Malmö Diet And Cancer Study Research Articles

FADD (Fas-Associated Protein With Death Domain), Caspase-3, and Caspase-8 and Incidence of Ischemic Stroke.

Background and Purpose- Apoptosis has been implicated in atherosclerosis and plaque rupture. This population-based study examined the relationship between 3 markers of apoptosis, that is, FADD (Fas-associated protein with death domain), caspase-3, and caspase-8, and incidence of ischemic stroke. Methods- The study population included 4356 participants from the MDCS (Malmö Diet and Cancer Study) cardiovascular cohort, without a history of stroke. Incidence of ischemic stroke was followed by linkages to local and national registers. Cox proportional hazards regression was used to assess the incidence of ischemic stroke in relation to quartiles of FADD, caspase-3, and caspase-8, adjusted for potential confounders. Results- During a mean follow-up period of 19.5±4.9 years, a total of 321 (7.4%) participants were diagnosed with incident ischemic stroke. Individuals with high levels of FADD and caspase-8 had a significantly increased risk of ischemic stroke, after adjustment for potential confounders. The multivariable-adjusted hazard ratios for Q4 versus Q1-Q3 of FADD and caspase-8 were 1.49 (95% CI, 1.18-1.87; P<0.01) and 1.77 (95% CI, 1.41-2.22; P<0.001), respectively. The hazard ratios per 1-SD increment of FADD and caspase-8 were 1.27 (95% CI, 1.14-1.41) and 1.31 (95% CI, 1.18-1.45), respectively. No association was observed for caspase-3 with ischemic stroke. Conclusions- Elevated levels of FADD and caspase-8, but not caspase-3, are associated with increased incidence of ischemic stroke.

Adherence to diet recommendations and risk of abdominal aortic aneurysm in the Malm\xf6 Diet and Cancer Study

The research examining the association between quality of diet and abdominal aortic aneurysm (AAA) is scarce. The aim of the present study was to explore the association between diet quality and development of AAA for middle-aged individuals in the Malmö Diet and Cancer Study (MDCS), a prospective cohort study with baseline data collection carried out between 1991 and 1996. At baseline, the study participants who were eligible for this study (n = 26133) documented their dietary habits in a food diary and questionnaire. Incident AAA cases during an average of 20.7 years of follow-up were identified by using registers. A diet quality index consisting of six components, saturated fat, polyunsaturated fat, fibre, sucrose, fruits and vegetables and fish and shellfish, was used to assess the diet quality. After adjusting for potential confounders, the diet quality index was not associated with incident AAA. However, a tendency of decreased risk was observed among individuals adhering to recommendations for fruit and vegetables compared with non-adherence. When comparing the risk of more extreme intake groups, high intakes of both fruits and vegetables were associated with decreased risk.

Polygenic Risk Score for Coronary Heart Disease Modifies the Elevated Risk by Cigarette Smoking for Disease Incidence.

Coronary heart disease (CHD) is a multifactorial disease with both genetic and environmental components. Smoking is the most important modifiable risk factor for CHD. Our aim was to test whether the increased CHD incidence by smoking is modified by genetic predisposition to CHD. Our study included 24 443 individuals from the MDCS (Malmö Diet and Cancer Study). A weighted polygenic risk score (PRS) was created by summing the number of risk alleles for 50 single-nucleotide polymorphisms associated with CHD. Individuals were classified as current, former, or never smokers. Interactions were primarily tested between smoking status and PRS and secondarily with individual single-nucleotide polymorphisms. Then, the predictive use of PRS for CHD incidence was tested among different smoking categories. During a median follow-up time of 19.4 years, 3217 incident CHD cases were recorded. The association between smoking and CHD was modified by the PRS (Pinteraction=0.005). The magnitude of increased incidence of CHD by smoking was highest among individuals in the lowest tertile of PRS (odds ratio, 1.42; 95% confidence interval, 1.29-1.56 per smoking risk category) compared with the highest tertile (odds ratio, 1.20; 95% confidence interval, 1.11-1.30 per smoking risk category). This interaction was stronger among men (Pinteraction=0.001) compared with women (Pinteraction=0.44). The PRS provided a significantly better net reclassification and discrimination on top of traditional risk factors among never smokers compared with current smokers (P<0.001). Genetic predisposition to CHD modifies the associated increased CHD risk by smoking. The PRS has a better predictive use among never smokers compared with smokers.

