STUDY QUESTION
Are PCOS risk variants identified in women of Han Chinese ethnicity also associated with risk of PCOS or the phenotypic features of PCOS in European women?
SUMMARY ANSWER
One variant, ...rs2268361-T, in the intron of FSHR was associated with PCOS and lower FSH levels, while another variant rs705702-G near the RAB5B and SUOX genes was associated with insulin and glucose levels after oral glucose testing in women with PCOS of European ethnicity.
WHAT IS KNOWN ALREADY
Three of the eleven variants associated with PCOS in the Han Chinese genome-wide association studies were also associated with PCOS in at least one European population when corrected for multiple testing (DENND1A, THADA and YAP1). However, additional replication is needed to establish the importance of these variants in European women and to determine the relationship to PCOS phenotypic traits.
STUDY DESIGN, SIZE, DURATION
The study was a case–control examination in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston (Boston 1). Replication was performed in women from Greece (cases n = 884 and controls n = 311) and an additional cohort from Boston (Boston electronic medical record (EMR); n = 350 cases and n = 1258 controls).
PARTICIPANTS/MATERIALS, SETTINGS, METHODS
Women had PCOS defined by the National Institutes of Health criteria in Boston 1 and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. The second cohort from Boston was defined using the EMR and natural language processing. Allele frequencies for variants associated with PCOS in Han Chinese women were examined in PCOS cases and controls, along with the relationship to quantitative traits.
MAIN RESULTS AND THE ROLE OF CHANCE
A variant rs2268361-T in an intron of FSHR was associated with PCOS (0.84 0.76–0.93, OR 95% CI; P = 0.002). The rs2268361-T was associated with lower FSH levels (−0.15 ± 0.05; P = 0.0029). A variant rs705702-G near RAB5B and SUOX was associated with insulin (−0.16 ± 0.05, P = 0.0029) and glucose levels (−0.20 ± 0.05, P = 0.0002) 120 min after an oral glucose test.
LIMITATIONS, REASONS FOR CAUTION
The study was large and contained replication cohorts, but was limited by a small number of controls in the Greek cohort and a small number of cases in the second Boston cohort. The second Boston group was identified using electronic medical record review, but was validated for the cardinal features of PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
This study demonstrates a cross-ethnic PCOS risk locus in FSHR in women of European ancestry with PCOS. The variant may influence FSH receptor responsiveness as suggested by the associated change in FSH levels. The relationship between a variant near RAB5B and SUOX and glucose stimulated insulin and glucose levels suggests an influence of one of these genes on glucose tolerance, but the absence of a relationship with PCOS points to potential differences in the international PCOS patient populations.
STUDY FUNDING/COMPETING INTERESTS
The project was supported by Award Number R01HD065029 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, award 1-10-CT-57 from the American Diabetes Association and the Partners Healthcare Center for Personalized Genetics Project Grant. C.K.W. is a consultant for Takeda Pharmaceuticals.
TRIAL REGISTRATION NUMBER
NCT00166569.
Coffee and tea are among the most commonly consumed nonalcoholic beverages worldwide, but methodological differences in assessing intake often hamper comparisons across populations. We aimed to (i) ...describe coffee and tea intakes and (ii) assess their contribution to intakes of selected nutrients in adults across 10 European countries.
Between 1995 and 2000, a standardized 24-h dietary recall was conducted among 36,018 men and women from 27 European Prospective Investigation into Cancer and Nutrition (EPIC) study centres. Adjusted arithmetic means of intakes were estimated in grams (=volume) per day by sex and centre. Means of intake across centres were compared by sociodemographic characteristics and lifestyle factors.
In women, the mean daily intake of coffee ranged from 94 g/day (~0.6 cups) in Greece to 781 g/day (~4.4 cups) in Aarhus (Denmark), and tea from 14 g/day (~0.1 cups) in Navarra (Spain) to 788 g/day (~4.3 cups) in the UK general population. Similar geographical patterns for mean daily intakes of both coffee and tea were observed in men. Current smokers as compared with those who reported never smoking tended to drink on average up to 500 g/day more coffee and tea combined, but with substantial variation across centres. Other individuals' characteristics such as educational attainment or age were less predictive. In all centres, coffee and tea contributed to less than 10% of the energy intake. The greatest contribution to total sugar intakes was observed in Southern European centres (up to ~20%).
