Publications by authors named "Sari Voutilainen"

103 Publications

Expression of markers of stem cell characteristics, epithelial-mesenchymal transition, basal-like phenotype, proliferation, and androgen receptor in metaplastic breast cancer and their prognostic impact.

Acta Oncol 2021 Sep 20;60(9):1233-1239. Epub 2021 Jul 20.

Comprehensive Cancer Centre, Helsinki University Hospital, Helsinki, Finland.

Background: Metaplastic breast cancer (MpBC) is a heterogeneous subtype of invasive mammary carcinoma associated with epithelial-mesenchymal transition (EMT) and cancer stem cell characteristics. Data regarding prognostic markers and potentially actionable targets for therapy are still limited. The present study aimed to characterize the immunohistochemical landscape of this rare malignancy and to identify potential prognostic factors and targets for therapy.

Material And Methods: A total of 75 patients diagnosed with MpBC over a 15-year period were included in the study. We performed immunohistochemical analyses for Ki-67 (MIB-1), epidermal growth factor receptor (EGFR), cytokeratin 5/6, vimentin, CD44, and androgen receptor (AR) and correlated their expression with clinicopathologic features and clinical outcomes. The -values for survival analyses were corrected for multiple testing (threshold 0.01).

Results: Most tumors expressed CK5/6 (73%), EGFR (59%), CD44 (81%), and vimentin (87%). Eighty-nine percent had a high Ki-67 index. Eighty-four percent were classified as basal-like (CK 5/6 or EGFR positive). AR was expressed in 21% of the tumors. The basal-like phenotype was significantly ( = 0.009) associated with inferior disease-free (DFS) and breast-cancer-specific overall survival (BCOS) with borderline significance ( = 0.01). In addition, a low Ki-67 index was associated with improved DFS ( = 0.033) and BCOS ( = 0.03).

Conclusion: Most MpBCs express basal markers (CK5/6, EGFR), epithelial-mesenchymal transition marker vimentin, and the stem cell marker CD44. Expression of basal-like markers was significantly related to inferior DFS. All the 11 patients with a lack of expression of basal markers survived without relapse.
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http://dx.doi.org/10.1080/0284186X.2021.1950927DOI Listing
September 2021

Dietary intake of choline and phosphatidylcholine and risk of type 2 diabetes in men: The Kuopio Ischaemic Heart Disease Risk Factor Study.

Eur J Nutr 2020 Dec 20;59(8):3857-3861. Epub 2020 Mar 20.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Purpose: To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk.

Methods: We included 2332 men aged 42-60 years at baseline in 1984-1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis.

Results: During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2-43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22-55%) lower relative risk (P trend < 0.001) of type 2 diabetes.

Conclusions: Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.
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http://dx.doi.org/10.1007/s00394-020-02223-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669791PMC
December 2020

Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 12;110(6):1416-1423

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline.

Objectives: We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study.

Methods: A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-ε4 compared with other phenotypes). These data were available for 1259 men.

Results: The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations.

Conclusion: Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz148DOI Listing
December 2019

Gut microbiota in Parkinson's disease: Temporal stability and relations to disease progression.

EBioMedicine 2019 Jun 18;44:691-707. Epub 2019 Jun 18.

Department of Neurology, Helsinki University Hospital, and Department of Neurological Sciences (Neurology), University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland. Electronic address:

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported differentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach.

Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2·25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing.

Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients.

Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progression, a longer follow-up period is required to confirm these findings.
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http://dx.doi.org/10.1016/j.ebiom.2019.05.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606744PMC
June 2019

Egg consumption, cholesterol intake, and risk of incident stroke in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 07;110(1):169-176

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism.

Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, in middle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations.

Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA.

Results: During the mean ± SD follow-up of 21.2 ± 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations.

Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype.This trial was registered at www.clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz066DOI Listing
July 2019

Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: a pooled analysis of prospective cohort studies.

