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Stefan Nickels,
Thérèse Truong,
Rebecca Hein,
Kristen Stevens,
Katharina Buck,
Sabine Behrens,
Ursula Eilber,
Martina Schmidt,
Lothar Häberle,
Alina Vrieling, [......],
Alice J. Sigurdson,
Michele M. Doody,
Pascal Guénel,
Paul D. P. Pharoah,
Marjanka K. Schmidt,
Per Hall,
Doug F. Easton,
Montserrat Garcia-Closas,
Roger L. Milne,
Jenny Chang-Claude
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ABSTRACT: Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2 , account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1<
PLoS Genet. 03/2013; 9(3):e1003284.
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Kyriaki Michailidou,
Per Hall,
Anna Gonzalez-Neira,
Maya Ghoussaini,
Joe Dennis,
Roger L Milne,
Marjanka K Schmidt,
Jenny Chang-Claude,
Stig E Bojesen,
Manjeet K Bolla, [......],
Sandra Deming-Halverson,
Martha Shrubsole,
Jirong Long,
Jacques Simard,
Montse Garcia-Closas,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Alison M Dunning,
Javier Benitez,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
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Stig E Bojesen,
Karen A Pooley,
Sharon E Johnatty,
Jonathan Beesley,
Kyriaki Michailidou,
Jonathan P Tyrer,
Stacey L Edwards,
Hilda A Pickett,
Howard C Shen,
Chanel E Smart, [......],
Simon A Gayther,
Paul D P Pharoah,
Roger R Reddel,
Ellen L Goode,
Mark H Greene,
Douglas F Easton,
Andrew Berchuck,
Antonis C Antoniou,
Georgia Chenevix-Trench,
Alison M Dunning
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ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
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Montserrat Garcia-Closas,
Fergus J Couch,
Sara Lindstrom,
Kyriaki Michailidou,
Marjanka K Schmidt,
Mark N Brook,
Nick Orr,
Suhn Kyong Rhie,
Elio Riboli,
Heather S Feigelson, [......],
Alison M Dunning,
Mark E Sherman,
Georgia Chenevix-Trench,
Stephen J Chanock,
Per Hall,
Paul D P Pharoah,
Celine Vachon,
Douglas F Easton,
Christopher A Haiman,
Peter Kraft
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ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
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Juliet D French,
Maya Ghoussaini,
Stacey L Edwards,
Kerstin B Meyer,
Kyriaki Michailidou,
Shahana Ahmed,
Sofia Khan,
Mel J Maranian,
Martin O'Reilly,
Kristine M Hillman, [......],
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Bruce A J Ponder,
Heli Nevanlinna,
Melissa A Brown,
Georgia Chenevix-Trench,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
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Stefan Nickels,
Thérèse Truong,
Rebecca Hein,
Kristen Stevens,
Katharina Buck,
Sabine Behrens,
Ursula Eilber,
Martina Schmidt,
Lothar Häberle,
Alina Vrieling, [......],
Alice J Sigurdson,
Michele M Doody,
Pascal Guénel,
Paul D P Pharoah,
Marjanka K Schmidt,
Per Hall,
Doug F Easton,
Montserrat Garcia-Closas,
Roger L Milne,
Jenny Chang-Claude
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ABSTRACT: Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
PLoS Genetics 03/2013; 9(3):e1003284. · 8.69 Impact Factor
