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Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study

Clendenen, Tess V; Hertzmark, Kathryn; Koenig, Karen L; Lundin, Eva; Rinaldi, Sabina; Johnson, Theron; Krogh, Vittorio; Hallmans, Goran; Idahl, Annika; Lukanova, Annekatrin; Zeleniuch-Jacquotte, Anne
Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; >/=55 years, n = 110 cases). Among women who were >/=55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged >/=55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.
PMID: 26925952
ISSN: 1868-8500
CID: 2009252

Serum Taurine and Stroke Risk in Women: A Prospective, Nested Case-Control Study

Wu, Fen; Koenig, Karen L; Zeleniuch-Jacquotte, Anne; Jonas, Saran; Afanasyeva, Yelena; Wojcik, Oktawia P; Costa, Max; Chen, Yu
BACKGROUND: Taurine (2-aminoethanesulfonic acid), a conditionally essential sulfur-containing amino acid, is mainly obtained from diet in humans. Experimental studies have shown that taurine's main biological actions include bile salt conjugation, blood pressure regulation, anti-oxidation, and anti-inflammation. METHODS: We conducted a prospective case-control study nested in the New York University Women's Health Study, a cohort study involving 14,274 women enrolled since 1985. Taurine was measured in pre-diagnostic serum samples of 241 stroke cases and 479 matched controls. RESULTS: There was no statistically significant association between serum taurine and stroke risk in the overall study population. The adjusted ORs for stroke were 1.0 (reference), 0.87 (95% CI, 0.59-1.28), and 1.03 (95% CI, 0.69-1.54) in increasing tertiles of taurine (64.3-126.6, 126.7-152.9, and 153.0-308.5 nmol/mL, respectively). A significant inverse association between serum taurine and stroke risk was observed among never smokers, with an adjusted OR of 0.66 (95% CI, 0.37-1.18) and 0.50 (95% CI, 0.26-0.94) for the second and third tertile, respectively (p for trend = 0.01), but not among past or current smokers (p for interaction < 0.01). CONCLUSIONS: We observed no overall association between serum taurine and stroke risk, although a protective effect was observed in never smokers, which requires further investigation. Taurine, Stroke, Epidemiology, Prospective, Case-control study, NYUWHS.
PMID: 26866594
ISSN: 1932-6203
CID: 1948722

Genotyping of Single Nucleotide Polymorphisms in DNA Isolated from Serum Using Sequenom MassARRAY Technology

Clendenen, Tess V; Rendleman, Justin; Ge, Wenzhen; Koenig, Karen L; Wirgin, Isaac; Currie, Diane; Shore, Roy E; Kirchhoff, Tomas; Zeleniuch-Jacquotte, Anne
BACKGROUND: Large epidemiologic studies have the potential to make valuable contributions to the assessment of gene-environment interactions because they prospectively collected detailed exposure data. Some of these studies, however, have only serum or plasma samples as a low quantity source of DNA. METHODS: We examined whether DNA isolated from serum can be used to reliably and accurately genotype single nucleotide polymorphisms (SNPs) using Sequenom multiplex SNP genotyping technology. We genotyped 81 SNPs using samples from 158 participants in the NYU Women's Health Study. Each participant had DNA from serum and at least one paired DNA sample isolated from a high quality source of DNA, i.e. clots and/or cell precipitates, for comparison. RESULTS: We observed that 60 of the 81 SNPs (74%) had high call frequencies (>/=95%) using DNA from serum, only slightly lower than the 85% of SNPs with high call frequencies in DNA from clots or cell precipitates. Of the 57 SNPs with high call frequencies for serum, clot, and cell precipitate DNA, 54 (95%) had highly concordant (>98%) genotype calls across all three sample types. High purity was not a critical factor to successful genotyping. CONCLUSIONS: Our results suggest that this multiplex SNP genotyping method can be used reliably on DNA from serum in large-scale epidemiologic studies.
PMID: 26274499
ISSN: 1932-6203
CID: 1721892

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study

Clendenen, Tess V; Ge, Wenzhen; Koenig, Karen L; Axelsson, Tomas; Liu, Mengling; Afanasyeva, Yelena; Andersson, Anne; Arslan, Alan A; Chen, Yu; Hallmans, Goran; Lenner, Per; Kirchhoff, Tomas; Lundin, Eva; Shore, Roy E; Sund, Malin; Zeleniuch-Jacquotte, Anne
Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.
PMID: 26488576
ISSN: 1932-6203
CID: 1810082

Circulating Estrogen Metabolites and Risk of Breast Cancer in Postmenopausal Women

