Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort.

While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9-year follow-up, 1,532 incident pancreatic cancer cases were identified among 184,559 at-risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50-2.58), diabetes (RR 1.32, 95% CI 1.14-1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08-1.46), current smoking (<20 pack-years RR 1.43, 95% CI 1.19-1.73; ≥20 pack-years RR 1.76, 95% CI 1.46-2.12), and red meat intake (RR 1.17, 95% CI 1.00-1.36) were associated with pancreatic cancer. After adjustment for these risk factors, Native Hawaiians (RR 1.60, 95% CI 1.30-1.98), Japanese Americans (RR 1.33, 95% CI 1.15-1.54), and African Americans (RR 1.20, 95% CI 1.01-1.42), but not Latino Americans (RR 0.90, 95% CI 0.76-1.07), had a higher risk of pancreatic cancer compared to European Americans. Interethnic differences in pancreatic cancer risk are not fully explained by differences in the distribution of known risk factors. The greater risks in Native Hawaiians and Japanese Americans are new findings and elucidating the causes of these high rates may improve our understanding and prevention of pancreatic cancer

Variation in genetic admixture and population structure among Latinos: the Los Angeles Latino eye study (LALES)

<p>Abstract</p> <p>Background</p> <p>Population structure and admixture have strong confounding effects on genetic association studies. Discordant frequencies for age-related macular degeneration (AMD) risk alleles and for AMD incidence and prevalence rates are reported across different ethnic groups. We examined the genomic ancestry characterizing 538 Latinos drawn from the Los Angeles Latino Eye Study [LALES] as part of an ongoing AMD-association study. To help assess the degree of Native American ancestry inherited by Latino populations we sampled 25 Mayans and 5 Mexican Indians collected through Coriell's Institute. Levels of European, Asian, and African descent in Latinos were inferred through the USC Multiethnic Panel (USC MEP), formed from a sample from the Multiethnic Cohort (MEC) study, the Yoruba African samples from HapMap II, the Singapore Chinese Health Study, and a prospective cohort from Shanghai, China. A total of 233 ancestry informative markers were genotyped for 538 LALES Latinos, 30 Native Americans, and 355 USC MEP individuals (African Americans, Japanese, Chinese, European Americans, Latinos, and Native Hawaiians). Sensitivity of ancestry estimates to relative sample size was considered.</p> <p>Results</p> <p>We detected strong evidence for recent population admixture in LALES Latinos. Gradients of increasing Native American background and of correspondingly decreasing European ancestry were observed as a function of birth origin from North to South. The strongest excess of homozygosity, a reflection of recent population admixture, was observed in non-US born Latinos that recently populated the US. A set of 42 SNPs especially informative for distinguishing between Native Americans and Europeans were identified.</p> <p>Conclusion</p> <p>These findings reflect the historic migration patterns of Native Americans and suggest that while the 'Latino' label is used to categorize the entire population, there exists a strong degree of heterogeneity within that population, and that it will be important to assess this heterogeneity within future association studies on Latino populations. Our study raises awareness of the diversity within "Latinos" and the necessity to assess appropriate risk and treatment management.</p