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ABSTRACT: BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration has been linked to mortality in several studies, but appropriate cutoffs to define risk categories are under debate. OBJECTIVE: We aimed to conduct a repeated-measurements analysis on the association of serum 25(OH)D concentrations with all-cause and cause-specific mortality, with particular attention given to the shape of dose-response relations. DESIGN: Concentrations of 25(OH)D were measured in n = 9578 baseline and n = 5469 5-y follow-up participants of the ESTHER study, which is a German population-based cohort aged 50-74 y at baseline. Deaths were recorded during 9.5 y of follow-up (median). Restricted cubic splines were used to assess dose-response relations and Cox regression with time-dependent variables to estimate hazard ratios. RESULTS: During follow-up, 1083 study participants died, of whom 350 individuals died of cardiovascular diseases, 433 individuals died of cancer, and 55 individuals died of respiratory diseases. The overall mortality [HR (95% CI)] of subjects with vitamin D deficiency [25(OH)D concentrations <30 nmol/L] or vitamin D insufficiency [25(OH)D concentrations from 30 to 50 nmol/L) was significantly increased [1.71 (1.43, 2.03) and 1.17 (1.02, 1.35), respectively] compared with that of subjects with sufficient 25(OH)D concentrations (>50 nmol/L)]. Vitamin D deficiency was also associated with increased cardiovascular mortality [1.39 (95% CI: 1.02, 1.89)], cancer mortality [1.42 (95% CI: 1.08, 1.88)] and respiratory disease mortality [2.50 (95% CI: 1.12, 5.56)]. The association of 25(OH)D concentrations with all-cause mortality proved to be a nonlinear inverse association with risk that started to increase at 25(OH)D concentrations <75 nmol/L. CONCLUSIONS: In this large cohort study, serum 25(OH)D concentrations were inversely associated with all-cause and cause-specific mortality. In particular, vitamin D deficiency [25(OH)D concentration <30 nmol/L] was strongly associated with mortality from all causes, cardiovascular diseases, cancer, and respiratory diseases.
American Journal of Clinical Nutrition 02/2013; · 6.67 Impact Factor
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ABSTRACT: Smoking is an established risk factor for cardiovascular events, such as myocardial infarction, stroke and cardiovascular death. However, most pertinent studies primarily relied on middle aged adults. We aimed to provide empirical evidence on the association of smoking with cardiovascular events and the benefits of smoking cessation in people aged 50 years or older. In a German population-based cohort study detailed information on lifetime smoking history was obtained from 8,807 individuals aged 50-74 years, without previous myocardial infarction (MI) or stroke. Cox proportional hazards regression was applied to estimate the impact of smoking on MI, stroke and cardiovascular death (CVD) as well as on the combined outcome of major cardiovascular events (MI, stroke or CVD). In addition, the impact of smoking and the benefits of smoking cessation were quantified by risk advancement periods (RAP). The cohort included 17.2 % current smokers, 31.7 % former smokers and 51.1 % never smokers. During a mean follow-up of 9.1 years, 261 participants experienced a first MI, 456 had a primary stroke and 274 died of cardiovascular reasons. Compared to never smokers, adjusted hazard ratios (95 % confidence intervals) of current smokers were 2.25 (1.62-3.12), 2.12 (1.65-2.73) and 2.45 (1.76-3.42) and RAPs were 19.3, 9.8 and 8.4 years for MI, stroke and CVD, respectively. Strong dose-response relationships were seen with both current and life-time amount of smoking. Most of the excess risk and risk advancement disappeared within 5 years after smoking cessation. Smoking is a strong risk factor for cardiovascular events even at older age. Smoking cessation is highly and rapidly beneficial also at advanced age.