Am J Clin Nutr 2019 04;109(4):1216-1223

Cardiovascular Health Research Unit.

Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.

Objective: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.

Methods: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.

Results: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.

Conclusions: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.
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http://dx.doi.org/10.1093/ajcn/nqz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500926PMC
April 2019

Dietary proteins and protein sources and risk of death: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 05;109(5):1462-1471

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Previous studies investigating protein intake in relation to mortality have provided conflicting results.

Objective: We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study.

Methods: The study population consisted of 2641 Finnish men, aged 42-60 y at baseline in 1984-1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs.

Results: During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P-trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P-trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P-trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P-trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n = 1094) compared with those without disease history (n = 1547) (P-interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality.

Conclusions: Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz025DOI Listing
May 2019

The dynamic course of peripartum depression across pregnancy and childbirth.

J Psychiatr Res 2019 06 15;113:72-78. Epub 2019 Mar 15.

Institute of Clinical Medicine, Psychiatry, University of Eastern Finland, Kuopio, Finland; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Psychiatry, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland.

Objective: Peripartum depression (PPD) pertaining to depression in pregnancy and postpartum is one of the most common complications around childbirth with enduring adverse effects on mother and child health. Although psychiatric symptoms may improve or worsen over time, relatively little is known about the course of PPD symptoms and possible fluctuations.

Methods: We applied a person-centered approach to examine PPD symptom patterns across pregnancy and childbirth. 824 women were assessed at three time points: first trimester (T1), third trimester (T2), and again at eight weeks (T3) postpartum. We assessed PPD symptoms, maternal mental health history, and childbirth variables.

Results: Growth mixture modeling (GMM) analysis revealed four discrete PPD symptom trajectory classes including chronic PPD (1.1%), delayed (10.2%), recovered (7.2%), and resilient (81.5%). Delivery complications were associated with chronic PPD but also with the recovered PPD trajectory class. History of mental health disorders was associated with chronic PPD and the delayed PPD class.

Conclusion: The findings underscore that significant changes in a woman's depression level can occur across pregnancy and childbirth. While a minority of women experience chronic PDD, for others depression symptoms appear to significantly alleviate over time, suggesting a form of recovery. Our findings support a personalized medicine approach based on the woman's symptom trajectory. Future research is warranted to identify the mechanisms underlying modifications in PPD symptoms severity and those implicated in recovery.
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http://dx.doi.org/10.1016/j.jpsychires.2019.03.016DOI Listing
June 2019

Metabolic Profiling of High Egg Consumption and the Associated Lower Risk of Type 2 Diabetes in Middle-Aged Finnish Men.

Mol Nutr Food Res 2019 03 18;63(5):e1800605. Epub 2018 Dec 18.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, 70210, Finland.

Scope: Higher egg intake was previously associated with a lower risk of developing type 2 diabetes (T2D) in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. Potential compounds that can explain this association are explored using nontargeted LC-MS-based metabolic profiling.

Methods And Results: Two hundred and thirty-nine baseline serum samples from the KIHD are analyzed in four groups: subjects with higher (mean intake one egg per day) or lower (mean intake two eggs per week) egg intake who developed T2D (cases) or remained heatlhy (controls) during the mean follow-up of 19.3 years. Different serum profiles of subjects who had either higher or lower egg intakes, and of those who developed type 2 diabetes or remained healthy, are observed. The higher baseline tyrosine level predicts higher odds of T2D (OR 1.94; 95% CI 1.45, 2.60; p < 0.001; FDR 0.023) along with an unknown hexose-containing compound (OR 2.13; 95% CI 1.57, 2.88; p < 0.001; FDR 0.005). Certain predominant metabolites in T2D cases are correlated positively with ones in the lower-egg-intake group and negatively with ones in the higher-egg-intake group.