Polymorphic repeat in AIB1 does not alter breast cancer risk

INTRODUCTION: A causal association between endogenous and exogenous estrogens and breast cancer has been established. Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development after binding to their respective steroid hormone receptors. Coactivator and corepressor proteins have recently been identified that interact with steroid hormone receptors and modulate transcriptional activation [1]. AIB1 (amplified in breast 1) is a member of the steroid receptor coactivator (SRC) family that interacts with estrogen receptor (ER)α in a ligand-dependent manner, and increases estrogen-dependent transcription [2]. Amplification and overexpression of AIB1 has been observed in breast and ovarian cancer cell lines and in breast tumors [2,3]. A polymorphic stretch of glutamine amino acids, with unknown biologic function, has recently been described in the carboxyl-terminal region of AIB1 [4]. Among women with germline BRCA1 mutations, significant positive associations were observed between AIB1 alleles with 26 or fewer glutamine repeats and breast cancer risk [5] AIM: To establish whether AIB1 repeat alleles are associated with breast cancer risk and specific tumor characteristics among Caucasian women. PATIENTS AND METHODS: We evaluated associations prospectively between AIB1 alleles and breast cancer risk in the Nurses' Health Study using a nested case-control design. The Nurses' Health Study was initiated in 1976, when 121 700 US-registered nurses between the ages of 30 and 55 years returned an initial questionnaire reporting medical histories and baseline health-related exposures. Between 1989 and 1990 blood samples were collected from 32 826 women. Eligible cases in this study consisted of women with pathologically confirmed incident breast cancer from the subcohort who gave a blood specimen. Cases with a diagnosis anytime after blood collection up to June 1, 1994, with no previously diagnosed cancer except for nonmelanoma skin cancer were included. Controls were randomly selected participants who gave a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the cases were diagnosed, and were matched to cases on year of birth, menopausal status, postmenopausal hormone use, and time of day, month and fasting status at blood sampling. The nested case-control study consisted of 464 incident breast cancer cases and 624 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Womens' Hospital, Boston, Massachusetts USA. Information regarding breast cancer risk factors was obtained from the 1976 baseline questionnaire, subsequent biennial questionnaires, and a questionnaire that was completed at the time of blood sampling. Histopathologic characteristics, such as stage, tumor size and ER and progesterone receptor (PR) status, were ascertained from medical records when available and used in case subgroup analyses. AIB1 repeat alleles were determined by automated fluorescence-based fragment detection from polymerase chain reaction (PCR)-amplified DNA extracted from peripheral blood lymphocytes. Fluorescent 5' -labeled primers were utilized for PCR amplification, and glutamine repeat number discrimination was performed using the ABI Prism 377 DNA Sequencer (Perkin-Elmer, Foster City, CA, USA). Genotyping was performed by laboratory personnel who were blinded to case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures (n = 110); concordance for the blinded samples was 100%. Methods regarding plasma hormone assays have previously been reported [6]. Conditional and unconditional logistic regression models, including terms for the matching variables and other potential confounders, were used to assess the association of AIB1 alleles and breast cancer characterized by histologic subtype, stage of disease, and ER and PR status. We also evaluated whether breast cancer risk associated with AIB1 genotype differed within strata of established breast cancer risk factors, and whether repeat length in AIB1 indirectly influenced plasma hormone levels. RESULTS: The case-control comparisons of established breast cancer risk factors among these women have previously been reported [7], and are generally consistent with expectation. The mean age of the women was 58.3 (standard deviation [SD] 7.1) years, ranging from 43 to 69 years at blood sampling. There were 188 premenopausal and 810 postmenopausal women, with mean ages of 48.1 (SD 2.8) years and 61.4 (SD 5.0) years, respectively, at blood sampling. Women in this study were primarily white; Asians, African-Americans and Hispanics comprised less than 1% of cases or controls. The distribution of AIB1 glutamine repeat alleles and AIB1 genotypes for cases and controls are presented in Table 1. Women with AIB1 alleles of 26 glutamine repeats or fewer were not at increased risk for breast cancer (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.75-1.36; Table 2). Results were also similar by menopausal status and in analyses additionally adjusting for established breast cancer risk factors. Among premenopausal women, the OR for women with at least one allele with 26 glutamine repeats or fewer was 0.82 (95% Cl 0.37-1.81), and among postmenopausal women the OR was 1.09 (95% Cl 0.78-1.52; Table 2). We did not observe evidence of a positive association between shorter repeat length and advanced breast cancer, defined as women with breast cancer having one or more involved nodes (OR 1.07, 95% Cl 0.64-1.78), or with cancers with a hormone-dependent phenotype (ER-positive: OR 1.16, 95% Cl 0.81-1.65; Table 3). No associations were observed among women who had one or more alleles with 26 glutamine repeats or fewer, with or without a family history of breast cancer (family history: OR 1.09; 95% Cl 0.46-2.58; no family history: OR 0.94; 95% Cl 0.68-1.31; test for interaction P = 0.65). We also did not observe associations with breast cancer risk to be modified by other established breast cancer risk factors. Among postmenopausal controls not using postmenopausal hormones, geometric least-squared mean plasma levels of estrone sulfate and estrone were similar among carriers and noncarriers of AIB1 alleles with 26 glutamine repeats or fewer (both differences: ≤ +3.5%; P >0.50). Mean levels of estradiol were slightly, but nonsignificantly elevated among carriers of alleles with 26 glutamine repeats or fewer (+11.6%; P = 0.08). DISCUSSION: In this population-based nested case-control study, women with at most 26 repeating glutamine codons (CAG/CAA) within the carboxyl terminus of AIB1 were not at increased risk for breast cancer. We did not observe shorter repeat alleles to be positively associated with breast cancer grouped by histologic subtype, stage of disease, or by ER and PR status. These data suggest that AIB1 repeat length is not a strong independent risk factor for postmenopausal breast cancer, and does not modify the clinical presentation of the tumor among Caucasian women in the general population