Coffee and tea intake and their contribution to energy and sugar intake differed greatly among European adults. Variation in consumption was mostly driven by geographical region.
Current use of oral contraceptives (OCs) has been reported to increase breast cancer risk slightly. In 1991/1992, a prospective cohort study specifically designed to examine the role of hormonal ...contraceptives in relation to breast cancer was conducted in Norway and Sweden. This study was entitled Women's Lifestyle and Health. Of 196,000 invited women aged 30-49 years, 106,844 women answered a 4-page questionnaire. Altogether, 103,027 women providing information on contraceptive use were included in the analysis presented here, and 1,008 primary invasive breast cancers were diagnosed throughout 1999 (end of follow-up). Proportional hazard regression was used to calculate relative risks (RRs) with adjustment for age and other possible confounders. An increased breast cancer risk was observed among women who were current/recent users of OCs of any type at the start of follow-up RR, 1.6; 96% confidence interval (CI), 1.2-2.1. Current/recent use (i.e., use in the year preceding cohort enrolment) of combined OCs (RR, 1.5; 95% CI, 1.0-2.0) and progestin-only pills (RR, 1.6; 95% CI, 1.0-2.4) entailed similar levels of increased risk. An increased risk of borderline significance was found among short-term (i.e., less than 13 months) users before age 20 years (RR, 1.3; 95% CI, 1.0-1.7) and before first full-term pregnancy (RR, 1.4; 95% CI, 1.0-1.8). Long-term users of OCs were at a higher risk of breast cancer than never users (test for trend, P = 0.005). Current/recent use of OCs is associated with an increased breast cancer risk. Use of combined OCs and progestin-only pills seem to increase the risk at the same level.
Objective: To assess the use of cod-liver oil supplements among Norwegian women and to examine dietary, lifestyle, demographic, and health factors associated with use of this supplement. Design: ...Cross-sectional study. Setting and subjects: The study is based on data from a food frequency questionnaire from 1998 answered by 37 226 women aged 41-55 y, who in 1991/1992 participated in the Norwegian component of the European Prospective Investigation into Cancer and Nutrition (EPIC). The Norwegian EPIC cohort was based on a random nation-wide sample of Norwegian women. Results: Cod-liver oil supplement use was reported by 44.7% of the participating women. Subjects with higher education, high physical activity level, and body mass index (BMI) in the normal range were more likely to use cod-liver oil supplements. Consumption did also increase with increased age as well as with increased reported consumption of fruits, vegetables, fatty fish, lean fish, and vitamin D (excluding the vitamin D contribution from cod-liver oil). Energy intake was higher among cod-liver oil users than nonusers. Whole-year daily users of cod-liver oil were also more likely to take other dietary supplements (OR=2.45, 95% CI: 2.28-2.62). Never smokers were more likely to use cod-liver oil supplements than current smokers. Conclusion: Use of cod-liver oil is associated with several sociodemographic factors, self-reported health issues, and intake of fish, fruit, and vegetables. When assessing the relationship between cod-liver oil use and occurrence of chronic diseases potential confounders need to be considered. Cod-liver oil use seemed not to be matched with vitamin D needs. Thus, emphasis on assessing vitamin D status by measuring levels in blood should be investigated further, in particular, among people living in northern latitudes.
Objective To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation ...into Cancer and Nutrition study. Methods Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. Results During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. Conclusion We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.
To compare food group intakes in grams, total energy and energy contribution from macronutrients between two random samples of women, using a standardized computer program (EPIC SOFT) with either a ...face-to-face or a telephone 24 h recall interview design.