Conclusion: Our current findings may underline some potential metabolites that can explain how egg intake is associated with a lower risk of T2D.
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http://dx.doi.org/10.1002/mnfr.201800605DOI Listing
March 2019

Intake of fermented and non-fermented dairy products and risk of incident CHD: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Br J Nutr 2018 12 29;120(11):1288-1297. Epub 2018 Oct 29.

Institute of Public Health and Clinical Nutrition,University of Eastern Finland,P.O. Box 1627,70211 Kuopio,Finland.

Recent dairy product studies have suggested that fermented rather than non-fermented dairy products might provide benefits on cardiovascular health, but the evidence is inconclusive. Therefore, we investigated whether fermented and non-fermented dairy products have distinct associations with the risk of incident CHD in a population with high dairy product intake. The present study included a total of 1981 men, aged 42-60 years, from the Kuopio Ischaemic Heart Disease Risk Factor Study, with no CHD at baseline. Dietary intakes were assessed with instructed 4-d food records. We used Cox's proportional hazards regression model to estimate the associations with the risk of CHD. Fatal and non-fatal CHD events were ascertained from national registries. During a mean follow-up of 20·1 years, 472 CHD events were recorded. Median intakes were 105 g/d for fermented (87 % low-fat products) and 466 g/d for non-fermented dairy products (60 % low-fat products). After adjusting for potential confounders, those in the highest (v. lowest) intake quartile of fermented dairy products had 27 % (95 % CI 5, 44; P-trend=0·02) lower risk of CHD. In contrast, those in the highest intake quartile of non-fermented dairy products had 52 % (95 % CI 13, 104; P-trend=0·003) higher risk of CHD. When analysed based on fat content, low-fat (<3·5 % fat) fermented dairy product intake was associated with lower risk (hazard ratio in the highest quartile=0·74; 95 % CI 0·57, 0·97; P-trend=0·03), but high-fat fermented dairy and low-fat or high-fat non-fermented dairy products had no association. These results suggest that fermented and non-fermented dairy products can have opposite associations with the risk of CHD.
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http://dx.doi.org/10.1017/S0007114518002830DOI Listing
December 2018

Kuopio birth cohort - design of a Finnish joint research effort for identification of environmental and lifestyle risk factors for the wellbeing of the mother and the newborn child.

BMC Pregnancy Childbirth 2018 Sep 21;18(1):381. Epub 2018 Sep 21.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.

Background: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child.

Methods: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omics; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics.

Discussion: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.
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http://dx.doi.org/10.1186/s12884-018-2013-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150990PMC
September 2018

The association between gestational diabetes mellitus and postpartum depressive symptomatology: A prospective cohort study.

J Affect Disord 2018 12 15;241:263-268. Epub 2018 Aug 15.

Institute of Clinical Medicine / Psychiatry, University of Eastern Finland, Kuopio, Finland; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland.

Background: The literature suggests an association between type 2 diabetes mellitus and depression, but data on the association between gestational diabetes mellitus (GDM) and postpartum depressive symptomatology (PPDS) are scarce.

Methods: Altogether, 1066 women with no previous mental health issues enrolled in the Kuopio Birth Cohort (KuBiCo, www.kubico.fi) were selected for this study. GDM was diagnosed according to the Finnish Current Care Guidelines. Depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS) during the third trimester of pregnancy and eight weeks after delivery. Additionally, a subgroup of women (n = 505) also completed the EPDS during the first trimester of pregnancy.

Results: The prevalence rates of GDM and PPDS in the whole study population were 14.1% and 10.3%, respectively. GDM was associated with an increased likelihood of belonging to the PPDS group (OR 2.23, 95% CI 1.23-4.05; adjusted for maternal age at delivery, BMI in the first trimester, smoking before pregnancy, relationship status, nulliparity, delivery by caesarean section, gestational age at delivery, neonatal intensive care unit admission and third-trimester EPDS scores). A significant association between GDM and PPDS was found in the subgroup of women with available data on first-trimester depression (n = 505).