European Journal of Epidemiology 02/2013; · 4.71 Impact Factor
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ABSTRACT: OBJECTIVE
Inflammatory processes contribute to both diabetes and cardiovascular risk. We wanted to investigate whether circulating concentrations of proinflammatory immune mediators and adiponectin in diabetic patients are associated with incident cardiovascular events.RESEARCH DESIGN AND METHODS
In 1,038 participants with diabetes of the population-based Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung (ESTHER) study, of whom 326 showed signs of renal dysfunction, Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for the association of increasing concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), IL-18, macrophage migration inhibitory factor (MIF), adiponectin, and leptin with cardiovascular events (myocardial infarction, stroke, or fatal cardiovascular event) during a follow-up period of 8 years.RESULTSDuring follow-up, 161 subjects with diabetes experienced a primary cardiovascular event. Proinflammatory markers were not associated with a higher risk for primary cardiovascular events in the total study population after adjustment for multiple confounders. However, IL-6 and MIF were associated with cardiovascular events in subjects with renal dysfunction (HR for the comparison of top vs. bottom tertile 1.98 [95% CI 1.12-3.52], P [trend] = 0.10 for IL-6; 1.48 [0.87-2.51], P [trend] = 0.04 for MIF). Adiponectin levels were associated with cardiovascular events in the total population (1.48 [1.01-2.21], P [trend] = 0.03), and the association was even more pronounced in the subgroup with renal dysfunction (1.97 [1.08-3.57], P [trend] = 0.02).CONCLUSIONS
In particular, the absence of an association between CRP and a U-shaped association of adiponectin levels with incident cardiovascular events show that associations between circulating immune mediators and cardiovascular risk differ between diabetic patients and subjects of the general population.
Diabetes care 02/2013; · 8.09 Impact Factor
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ABSTRACT: Plausible mechanisms of how vitamin D deficiency may contribute to the development of diabetes mellitus have been proposed but longitudinal cohort studies have yielded heterogeneous results. In 7,791 initially diabetes-free participants of a German population-based cohort, aged 50-74 years, adjusted Cox regression models were employed to estimate hazard ratios (HR) with 95 % confidence intervals (CI) for the association of serum 25-hydroxyvitamin D (25(OH)D) quintiles and incident diabetes. Dose-response relationships were assessed with restricted cubic spline curves. Additionally, analyses accounting for the competing risks of diabetes and death were performed. During 8 years of follow-up, 829 study participants developed diabetes. In women, diabetes risk was significantly increased in the lowest 25(OH)D quintile (HR, 1.38; 1.09-1.75) and non-significantly increased in the 2nd quintile (HR, 1.24; 0.98-1.55) compared to women in 25(OH)D quintiles 3-5. The dose-response relationship showed a non-linear inverse association with risk starting to increase at 25(OH)D levels below 70 nmol/L (statistically significant: below 40 nmol/L). In men, 25(OH)D levels were not associated with diabetes incidence. Renal dysfunction was an effect modifier with a more than doubled diabetes risk in 25(OH)D quintile 1 and an about 1.5-fold risk in quintile 2 compared to quintiles 3-5 if subjects had renal dysfunction. The observed associations were not influenced by the competing risk of death. In this large cohort study of older adults, serum 25(OH)D levels were inversely associated with incident diabetes in women but not in men. The association was particularly strong in subjects with renal dysfunction.
European Journal of Epidemiology 01/2013; · 4.71 Impact Factor
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ABSTRACT: OBJECTIVES: To develop and evaluate a modification of the Fried frailty assessment using population-independent cutpoints and to determine frailty prevalence of community-dwelling elderly people in a German population. DESIGN: Cross-sectional analysis of 8-year follow-up data of a large German cohort study. SETTING: Saarland, Germany. PARTICIPANTS: Three thousand one hundred twelve community-dwelling adults aged 59 and older. MEASUREMENTS: Frailty was operationalized using modified Fried frailty criteria. Criteria were categorized according to quintiles (lowest-quintile approach) or using population-independent cutpoints derived from the literature (population-independent approach). Agreement and construct validity of frailty classification according to both approaches were evaluated according to weighted kappa (κ) and Spearman rank correlation (r(Sp) ). Associations between frailty and covariates were assessed using multiple logistic regression models. RESULTS: Although more participants were identified as frail according to the population-independent index (8.9%) than the lowest-quintile index (6.5%), agreement and correlation of frailty classification using both approaches was high (κ = 0.75 and r(Sp) = 0.84). Sex differences in frailty prevalence were more pronounced when the population-independent approach was used (women 11.4%; men 6.1%). Similarly strong significant associations with sociodemographic, lifestyle, and medical factors such as older age, female sex, smoking, and obesity were seen for both approaches. CONCLUSION: The modified Fried index using literature-derived cutpoints independent from the frailty criteria distributions in the underlying study population showed good correlation with the lowest-quintile approach and enables prevalence estimates that are directly comparable between different populations.