Genetic Architecture of the Cardiovascular Risk Proteome.

We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmö Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research.

ST segment depression on 24-hour electrocardiography predicts incident atrial fibrillation in two population-based cohorts.

ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmö Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development. There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women. ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk.

Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease

BackgroundBoth genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.MethodsUsing a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts — 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women’s Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) — and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.ResultsThe relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.ConclusionsAcross four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.)

Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age.

Background/Objective:Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages.Methods:We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.Results:In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10−8) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: −0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: −0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.Conclusions:Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.

Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: The Malmö Diet and Cancer Study

ObjectiveTo evaluate the progression of carotid intima-media thickness (IMT) in the common carotid artery (CCA) and the bifurcation over a mean follow-up of 16 years in relation to cardiovascular risk factors. MethodsThe study population included 3426 middle-aged Swedish men and women participating in the 1991–1994 (baseline) and the 2007–2012 (re-examination) investigation of the cardiovascular cohort of the Malmö Diet and Cancer Study (MDCS). ResultsThere were differences in risk factor patterns in arterial segments in that diabetes and male sex were associated with the progression of IMT in the bifurcation, but not in the CCA, and high-density lipoprotein cholesterol (HDL) was associated with the progression of IMT in the CCA, but not in the bifurcation. Favourable changes in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL) and HDL during follow-up decreased the IMT progression rate in the CCA. There was a cumulative relationship between traditional cardiovascular risk factors (i.e., regular smoking, LDL/HDL-ratio ≥ 3, hypertension) and IMT progression rates. The odds ratio (OR) of high IMT CCA progression rate (>75th percentile) was 1.0 (reference), 1.4 (95% CI: 1.1, 1.7), 1.7 (95% CI: 1.3, 2.2) and 2.1 (95% CI: 1.4, 3.1), respectively, for individuals with none, one, two, and three risk factors. ConclusionThere were differences in the associations between risk factors and progression rate in different arterial segments. Favourable changes in SBP and lipids during the follow-up period were associated with reduced IMT progression rates in the CCA.

The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study.

BackgroundChromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers.MethodsMultivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmö Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow-up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan® Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline.ResultsEach rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10–1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91–0.996]), wine intake (HR, 0.91 [CI: 0.86–0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86–0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction = 0.043), and to non- and low consumers of wine (Pinteraction = 0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction = 0.015 and 0.049, respectively).ConclusionsOur results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0138-x) contains supplementary material, which is available to authorized users.

Validation of plasma proneurotensin as a novel biomarker for the prediction of incident breast cancer.

High fasting plasma proneurotensin concentration was associated with the development of breast cancer in the Malmö Diet and Cancer Study (MDCS). Here, we aimed at replicating the initial finding in an independent second cohort. The Malmö Preventive Project (MPP) is a population study and comprised 18,240 subjects when examined in 2002-2006. Of women without history of breast cancer at examination, we included all who developed breast cancer during follow-up (n = 130) until December 31, 2010, and a random sample of women without breast cancer until the end of follow-up (n = 1,439) for baseline plasma proneurotensin assessment (mean age, 70.0 ± 4.4 years). Proneurotensin was measured in fasting plasma samples and was related to the risk of later breast cancer development using multivariate logistic regression. Proneurotensin [odds ratio (OR) per standard deviation (SD) increment of LN-transformed proneurotensin] was significantly related to incident breast cancer [OR, 2.09; 95% confidence interval (CI), 1.79-2.44; P < 0.001; adjusted for age, body mass index (BMI), smoking, and hormone replacement therapy]. The effect estimate in the MPP was larger than in the discovery cohort (MDCS), with the main difference between the two cohorts being that women of the MPP study were on the average about 10 years older and follow-up time was shorter than that of the MDCS. As initially found in the MDCS, fasting plasma proneurotensin was significantly associated with the development of breast cancer in the MPP study as well. Measurement of plasma proneurotensin warrants further investigation as a blood-based marker for early breast cancer detection.