Limitations: The participation rate of the KuBiCo study was relatively low (37%).

Conclusions: Women with GDM may be at increased risk of PPDS. Future studies should investigate whether these women would benefit from a closer follow-up and possible supportive interventions during pregnancy and the postpartum period to avoid PPDS.
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http://dx.doi.org/10.1016/j.jad.2018.08.070DOI Listing
December 2018

Evolutionary methods for variable selection in the epidemiological modeling of cardiovascular diseases.

BioData Min 2018 14;11:18. Epub 2018 Aug 14.

1Department of Environmental and Biological Sciences, University of Eastern Finland, Yliopistonranta 1 E, 70211 Kuopio, Finland.

Background: The redundancy of information is becoming a critical issue for epidemiologists. High-dimensional datasets require new effective variable selection methods to be developed. This study implements an advanced evolutionary variable selection method which is applied for cardiovascular predictive modeling. The epidemiological follow-up study KIHD (Kuopio Ischemic Heart Disease Risk Factor Study) was used to compare the designed variable selection method based on an evolutionary search with conventional stepwise selection. The sample contains in total 433 predictor variables and a response variable indicating incidents of cardiovascular diseases for 1465 study subjects.

Results: The effectiveness of variable selection methods was investigated in combination with two models: Generalized Linear Logistic Regression and Support Vector Machine. We managed to decrease the number of variables from 433 to 38 and save the predictive ability of the models used. Their performance was evaluated with an F-score metric. At most, we gained 65.6% and 67.4% of the F-score before and after variable selection respectively. All the results were averaged over 5-folds of a cross-validation procedure.

Conclusions: The presented evolutionary variable selection method allows a reduced set of variables to be chosen which are relevant to predicting cardiovascular diseases. A reference list of the most meaningful variables is introduced to be used as a basis for new epidemiological studies. In general, the multicollinearity of variables enables different combinations of predictors to be used and the same performance of models to be attained.
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http://dx.doi.org/10.1186/s13040-018-0180-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092817PMC
August 2018

Intake of Different Dietary Proteins and Risk of Heart Failure in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study.

Circ Heart Fail 2018 06;11(6):e004531

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio.

Background: Animal and plant protein intakes have indicated opposite associations with cardiovascular mortality risk. Whether dietary proteins are associated with risk of heart failure (HF) is unclear. Thus, we examined the associations of proteins from different food sources with risk of HF.

Methods And Results: The study included 2441 men aged 42 to 60 years at the baseline examinations in 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Protein intakes at baseline were assessed with 4-day dietary records. Data on incident HF cases were obtained from national registers. HF risk according to protein intake was estimated by Cox proportional hazard ratios. During the mean follow-up of 22.2 years, 334 incident HF cases occurred. Higher intake of total protein indicated a trend toward increased risk of HF (multivariable-adjusted hazard ratio in the highest versus lowest quartile=1.33; 95% confidence interval: 0.95-1.85; -trend=0.05). The associations between specific types and sources of protein with incident HF were consistent with this overall finding although not all associations reached statistical significance. For example, the hazard ratio in the highest versus lowest quartile was 1.43 (95% confidence interval: 1.00-2.03; -trend=0.07) for total animal protein and 1.17 (95% confidence interval: 0.72-1.91; -trend=0.35) for total plant protein.

Conclusions: In middle-aged men, higher protein intake was marginally associated with increased risk of HF.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03221127.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023591PMC
June 2018

Serum adiponectin/Ferritin ratio in relation to the risk of type 2 diabetes and insulin sensitivity.

Diabetes Res Clin Pract 2018 Jul 17;141:264-274. Epub 2018 May 17.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, FI70211 Kuopio, Finland.

Aims: Body iron inhibits the metabolism of adiponectin, an insulin sensitizing adipokine. We investigated the relationships of baseline and average of 4-year change in values of serum adiponectin (sA), serum ferritin (sF) and sA/sF ratio on type 2 diabetes (T2D) risk and insulin sensitivity (Matsuda ISI) and secretion (disposition index; DI).