Arslan, Alan A; Koenig, Karen L; Lenner, Per; Afanasyeva, Yelena; Shore, Roy E; Chen, Yu; Lundin, Eva; Toniolo, Paolo; Hallmans, Goran; Zeleniuch-Jacquotte, Anne
Background: It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16alpha-hydroxylation pathway may be inversely associated with breast cancer risk. Methods: We examined the associations of invasive breast cancer risk with circulating 2-OHE1, 16alpha-OHE1, and the 2-OHE1:16alpha-OHE1 ratio in a case-control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16alpha-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation. Results: Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16alpha-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (p
PMID: 24769889
ISSN: 1055-9965
CID: 922822

Association between Class III Obesity (BMI of 40-59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies

Kitahara, Cari M; Flint, Alan J; Berrington de Gonzalez, Amy; Bernstein, Leslie; Brotzman, Michelle; MacInnis, Robert J; Moore, Steven C; Robien, Kim; Rosenberg, Philip S; Singh, Pramil N; Weiderpass, Elisabete; Adami, Hans Olov; Anton-Culver, Hoda; Ballard-Barbash, Rachel; Buring, Julie E; Freedman, D Michal; Fraser, Gary E; Beane Freeman, Laura E; Gapstur, Susan M; Gaziano, John Michael; Giles, Graham G; Hakansson, Niclas; Hoppin, Jane A; Hu, Frank B; Koenig, Karen; Linet, Martha S; Park, Yikyung; Patel, Alpa V; Purdue, Mark P; Schairer, Catherine; Sesso, Howard D; Visvanathan, Kala; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Hartge, Patricia
BACKGROUND: The prevalence of class III obesity (body mass index [BMI]>/=40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. METHODS AND FINDINGS: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m2) compared with those classified as normal weight (BMI 18.5-24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976-2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. CONCLUSIONS: Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary.
PMID: 25003901
ISSN: 1549-1277
CID: 1066322

Circulating prolactin levels and risk of epithelial ovarian cancer

Clendenen, Tess V; Arslan, Alan A; Lokshin, Anna E; Liu, Mengling; Lundin, Eva; Koenig, Karen L; Berrino, Franco; Hallmans, Goran; Idahl, Annika; Krogh, Vittorio; Lukanova, Annekatrin; Marrangoni, Adele; Muti, Paola; Nolen, Brian M; Ohlson, Nina; Shore, Roy E; Sieri, Sabina; Zeleniuch-Jacquotte, Anne
PURPOSE: Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown. METHODS: We conducted a nested case-control study of 230 cases and 432 individually matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls. RESULTS: Prolactin levels were significantly lower among post- versus pre-menopausal women, parous versus nulliparous women, and past versus never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (OR(Q4vsQ1) 1.56, 95 % CI 0.94, 2.63, p trend 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood >/=5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI >/=25 kg/m(2) (OR(Q4vsQ1) 3.10, 95 % CI 1.39, 6.90), but not for women with BMI <25 kg/m(2) (OR(Q4vsQ1) 0.81, 95 % CI 0.40, 1.64). CONCLUSIONS: Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.
PMID: 23378139
ISSN: 0957-5243
CID: 222782

Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study

Scarmo, Stephanie; Afanasyeva, Yelena; Lenner, Per; Koenig, Karen L; Horst, Ronald L; Clendenen, Tess V; Arslan, Alan A; Chen, Yu; Hallmans, Goran; Lundin, Eva; Rinaldi, Sabina; Toniolo, Paolo; Shore, Roy E; Zeleniuch-Jacquotte, Anne
INTRODUCTION: Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH)D) in breast cancer development, but the results of epidemiological studies have been inconsistent. METHODS: We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH)D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: No association was observed between circulating levels of 25(OH)D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH)D > 0.70). An inverse association between 25(OH)D levels and breast cancer risk was observed among women who were
PMID: 23442740
ISSN: 1465-5411
CID: 316582

Serum taurine and risk of coronary heart disease: a prospective, nested case-control study

Wojcik, OP; Koenig, KL; Zeleniuch-Jacquotte, A; Pearte, C; Costa, M; Chen, Y
PURPOSE: Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk. METHODS: We conducted a case-control study nested in the New York University Women's Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels. RESULTS: Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber and iron, and negatively related to dietary intake of saturated fat (all p values 250 mg/dL) (adjusted OR = 0.39 (0.19-0.83) for the third versus first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk. CONCLUSIONS: The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.
PMID: 22322924
ISSN: 1436-6207
CID: 162479

Genetic variants in hormone-related genes and risk of breast cancer

Clendenen, Tess; Zeleniuch-Jacquotte, Anne; Wirgin, Isaac; Koenig, Karen L; Afanasyeva, Yelena; Lundin, Eva; Arslan, Alan A; Axelsson, Tomas; Forsti, Asta; Hallmans, Goran; Hemminki, Kari; Lenner, Per; Roy, Nirmal; Shore, Roy E; Chen, Yu
Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.
PMID: 23935996
ISSN: 1932-6203
CID: 495042