CEREBRAL MICROBLEEDS DO NOT AFFECT COGNITIVE PERFORMANCE IN HEALTHY ELDERLY

Cerebral microbleeds (CMBs) are small perivascular hemorrhages, seen as focal lesions on MRI, and are considered a marker of cerebral small vessel disease. The prevalence is 15% in the general population, and increases with age. In several studies CMBs have been associated with worse cognitive performance in different domains. The association has mainly been studied in memory clinic settings or in the general population. The aim of the present study was to investigate the association between presence of CMBs and cognition in individuals without any cognitive disability. 207 individuals without cognitive symptoms, who scored > 27 points on Mini-Mental State Examination (MMSE), were recruited from the longitudinal population-based Malmö Diet and Cancer Study (MDCS). The subjects (mean age, 72 years; 60 % women) underwent 3T MRI with visual rating of CMBs on gradient-echo T2*-weighted sequences. A set of tests covering the cognitive domains of episodic memory, speed and attention, executive function and language fluency were performed. Risk factor profiles were collected from MDCS baseline (1991-1994), on average 19 years (range 16 to 21 years) prior to the present data collection. Logistic regression with presence of CMBs as dependent variable was performed. Baseline independent variables: sex, age, education, smoking, Body Mass Index, blood pressure, blood pressure-lowering drugs, total cholesterol, lipid-lowering drugs, fasting-blood glucose and anti-diabetic medication, were included in the model. CMBs were detected in 25 of 207 individuals (12%). No association was found between the tested cognitive domains and presence of CMBs using linear regression models adjusted for age, sex and education. Multivariate logistic regression showed that male sex independently increased the risk of presence of CMBs (OR 2.83, [95% CI 1.15 to 6.95], p=0.024). None of the cardiovascular risk factors were associated with CMBs. In our population of cognitively healthy elderly, 12% had CMBs. However, the presence of CMBs did not affect cognitive performance. Mid-life cardiovascular risk factors were not associated with the presence of CMBs later in life.

Smoking- and alcohol habits in relation to the clinical picture of women with microscopic colitis compared to controls

BackgroundMicroscopic colitis (MC) induces gastrointestinal symptoms, which are partly overlapping with irritable bowel syndrome (IBS), predominately in middle-aged and elderly women. The etiology is unknown, but association with smoking has been found. The aim of this study was to examine whether the increased risk for smokers to develop MC is a true association, or rather the result of confounding factors. Therefore, patients suffering from MC and population-based controls from the same geographic area were studied regarding smoking- and alcohol habits, and other simultaneous, lifestyle factors, concerning the clinical expression of the disease.MethodsWomen at the age of 73 years or younger, who had been treated for biopsy-verified MC at any of the Departments of Gastroenterology in Skåne, between 2002 and 2010, were invited to the study (240 patients). Women (737) from the population-based prospective cohort study, Malmö Diet and Cancer Study (MDCS), served as controls. A self-administered questionnaire about lifestyle factors, gastrointestinal symptoms, medical conditions and medication at the time for the study was sent by post.ResultsAltogether, 131 women with MC could be included after age-matching with controls (median age 56 years) and exclusion of secondary MC. Patients were divided into persistent MC (MC1) and transient MC (MC2). Past smoking was associated with increased risk to develop MC2 (OR = 2.67, 95 CI = 1.15–6.23), whereas current smoking was associated with increased risk to develop MC1 (OR = 3.18, 95 CI = 1.57–6.42). Concomitant symptoms of IBS were associated with smoking (OR = 4.24, 95 CI = 1.92–9.32). Alcohol drinking had no association with MC or IBS.ConclusionsThe results suggest that past smoking is associated with transient MC, whereas current smoking is associated with persistent MC. Smoking is associated with MC patients with concomitant IBS-like symptoms.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Determinants of serum levels of vitamin D: a study of life-style, menopausal status, dietary intake, serum calcium, and PTH