Journal of the American Geriatrics Society 10/2012; · 3.74 Impact Factor
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ABSTRACT: OBJECTIVES: Recent animal studies have suggested a key role for cellular prion protein (PrPc) in the pathological consequences of amyloid plaque formation, the hallmark of Alzheimer's disease. This epidemiological study investigated whether serum concentrations of PrPc are associated with cognitive functioning in humans. DESIGN, SETTING, PARTICIPANTS: Cross-sectional study of 1,322 participants from the elderly general population in Germany, aged 65+ years at baseline (2000-2002). MEASUREMENTS: Cognitive functioning was assessed by the COGTEL phone interview 5years after baseline. Serum PrPc was determined by a commercial immunoassay. RESULTS: In multiple linear regression adjusted for important confounders, subjects in higher PrPc quintiles appeared to have lower cognitive functioning scores than those in the lowest PrPc quintile. Spline regression suggested pronounced non-linearity with an inverse association between PrPc and cognitive functioning levelling off beyond median PrPc. Cognitive subdomain-specific models produced somewhat heterogeneous results. CONCLUSION: The findings are suggestive of an independent association of PrPc with cognitive functioning in humans. Confirmatory and longitudinal studies are needed to elucidate the potential of PrPc for applications in early risk stratification for cognitive impairment.
Experimental gerontology 08/2012; · 3.34 Impact Factor
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Rebecca Hein,
Melanie Maranian,
John L. Hopper,
Miroslaw K. Kapuscinski,
Melissa C. Southey,
Daniel J. Park,
Marjanka K. Schmidt,
Annegien Broeks,
Frans B. L. Hogervorst,
H. Bas Bueno-de-Mesquit, [......],
Polly A. Newcomb,
Linda Titus,
Kathleen M. Egan,
Georgia Chenevix-Trench,
Antonis C. Antoniou,
Manjeet K. Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F. Easton,
Alison M. Dunning
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ABSTRACT: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER−) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26–1.48), p = 7.6×10−14 in Asians and 1.09 (95% CI 1.07–1.11), p = 6.8×10−18 in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19–1.41), p = 1.2×10−9 in Asians and 1.12 (95% CI 1.08–1.17), p = 3.8×10−9 in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER− than ER+ tumours in Europeans [OR (ER−) = 1.20 (95% CI 1.15–1.25), p = 1.8×10−17 versus OR (ER+) = 1.07 (95% CI 1.04–1.1), p = 1.3×10−7, pheterogeneity = 5.1×10−6]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER− tumours.
PLoS ONE 08/2012; 7(8). · 4.09 Impact Factor
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ABSTRACT: OBJECTIVE.: To compare the public health implications of using unstandardized immunoassay measurements of serum 25-hydroxyvitamin D [25(OH)D] concentrations versus using measurements standardized by liquid chromatography tandem-mass spectrometry (LC-MS/MS) when assessing the prevalence of 25(OH)D insufficiency and deficiency in various subgroups of individuals. METHOD.: We standardized immunoassay-based measurements of 25(OH)D with LC-MS/MS in a population-based sample of 5386 women aged 50-74 recruited in 2000-2002 in Germany. We used multivariate regression to assess 25(OH)D determinants and the association of vitamin D deficiency with health status. RESULTS.: Prevalences of 25(OH)D levels <50nmol/L (insufficiency) and <30nmol/L (deficiency) decreased considerably by standardization. The decrease in vitamin D deficiency (from 64.4% to 17.9%) was particularly strong in March-May among women aged ≥65. Independent of season of blood draw and standardization, women ≥70years, obese, or currently smoking had an increased risk of having 25(OH)D levels <30nmol/L. CONCLUSION.: The proportion of older women with vitamin D deficiency in Germany is much lower than previously reported, but prevalence of vitamin D insufficiency is high. Standardization of 25(OH)D values by immunoassay methods to LC-MS/MS equivalent values or direct measurement by LC-MS/MS is indispensable in drawing valid conclusions about the health implications of vitamin D deficiency or insufficiency.