Two groups of Norwegian women living in Tromsø were drawn at random from the Norwegian Women and Cancer Study (NOWAC) cohort. The EPIC SOFT computer program was used to conduct single 24 h dietary recalls either by telephone or face to face. For the latter, 160 women were invited, of whom 111 responded positively (crude response rate=69.4%) and 102 were interviewed. For the telephone option, 180 were invited to participate, 109 responded positively (crude response rate=60.6%) and 103 were interviewed.
The two groups of women were similar with respect to age, body mass index, basal metabolic rate, smoking, education, physical activity and special diet status. No statistically significant difference in dietary intake was found between interviews conducted by telephone and face-to-face, except for 'egg and egg products' (P<0.01), for which intake was higher in the telephone group. Total energy intake differed, but the difference was attributable to one interviewer. The distribution of energy-contributing nutrients was not significantly different between groups, except for reported energy percentage from protein (P=0.02), which was significantly higher in the face-to-face group.
The telephone vs face-to-face interview design did not influence recalled diet when using the EPIC SOFT program.
ABSTRACTPolycystic ovary syndrome (PCOS) affects 7% to 10% of reproductive-age women. The etiology of the syndrome is poorly understood. Twin studies suggest that the pathogenesis of PCOS in more ...than 70% of cases can be explained by genetic influences. Risk loci for genetic variants associated with the syndrome have been identified in women of Han Chinese ethnicity. Two genome-wide association studies in Han Chinese women identified risk loci for 11 genetic variants. Three of these 11 variants were also associated with PCOS in at least 1 European population when corrected for multiple testing, including DENND1A, THADA, and YAP1. The PCOS variants identified require additional replication in Greek and US women to establish the importance of these variants and to determine their relationship to PCOS phenotypic traits.This case-control study was designed to investigate whether PCOS risk variants identified in women of Han Chinese ethnicity were also associated with risk of PCOS or its phenotypic features in European and US women. The discovery cohort was composed of women with PCOS (n = 485) and control subjects (n = 407) from Boston (Boston 1). Susceptibility variants were examined in replicate populations in Greece (cases n = 884 and control subjects n = 311), and a second cohort from Boston identified through the electronic medical record (EMR), n = 350 cases and n = 1258 control subjects).Women in Boston 1 and Greece (n = 783) had PCOS defined by the National Institutes of Health criteria (irregular menses and clinical or biochemical hyperandrogenism n = 527), with additional subjects fulfilling the Rotterdam criteria (clinical or biochemical hyperandrogenism, polycystic ovary morphology, and regular menstrual cycles n = 101). Control subjects in Boston and Greece had regular menses and no hyperandrogenism. The second Boston cohort was defined using the EMR and natural language processing. Allele frequencies for PCOS risk variants identified in Han Chinese women were examined in PCOS cases and control subjects, along with the relationship to quantitative traits.One variant, rs2268361-T, in the intron of follicle-stimulating hormone receptor (FSHR) was associated with PCOS; the combined odds ratio was 0.84 (95% confidence interval, 0.76–0.93; P = 0.002). This variant was associated with lower follicle-stimulating hormone (FSH) levels (−0.15 ± 0.05; P = 0.0029). Another variant, rs705702-G, near the RAB5B and SUOX genes, was associated with lower insulin (−0.16 ± 0.05; P = 0.0029) and glucose levels (−0.20 ± 0.05; P = 0.0002) 120 minutes after an oral glucose test, suggesting better insulin sensitivity.Although the study was large and contained replication cohorts, the findings were limited by a small number of control subjects in the Greek cohort and a small number of cases in the second Boston cohort. Moreover, it was possible that the second Boston cohort identified with EMR review could contribute to the observed differences; this cohort, however, was validated for the cardinal features of PCOS.These findings show that a PCOS risk variant present in Han Chinese women in the region of FSHR is also associated with PCOS in women of European ethnicity. This cross-ethnic PCOS risk locus, rs2268361-T, may influence FSH receptor responsiveness as suggested by the associated change in FSH levels and suggest that disrupting FSH stimulation of follicle development is a key etiologic feature of PCOS.The association between the rs705702-G variant near the RAB5B and SUOX genes and glucose-stimulated insulin and glucose levels suggests that 1 of these genes could influence insulin resistance in women with PCOS; the absence of a relationship with PCOS, however, points to potential differences in the international PCOS patient populations.