BackgroundLow blood levels of vitamin D (25-hydroxy D3, 25OHD3) in women have been associated with an increased risk of several diseases. A large part of the population may have suboptimal 25OHD3 levels but high-risk groups are not well known. The aim of the present study was to identify determinants for serum levels of 25OHD3 in women, i.e. factors such as lifestyle, menopausal status, diet and selected biochemical variables.MethodsThe study was based on women from the Malmö Diet and Cancer Study (MDCS), a prospective, population-based cohort study in Malmö, Sweden. In a previous case–control study on breast cancer, 25OHD3 concentrations had been measured in 727 women. In these, quartiles of serum 25OHD3 were compared with regard to age at baseline, BMI (Body Max Index), menopausal status, use of oral contraceptives or menopausal hormone therapy (MHT) , life-style (e.g. smoking and alcohol consumption), socio-demographic factors, season, biochemical variables (i.e. calcium, PTH, albumin, creatinine, and phosphate), and dietary intake of vitamin D and calcium. In order to test differences in mean vitamin D concentrations between different categories of the studied factors, an ANOVA test was used followed by a t-test. The relation between different factors and 25OHD3 was further investigated using multiple linear regression analysis and a logistic regression analysis.ResultsWe found a positive association between serum levels of 25OHD3 and age, oral contraceptive use, moderate alcohol consumption, blood collection during summer/ autumn, creatinine, phosphate, calcium, and a high intake of vitamin D. Low vitamin D levels were associated with obesity, being born outside Sweden and high PTH levels.ConclusionsThe present population-based study found a positive association between serum levels of 25OHD3 and to several socio-demographic, life-style and biochemical factors. The study may have implications e. g. for dietary recommendations. However, the analysis is a cross-sectional and it is difficult to suggest Lifestyle changes as cause- effect relationships are difficult to assess.

Genetic susceptibility to obesity and diet intakes: association and interaction analyses in the Malmö Diet and Cancer Study

Gene–environment interactions need to be studied to better understand the obesity. We aimed at determining whether genetic susceptibility to obesity associates with diet intake levels and whether diet intakes modify the genetic susceptibility. In 29,480 subjects of the population-based Malmö Diet and Cancer Study (MDCS), we first assessed association between 16 genome-wide association studies identified obesity-related single-nucleotide polymorphisms (SNPs) with body mass index (BMI) and associated traits. We then conducted association analyses between a genetic risk score (GRS) comprising of 13 replicated SNPs and the individual SNPs, and relative dietary intakes of fat, carbohydrates, protein, fiber and total energy intake, as well as interaction analyses on BMI and associated traits among 26,107 nondiabetic MDCS participants. GRS associated strongly with increased BMI (P = 3.6 × 10−34), fat mass (P = 6.3 × 10−28) and fat-free mass (P = 1.3 × 10−24). Higher GRS associated with lower total energy intake (P = 0.001) and higher intake of fiber (P = 2.3 × 10−4). No significant interactions were observed between GRS and the studied dietary intakes on BMI or related traits. Of the individual SNPs, after correcting for multiple comparisons, NEGR1 rs2815752 associated with diet intakes and BDNF rs4923461 showed interaction with protein intake on BMI. In conclusion, our study does not provide evidence for a major role for macronutrient-, fiber- or total energy intake levels in modifying genetic susceptibility to obesity measured as GRS. However, our data suggest that the number of risk alleles as well as some of the individual obesity loci may have a role in regulation of food and energy intake and that some individual loci may interact with diet.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-013-0352-8) contains supplementary material, which is available to authorized users.

Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers

ObjectiveThe brain derived neurotrophic factor (BDNF) locus has been implicated in psychiatric and substance related disorders. Recent genome-wide association studies (GWAS) have shown strong associations between single nucleotide polymorphisms in...

Smoking, low formal level of education, alcohol consumption, and the risk of rheumatoid arthritis

Objective: Suggested predictors of rheumatoid arthritis (RA) include environmental exposure, such as smoking. Our purpose was to investigate potential predictors of RA in a nested case–control study based on a prospective cohort.Method: Between 1991 and 1996, 30 447 persons were included in the Malmö Diet and Cancer Study (MDCS). Individuals who developed RA after inclusion up to 31 December 2004 were identified by linking the database to different registers. Four controls were selected for every case. Data on lifestyle factors were collected in the MDCS.Results: We identified 172 incident cases of RA [36 men/136 women, mean age at diagnosis 63 years, 69% rheumatoid factor (RF) positive, median time from inclusion to diagnosis 5 (range 1–13) years]. In bivariate analyses, baseline smoking [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.31–3.12] and a low level of formal education (i.e. ≤ 8 years; OR 2.42, 95% CI 1.18–4.93 vs. University degree) predicted subsequent development of RA. Infrequent baseline alcohol consumption was a predictor of RA (OR 3.47, 95% CI 1.91–6.30) compared to recent use (within the past month), and individuals with moderate baseline alcohol consumption (3.5–15.2 g/day vs. < 3.5 g/day) tended to have a reduced risk of RA (OR 0.48, 95% CI 0.22–1.05) in multivariate analyses, adjusted for smoking and level of education.Conclusions: Smoking and a low level of formal education were found to be independent predictors of RA. Moderate alcohol consumption may also be associated with a reduced risk.

