohort Study (MEC). Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
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