Preventive Medicine 06/2012; 55(3):228-32. · 3.22 Impact Factor
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ABSTRACT: The aim of the study was the gender specific analysis of cross-sectional and longitudinal associations between body mass index class (BMI-class) and symptoms of depression in a representative sample of elderly German people.
At the baseline of the ESTHER study (2000-2002), 9953 participants completed a comprehensive questionnaire including items regarding weight, height, and depression history. After five years, 7808 participants again completed the questionnaire and the 15-item geriatric depression scale (GDS-15). BMI was classified into five classes: normal weight, 18.5≤BMI<25; overweight, 25≤BMI<30; obesity class I, 30≤BMI<35; obesity class II, 35≤BMI<40; obesity class III, BMI≥40.
Logistic regression analysis for the cross-sectional data at five-year follow-up, adjusted for age, education, marital status, smoking, multimorbidity, physical activity, self-perceived cognitive impairment, and use of antidepressants, showed that the odds for depression were significantly elevated for women in obesity class II and significantly decreased for overweight men. The longitudinal analysis showed a similar pattern: Women in obesity classes II and III at baseline had significantly higher odds for being depressive five years later than women with normal weight at baseline (class II: OR=1.67; 95%CI=[1.06; 2.64]; class III: OR=2.93; 95%CI=[1.37; 6.26]; overweight men had lower odds than normal-weight men (OR=0.69; 95%CI=[0.51;0.92]).
The relationship between obesity and symptoms of depression appears to be heterogeneous across BMI-classes. Women are more affected than men by obesity class II and III; overweight appears to be associated with reduced risk of depression in elderly men.
Journal of psychosomatic research 05/2012; 72(5):376-82. · 2.91 Impact Factor
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ABSTRACT: Although a positive association between type 2 diabetes mellitus (T2DM) and colorectal cancer is well established, uncertainty exists about risk differences in diabetic men and women when considering colorectal neoplasia (CN). The main objective was to examine gender-specific associations of T2DM with CN in a population-based cohort study of adults in Germany. This analysis is based on participants of the ESTHER-study, a population-based cohort study. Participants were 50-74 years old at baseline and underwent colonoscopy during 5 year follow-up. CN detected at colonoscopy were validated by medical records review. Total and gender-specific associations of T2DM at baseline and CN were estimated using log-binomial regression. Overall, 55 cases of CN were detected in 166 participants with T2DM and 328 cases in 1,360 participants without T2DM. In women, CN was found in 32 % of participants with T2DM and in 18 % without T2DM (adjusted prevalence ratio (PR): 1.66 95 % CI 1.04-2.64). In men, prevalence for CN was 35 % for those with T2DM and 33 % for those without T2DM (adjusted PR = 1.01; 95 % CI 0.71-1.43). T2DM might have a stronger impact on CN among women than among men. Further research should examine possible reasons for these differences.
European Journal of Epidemiology 04/2012; 27(5):341-7. · 4.71 Impact Factor
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ABSTRACT: The aim of the study was to assess the longitudinal association between cardiovascular risk factors including albuminuria and other variables (e.g. awareness of hypertension, number of types of antihypertensive drugs, comorbidity), and health-related quality of life (HRQOL) in a large cohort of patients with hypertension, over a follow-up period of 5 years.
Nine thousand nine hundred and fifty-three participants of the ESTHER (Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen) study - a population-based cohort study of middle-aged and older adults aged 50-74 years at baseline - were recruited by general practitioners (GPs) in 2000-2002 and included in the follow-up (2005-2007). HRQOL at baseline and follow-up was measured using the Short-Form General Health Survey (SF-12). Mental component scores (MCS) and physical component scores (PCS) were calculated. Multiple linear regression models were used to determine longitudinal predictors of HRQOL at follow-up.