Methods: Prospective analyses were conducted in participants with impaired glucose tolerance of the Finnish Diabetes Prevention Study (n = 516) recruited in 1993-1998. Cox and linear regression analyses were used to investigate the associations of sA, sF and sA/sF ratio, as continuous variables, with incident T2D, Matsuda ISI, and DI.

Results: During the mean follow-up of 8.2 years, 157 incident T2D cases occurred (intervention group, n = 65 and control group, n = 92). In adjusted models, baseline sA and sA/sF ratio were inversely associated with T2D risk (HR = 0.49, 95% CI 0.31-0.76, P = 0.002 and HR = 0.83, 95% CI 0.70-0.99, P = 0.044, respectively). Furthermore, a direct association was observed with Matsuda ISI (β=0.13, 95% CI 0.03-0.22, P = 0.009, for sA and β=0.04, 95% CI 0.01-0.07, P = 0.035, for sA/sF ratio) during the average 4-year follow-up. The changes in sA and sA/sF ratio were also inversely associated with T2D risk (HR = 0.36, 95% CI 0.20-0.63, P < 0.001 and HR = 0.76, 95% CI 0.62-0.92, P = 0.006, respectively), and directly with Matsuda ISI (β=0.27, 95% CI 0.17-0.38, P < 0.001, for sA and β=0.07, 95% CI 0.03-0.11, P < 0.001, for sA/sF ratio). No consistent associations were found with DI CONCLUSIONS: Baseline levels and changes during the follow-up in sA and sA/sF ratio are related to T2D risk and insulin sensitivity.
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http://dx.doi.org/10.1016/j.diabres.2018.05.012DOI Listing
July 2018

Serum n-6 polyunsaturated fatty acids and risk of death: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2018 03;107(3):427-435

University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland.

Background: The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.

Objective: We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.

Design: We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.

Results: During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend < 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend < 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction > 0.13).

Conclusions: Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.
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http://dx.doi.org/10.1093/ajcn/nqx063DOI Listing
March 2018

The associations of serum n-6 polyunsaturated fatty acids with serum C-reactive protein in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Eur J Clin Nutr 2018 03 6;72(3):342-348. Epub 2017 Nov 6.

University of Eastern Finland, Institute of Public Health and Clinical Nutrition, P.O. Box 1627, 70211, Kuopio, Finland.

Background/objectives: There are concerns that high intake of n-6 polyunsaturated fatty acids (PUFA) may promote inflammation, because the end-product of n-6 PUFA metabolism, arachidonic acid, is a precursor for pro-inflammatory eicosanoids. Our aim was to investigate cross-sectional associations of the serum n-6 PUFAs, objective biomarkers for exposure, with serum high-sensitivity C-reactive protein (CRP), a key inflammation marker.

Subjects/methods: The study included 1287 generally healthy men aged 42-60 years from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study, examined in 1984-1989. ANCOVA and logistic regression were used for analyses.

Results: In the multivariable-adjusted analyses, both serum total n-6 PUFA and linoleic acid, the predominant n-6 PUFA, were associated with lower CRP. The mean CRP concentrations in quartiles of linoleic acid were 1.86, 1.51, 1.53, and 1.37 mg/L (P-trend = 0.001). The odds ratio for elevated CRP (>3 mg/L) in the highest vs. the lowest quartile was 0.47 (95% confidence interval (CI) 0.25-0.87, P-trend = 0.01). Arachidonic acid or the mainly endogenously produced n-6 PUFAs, gamma-linolenic acid and dihomo-gamma-linolenic acid, were not associated with higher CRP, either. Age, body mass index, or serum long-chain n-3 PUFA concentration did not modify the associations (P-interactions > 0.14).