Genetic predisposition, parity, age at first childbirth and risk for breast cancer

BackgroundRecent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk.MethodsThe Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI).ResultsSix of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons.ConclusionsThe results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

Role of TCF7L2 risk variant and dietary fibre intake on incident type 2 diabetes

Aims/hypothesisThe T allele of transcription factor 7-like 2 gene variant, TCF7L2 rs7903146, increases the risk of type 2 diabetes by 40–50%. As TCF7L2 rs7903146 has been associated with diminished incretin effect we investigated whether interaction between dietary intake of carbohydrate, fat, protein or fibre and this variant affects the risk of type 2 diabetes.MethodsA cohort of 24,799 non-diabetic individuals from the Malmö Diet and Cancer Study (MDCS), with dietary data obtained by a modified diet history method, were followed up for 12 years, with 1,649 recordings of incident type 2 diabetes made. Risk of type 2 diabetes in strata of diet quintiles was analysed prospectively adjusting for potential confounders. Cross-sectional analyses were performed on baseline fasting glucose and HbA1c levels in a subset of 5,216 randomly selected individuals from the MDCS.ResultsThe elevated risk of type 2 diabetes with rs7903146 (OR 1.44, 95% CI 1.33, 1.56, p = 4.6 × 10−19) increased with higher intake of dietary fibre (OR 1.24, 95% CI 1.04, 1.47 to OR 1.56, 95% CI 1.31, 1.86 from the lowest to highest quintile; p interaction = 0.049). High intake of dietary fibre was inversely associated with diabetes incidence only among CC genotype carriers (OR 0.74, 95% CI 0.58, 0.94 per quintile, p = 0.025). The T allele was associated with 0.027% elevated HbA1c (p = 0.02) and this effect increased with higher intake of fibre (from −0.021% to 0.079% for the lowest to the highest quintile, p interaction = 0.02). Each quintile of higher fibre intake was associated with lower HbA1c levels among CC and CT but not among TT genotype carriers (−0.036%, p = 6.5 × 10−7; −0.023%, p = 0.009; and 0.012%, p = 0.52, respectively).Conclusions/interpretationOur study suggests that dietary fibre intake may modify the association between TCF7L2 rs7903146 and incidence of type 2 diabetes, and that higher fibre intake may associate with protection from type 2 diabetes only among non-risk allele carriers.

Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmö Diet and Cancer Study

Background Soluble urokinase plasminogen activator receptor (suPAR) is a highly sensitive marker that reflects increased inflammation and is positively correlated with pro-inflammatory biomarkers. The aim of this study was to explore the relationship between suPAR, cardiovascular disease (CVD) risk factors and incidence of CVD. Methods suPAR was assessed in a random sample of participants ( N = 569), aged 63–68 years (mean age 65.5), from the Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. Baseline examination was conducted between 1991 and 1994. suPAR in blood was analysed using a commercially available assay (suPARnostic). Cox regression analysis was used to investigate the incidence of CVD (coronary events or ischemic stroke), in relation to sex-specific tertiles of suPAR. Results Significantly higher plasma levels of suPAR was found in women, smokers, diabetics and older subjects. suPAR was significantly positively correlated with markers of systemic inflammation (i.e., high sensitive C-reactive protein (hsCRP) and white blood cells (WBC), but not to lipoprotein-associated phospholipase A2 (Lp-PLA 2), a specific vascular inflammatory biomarker.87 subjects had a CVD event during follow-up (mean 14.1 years). In an age/sex-adjusted model, the hazard ratio (HR) for incident CVD was 2.53 (95%CI: 1.44–4.46) for the top compared to the bottom tertile of suPAR. This association remained significant after further adjustment for smoking, low density lipoprotein (LDL), systolic blood pressure, use of anti-hypertensive medication, diabetes, hsCRP, WBC and Lp-PLA 2 (HR: 2.25; 1.07–4.72). Conclusion Elevated levels of suPAR are, independently of established cardiovascular risk factors, associated with an increased incidence of CVD in elderly subjects.