To evaluate under- and overreporting and their determinants in the EPIC 24-hour diet recall (24-HDR) measurements collected in the European Prospective Investigation into Cancer and Nutrition (EPIC).
...Cross-sectional analysis. 24-HDR measurements were obtained by means of a standardised computerised interview program (EPIC-SOFT). The ratio of reported energy intake (EI) to estimated basal metabolic rate (BMR) was used to ascertain the magnitude, impact and determinants of misreporting. Goldberg's cut-off points were used to identify participants with physiologically extreme low or high energy intake. At the aggregate level the value of 1.55 for physical activity level (PAL) was chosen as reference. At the individual level we used multivariate statistical techniques to identify factors that could explain EI/BMR variability. Analyses were performed by adjusting for weight, height, age at recall, special diet, smoking status, day of recall (weekday vs. weekend day) and physical activity.
Twenty-seven redefined centres in the 10 countries participating in the EPIC project.
In total, 35 955 men and women, aged 35-74 years, participating in the nested EPIC calibration sub-studies.
While overreporting has only a minor impact, the percentage of subjects identified as extreme underreporters was 13.8% and 10.3% in women and men, respectively. Mean EI/BMR values in men and women were 1.44 and 1.36 including all subjects, and 1.50 and 1.44 after exclusion of misreporters. After exclusion of misreporters, adjusted EI/BMR means were consistently less than 10% different from the expected value of 1.55 for PAL (except for women in Greece and in the UK), with overall differences equal to 4.0% and 7.4% for men and women, respectively. We modelled the probability of being an underreporter in association with several individual characteristics. After adjustment for age, height, special diet, smoking status, day of recall and physical activity at work, logistic regression analyses resulted in an odds ratio (OR) of being an underreporter for the highest vs. the lowest quartile of body mass index (BMI) of 3.52 (95% confidence interval (CI) 2.91-4.26) in men and 4.80 (95% CI 4.11-5.61) in women, indicating that overweight subjects are significantly more likely to underestimate energy intake than subjects in the bottom BMI category. Older people were less likely to underestimate energy intake: ORs were 0.58 (95% CI 0.45-0.77) and 0.74 (95% CI 0.63-0.88) for age (> or =65 years vs. <50 years). Special diet and day of the week showed strong effects.
EI tends to be underestimated in the vast majority of the EPIC centres, although to varying degrees; at the aggregate level most centres were below the expected reference value of 1.55. Underreporting seems to be more prevalent among women than men in the EPIC calibration sample. The hypothesis that BMI (or weight) and age are causally related to underreporting seems to be confirmed in the present work. This introduces further complexity in the within-group (centre or country) and between-group calibration of dietary questionnaire measurements to deattenuate the diet-disease relationship.
The risk of ovarian epithelial neoplasia following use of hormonal contraceptives (HC) was examined in data from the Norwegian-Swedish Women's Lifestyle and Health cohort including 103551 women aged ...30-49 years in 1991-92. Follow-up through 2000 produced 214 incident cases of histologically confirmed epithelial ovarian neoplasias (135 invasive and 79 borderline cases). Using the Cox proportional hazard models, ever having used HC was associated with a decreased relative risk of epithelial ovarian cancer of 0.6 (95% CI 0.5-0.8). The effect of duration of HC use was convincing (P for trend <0.0001), and more important than age at start of use or time since first or last use. There was no significant difference between the effects of combined oral contraceptives and progestins-only contraceptives on risk (P=0.98). Similarly, there was no significant difference between the effects of ever use of HC on invasive and borderline ovarian neoplasia (P=0.37). In this cohort, use of HC seems to reduce the risk of epithelial ovarian neoplasia markedly and persistently in relation to the duration of use.
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