Body mass index in young Dutch adults : its development and the etiology of its development

Follow-up studies of long duration have shown a U-shaped relationship between mortality/morbidity and the body mass index (BMI, weight/height 2). The risk to health posed by obesity appears to be larger in younger subjects than in older subjects. Though this might suggest that a moderate weight gain after the termination of growth may not increase the risk to health, this contention is not supported by other observations (Chapter 1). These are: (1) the range of relative weight associated with minim= mortality does not seem to shift to higher values with increasing age, at least not in men. (2) Diseases associated with overweight at younger ages need not be the same as those associated with overweight at older ages. (3) Cohort effects may bias the age trend in the risk associated with overweight. (4) Longitudinal studies on adults show that changes in body weight are associated with changes in risk factors of diseases. (5) Anthropometric studies show that even at the same weight, the fat mass increases with increasing age. In addition, several studies suggest that weight gained during adulthood mainly accumulates in the abdomen, which means a shift to a fat distribution more strongly associated with risk to health. The risk to health therefore does not seem to remain constant if body weight increases during adulthood.As part of an extensive mixed-longitudinal study (Chapter 2), this thesis deals with the development of the BMI and the etiology of this development in young adults. In addition, one methodological study is described. These studies build m cross-sectional observations that were made in the first examination of the study.In spring 1980, all residents of Dutch nationality in the county of Ede, born in 1948-1950, 1953-1955, 1958-1960 were invited by mail to participate in the study. Participants in spring 1980 (N=3936) were followed for four years (1980-1984) in two groups, the follow-up group (N=1670) and the control group (N=2266). From spring 1981 onward the follow-up group was approached twice a year in seven consecutive examinations. The control group was re-measured in spring 1984 only. At each examination a questionnaire was completed and body weight in light indoor clothing and without shoes was measured to the nearest 0.5 kg. Body height was measured to the nearest 0.1 cm in spring 1980. Subgroups of the follow-up and control groups were additionally examined for the studies described in Chapter 7 and 8.The development of the BMI is dealt with in Chapter 3, in which the mixed-longitudinal design of the study was utilized, and Chapter 4, in which the data were analyzed longitudinally. Over the four years, the change in BMI of the follow-up group was the same as that of the control group. Prom 19 to 35 years of age the median BMI increased from 22.1 kg/m 2to 24.4 kg/m 2in men and from 21.1 kg/m 2to 23.0 kg/m 2in women (Chapter 3). This increment in BMI gave rise to an incidence of moderate overweight (BMI>25 kg/m 2) which increased from 4.8% per 4 years to 15.5% per 4 years in men, and was more stable (5.3-5.7% per 4 years) in women (Chapter 4). Thus, especially in men, young adulthood appears to be a critical period for the development of overweight.The age-reference curves (Chapter 3) suggested that the variation of the BMI over subjects was independent of age. In accordance, the longitudinal analyses showed that the initial BMI and the rate of gain in BMI were unrelated in men and only slightly negatively related in women. Thus, overweight subjects did not appear to gain more or less body mass than non-overweight subjects.The within-subjects standard deviation of the yearly measured BMI was 0.69 kg/m 2in men and 0.74 kg/m 2in women (Chaper 4). This fluctuation was larger in overweight subjects than in normal-weight subjects and was larger in subjects with a larger long-term change (gain or loss) in BMI than in subjects who had a more stable BMI. The considerable fluctuation in BMI may mask the gradual long-term increment in BMI and may thus hinder young adults from being aware that they are becoming overweight.The effect of dieting is dealt with in Chapter 5. After two years of follow-up, the average decrease in body mass as a result of dieting was -0.5 kg/m 2(95% confidence interval (CI):-1.0,+0.0) in men and -0.4 kg/m 2(95%CI:-0.8,+0.0) in women. This approximately amounts to an average weight reduction of 1.5 kg in men and 1.0 kg in women. The effect of dieting was most pronounced in men whose initial BMI was high, who dieted during the summer, or who dieted more frequently, and in women who were older than 30 or who dieted on medical advice. Though subjects who have already developed severe overweight may achieve a larger reduction in the risk to health by losing the same amount of body mass as subjects who are only moderately overweight, it is unlikely that the benefit is large unless they persist. However, the effect of dieting may be enough to prevent the age-related gain in body mass and thus dieting may especially play a part in the prevention of overweight.Chapter 6 deals with the changes in BMI in relation to number of life events experienced. During the first year of follow-up several subgroups of men and women who experienced many life events and several subgroups of men who experienced few life events showed a gain in body mass. After another year of follow-up this gain in body mass had disappeared in almost all subgroups; compared with dieting ran with an intermediate number of life events, dieting men with few life events gained +1.3 kg/m 2(95%CI:+0.0,+2.6) more body mass, whereas dieting men with many life events gained +1.8 kg/m 2(95%CI: +0.5,+3.0) more body mass. Thus, life events seem to have an impact on the etiology of overweight in men.One life event in women is considered more specifically (Chapter 7); i.e. pregnancy. Women who breastfed their child for more than two months gained more body mass than was expected from aging. Nine months postpartum they were +0.6 kg/m 2(90%CI: +0.1,+1.0) heavier than expected. This difference was slightly smaller (not significantly) in women who breastfed their child for 0-2 months. Women who used bromocriptine to stop lactation lost body mass unexpectedly.In a methodological study (Chapter 8) the impact of adjustment of the BMI for body diameters (i.e. knee, wrist, elbow, shoulder, pelvis and hip) on the prediction of body fatness was examined. In addition to what was explained by the BMI, 6% of the variation in body fatness was explained by the shoulder diameter in men, and also 6% by the knee diameter in women. This improvement in estimating body fatness by the diameters, used as continuous variables, was considered too small to justify frame categories being included in weight-height tables. Instead of frame size, fat distribution might be a more useful attribute in these tables.In the last chapter (Chapter 9) several aspects relating to the validity of the mixed-longitudinal study are discussed. The main conclusions of this thesis are:- Young adulthood seems to be a critical period in the development of moderate overweight, expecially in men.- The age-related gain in BMI of overweight young adults and of young adults of normal weight is similar.- Overweight subjects are unlikely to decrease their risk to health markedly by dieting as generally practiced, unless they persist. Dieting may be more effective in preventing overweight.- The experience of many life events may play a part in the etiology of overweight in men, as does the experience of few life events.- Women who breastfeed their child for more than two months may gain more body mass than expected from aging. - In weight-height tables the fat distribution might be a more useful attribute than frame size categories.</TT