Four thousand, two hundred and three patients with hypertension (98.2%) responded to the SF-12 both at baseline and after 5 years and were therefore included in the study. Smoking status, BMI, diabetes, macroalbuminuria, comorbid diseases, history of depression, and lower HRQOL at baseline predicted lower PCS at the 5-year follow-up. Lower MCS after 5 years was predicted by smoking status, dyslipidaemia, a reported history of depression, and HRQOL at baseline. No significant association was detected between awareness of hypertension and any HRQOL component score after 5 years.
Macroalbuminuria and other variables related to increased cardiovascular risk have a negative impact on PCS. Suggestions of a link of treatment and awareness of hypertension with HRQOL from previous cross-sectional studies are not supported by our longitudinal findings.
Journal of hypertension 04/2012; 30(7):1364-72. · 4.02 Impact Factor
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Diether Lambrechts,
Therese Truong,
Christina Justenhoven,
Manjeet K Humphreys,
Jean Wang,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Melissa C Southey,
Marjanka K Schmidt, [......],
Daehee Kang,
Keun-Young Yoo,
Dong-Young Noh,
Annika Lindblom,
Sara Margolin,
Alison M Dunning,
Paul D P Pharoah,
Douglas F Easton,
Pascal Guénel,
Hiltrud Brauch
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ABSTRACT: A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Human Mutation 03/2012; 33(7):1123-32. · 5.69 Impact Factor
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ABSTRACT: To assess the cardiovascular risk of diabetic subjects with chronic kidney disease (CKD) based on different estimated glomerular filtration rate (eGFR) equations and to evaluate which definition of CKD best improves cardiovascular risk prediction of the Framingham Cardiovascular Risk Score (Framingham-CV-RS).
CKD was defined as eGFR <60 mL/min/1.73 m(2), estimated by the creatinine-based Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations and a cystatin C-based equation (CKD-CysC). Cox regression was used to estimate hazard ratios (HRs) of subjects with CKD for incident cardiovascular events in a cohort of 1,153 individuals with diabetes (baseline age 50-74 years). Furthermore, the CKD definitions were added individually to a reference model comprising the Framingham-CV-RS variables and HbA(1c), and measures of model discrimination and reclassification were assessed.
During 5 years of follow-up, 95 individuals had a primary cardiovascular event. Crude HRs were increased for all CKD definitions. However, after adjusting for established cardiovascular risk factors, HRs for both creatinine-based CKD definitions were attenuated to point estimates of 1.03, whereas the HRs for the cystatin C-based CKD definition remained significantly increased (HR 1.75 [95% CI 1.07-2.87]). Extension of the reference model by the different CKD definitions resulted in an increase in the c statistic only when adding CKD-CysC (from 0.638 to 0.644) along with a net reclassification improvement of 8.9%.
Only the cystatin C-based CKD definition was an independent risk predictor for cardiovascular events in our diabetic study cohort and indicated a potentially better clinical utility for cardiovascular risk prediction than creatinine-based equations.
Diabetes care 02/2012; 35(4):879-86. · 8.09 Impact Factor
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Kristen N Stevens,
Zachary Fredericksen,
Celine M Vachon,
Xianshu Wang,
Sara Margolin,
Annika Lindblom,
Heli Nevanlinna,
Dario Greco,
Kristiina Aittomäki,
Carl Blomqvist, [......],
Marie-Rose Christiaens,
Georgia Chenevix-Trench,
Jonathan Beesley,
Xiaoqing Chen,
Arto Mannermaa,
Veli-Matti Kosma,
Jaana M Hartikainen,
Ylermi Soini,
Douglas F Easton,
Fergus J Couch
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ABSTRACT: The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
Cancer Research 02/2012; 72(7):1795-803. · 7.86 Impact Factor