Polymorphic repeat in AIB1 does not alter breast cancer risk

We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

INTRODUCTION: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. METHODS: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. RESULTS: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). CONCLUSION: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone

A High-Density Admixture Scan in 1,670 African Americans with Hypertension

Hypertension (HTN) is a devastating disease with a higher incidence in African Americans than European Americans, inspiring searches for genetic variants that contribute to this difference. We report the results of a large-scale admixture scan for genes contributing HTN risk, in which we screened 1,670 African Americans with HTN and 387 control individuals for regions of the genome with elevated proportion of African or European ancestry. No loci were identified that were significantly associated with HTN. We also searched for evidence of an admixture signal at 40 candidate genes and eight previously reported linkage peaks, but none appears to contribute substantially to the differential HTN risk between African and European Americans. Finally, we observed nominal association at one of the loci detected in the admixture scan of Zhu et al. 2005 (p = 0.016 at 6q24.3 correcting for four hypotheses tested), although we caution that the significance is marginal and the estimated odds ratio of 1.19 per African allele is less than what would be expected from the original report; thus, further work is needed to follow up this locus

A case–control analysis of smoking and breast cancer in African American women: findings from the AMBER Consortium

Recent population studies suggest a role of smoking in the etiology of breast cancer, but few have been conducted among African American women. In a collaborative project of four large studies, we examined associations between smoking measures and breast cancer risk by menopause and hormone receptor status [estrogen receptor-positive (ER+), ER-negative (ER−) and triple-negative (ER−, PR−, HER2−)]. The study included 5791 African American women with breast cancer and 17376 African American controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in multivariable logistic regression analysis with adjustment for study and risk factors. Results differed by menopausal status. Among postmenopausal women, positive associations were observed for long duration and greater pack-years of smoking: relative to never smoking, fully adjusted ORs were 1.14 (95% CI: 1.03–1.26) for duration ≥20 years and 1.16 (95% CI: 1.01–1.33) for ≥20 pack-years. By contrast, inverse associations were observed among premenopausal women, with ORs of 0.80 (95% CI: 0.68–95) for current smoking and 0.81 (95% CI: 0.69–0.96) for former smoking, without trends by duration. Associations among postmenopausal women were somewhat stronger for ER+ breast cancer. The findings suggest that the relation of cigarette smoking to breast cancer risk in African American women may vary by menopausal status and breast cancer subtype

Postmenopausal Female Hormone Use and Estrogen Receptor–Positive and –Negative Breast Cancer in African American Women

Use of estrogen with progestin (combination therapy) is associated with increased incidence of estrogen receptor–positive (ER+) breast cancer in observational studies and randomized trials among postmenopausal white women. Whether this is also the case among African American women is not established

The signature of the first stars in atomic hydrogen at redshift 20

Dark and baryonic matter moved at different velocities in the early Universe, which strongly suppressed star formation in some regions. This was estimated to imprint a large-scale fluctuation signal of about 2 mK in the 21-cm spectral line of atomic hydrogen associated with stars at a redshift of 20, although this estimate ignored the critical contribution of gas heating due to X-rays and major enhancements of the suppression. A large velocity difference reduces the abundance of halos and requires the first stars to form in halos of about a million solar masses, substantially greater than previously expected. Here we report a simulation of the distribution of the first stars at z=20 (cosmic age of ~180 Myr), incorporating all these ingredients within a 400 Mpc box. We find that the 21-cm signature of these stars is an enhanced (10 mK) fluctuation signal on the 100-Mpc scale, characterized by a flat power spectrum with prominent baryon acoustic oscillations. The required sensitivity to see this signal is achievable with an integration time of a thousand hours with an instrument like the Murchison Wide-field Array or the Low Frequency Array but designed to operate in the range of 50-100 MHz.Comment: 27 pages, 5 figures, close (but not exact) match to accepted version. Basic results unchanged from first submitted version, but justification strengthened, title and abstract modified, and substantial Supplementary Material added. Originally first submitted for publication on Oct. 12, 201