Agreement between oral contraceptive users and prescribers: implications for case-control studies

Case-control studies examining the effects of oral contraceptives (OC) are prone to misclassification bias due to errors in assessment of OC use. Concern about inaccurate exposure histories has increased since current studies require women to recall OC use over prolonged periods of time. In preparation for a case-control study of breast cancer and OC use, an investigation was carried out to assess agreement between women's lifetime histories of OC use (covering a period of up to 20 years) and prescribers' records. OC histories were obtained during personal interview with 218 women who had used OC at some point in their lives (127 breast cancer patients, 91 controls). Recall was aided by an album with color photographs of all OC marketed in the Netherlands from 1962 onwards (n = 65), and a calendar that covered the women's life span from date of birth to menopause. The participants were asked for the names of all physicians who prescribed OC for them. The rate of response from the prescribers was high (94%), but only half of the forms provided useful information. Patient-prescriber agreement on brand names (including dosage) was 70%. About half of the women agreed with their prescribers on starting dates to within less than a year's difference. Approximately the same percentage of agreement was found for stopping dates. Multiple linear regression indicated that agreement on brand names and dates of usage was lower for women of low socioeconomic status, for healthy women (as compared to breast cancer patients) and for periods of pill use that had to be recalled from the more distant past. Agreement on total duration of use was high enough to permit testing of a moderately strong duration-response relationship in a case-control study

Timing of risk reducing mastectomy in breast cancer patients carrying a BRCA1/2 mutation: retrospective data from the Dutch HEBON study

It is expected that rapid genetic counseling and testing (RGCT) will lead to increasing numbers of breast cancer (BC) patients knowing their BRCA1/2 carrier status before primary surgery. Considering the potential impact of knowing one’s status on uptake and timing of risk-reducing contralateral mastectomy (RRCM), we aimed to evaluate trends over time in RRCM, and differences between carriers identified either before (predictively) or after (diagnostically) diagnosis. We collected data from female BRCA1/2 mutation carriers diagnosed with BC between 1995 and 2009 from four Dutch university hospitals. We compared the timing of genetic testing and RRCM in relation to diagnosis in 1995–2000 versus 2001–2009 for all patients, and predictively and diagnostically tested patients separately. Of 287 patients, 219 (76 %) had a diagnostic BRCA1/2 test. In this cohort, the median time from diagnosis to DNA testing decreased from 28 months for those diagnosed between 1995 and 2000 to 14 months for those diagnosed between 2001 and 2009 (p < 0.001). Similarly, over time women in this cohort underwent RRCM sooner after diagnosis (median of 77 vs. 27 months, p = 0.05). Predictively tested women who subsequently developed BC underwent an immediate RRCM significantly more often than women who had a diagnostic test (21/61, 34 %, vs. 13/170, 7.6 %, p < 0.001). Knowledge of carrying a BRCA1/2 mutation when diagnosed with BC influenced decisions concerning primary surgery. Additionally, in more recent years, women who had not undergone predictive testing were more likely to undergo diagnostic DNA testing and RRCM sooner after diagnosis. This suggests the need for RGCT to guide treatment decisions

Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

Purpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. Results Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC d

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Item does not contain fulltextBACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction &lt; 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers

Background In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival beneft of BRRM over BC surveillance has been reported yet. Methods In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specifc mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20–0.90) for overall mortality and 0.06 (95% CI 0.01–0.46) for BC-specifc mortality. BC-specifc survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15–1.36). BC-specifc survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specifc survival as surveillance. Our fndings support a more individualized counseling based on BRCA mutation type

Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers

Background: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. Methods: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. Results: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46–1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39–1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60–2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. Conclusion: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2