Conclusions: Serum n-6 PUFAs were not associated with increased inflammation in men. In contrast, the main n-6 PUFA linoleic acid had a strong inverse association with the key inflammation marker, CRP.
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http://dx.doi.org/10.1038/s41430-017-0009-6DOI Listing
March 2018

Follicle-Stimulating Hormone Levels and Subclinical Atherosclerosis in Older Postmenopausal Women.

Am J Epidemiol 2018 01;187(1):16-26

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Recent studies of perimenopausal women suggest that follicle-stimulating hormone (FSH) levels may be associated with atherosclerosis, independent of estradiol. Whether FSH is related to atherosclerosis in older postmenopausal women, who have completed the menopausal transition, remains unknown. We assessed the relationship of serum FSH and estradiol levels with carotid artery intima-media thickness (IMT) among 587 postmenopausal participants in the Kuopio Ischemic Heart Disease Risk Factor Study (Kuopio, Finland). Participants were aged 53-73 years and not using hormone therapy at baseline (1998-2001). Mean IMT was measured via high-resolution ultrasonography. We observed a significant inverse association between FSH levels and IMT. Mean IMTs among women in quartiles 1-4 of FSH were 0.94 mm, 0.91 mm, 0.87 mm, and 0.85 mm, respectively (P-trend < 0.001). After adjustment for age, estradiol, testosterone, body mass index (weight (kg)/height (m)2), lipids, and other factors, FSH levels remained significantly associated with IMT (regression coefficients for quartiles 2-4 vs. quartile 1 were -0.038, -0.045, and -0.062, respectively; P-trend = 0.01). Findings were strongest in women aged 64-73 years (P-trend = 0.006) and did not vary by body mass index. In contrast, estradiol levels were not related to IMT. In summary, high postmenopausal FSH levels were associated with a lower atherosclerotic burden, independent of estradiol, adiposity, and other factors. Our findings warrant replication and the further exploration of potential underlying mechanisms.
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http://dx.doi.org/10.1093/aje/kwx174DOI Listing
January 2018

Intake of different dietary proteins and risk of type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Br J Nutr 2017 Mar 11;117(6):882-893. Epub 2017 Apr 11.

Institute of Public Health and Clinical Nutrition,University of Eastern Finland,PO Box 1627,70211 Kuopio,Finland.

The roles of different dietary proteins in the aetiology of type 2 diabetes (T2D) remain unclear. We investigated the associations of dietary proteins with the risk of incident T2D in Finnish men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study. The study included 2332 men aged 42-60 years at the baseline examinations in 1984-1989. Protein intakes were calculated from 4-d dietary records. Incident T2D was determined by self-administered questionnaires, fasting blood glucose measurements, 2-h oral glucose tolerance tests, and with national registers. The multivariable-adjusted risk of T2D on the basis of protein intakes was compared by the Cox proportional hazard ratios (HR). During the mean follow-up of 19·3 years, 432 incident T2D cases were identified. Total, animal, meat or dairy product protein intakes were not associated with risk of T2D when the potential confounders were accounted for. Plant (multivariable-adjusted extreme-quartile HR 0·65; 95 % CI 0·42, 1·00; P trend 0·04) and egg (HR 0·67; 95 % CI 0·44, 1·00; P trend 0·03) protein intakes were associated with a decreased risk of T2D. Adjustments for BMI, plasma glucose and serum insulin slightly attenuated associations. Replacing 1 % energy from carbohydrates with energy from protein was associated with a 5 % (95 % CI 0, 11) increased risk of T2D, but adjustment for fibre intake attenuated the association. Replacing 1 % of energy from animal protein with energy from plant protein was associated with 18 % (95 % CI 0, 32) decreased risk of T2D. This association remained after adjusting for BMI. In conclusion, favouring plant and egg proteins appeared to be beneficial in preventing T2D.
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http://dx.doi.org/10.1017/S0007114517000745DOI Listing
March 2017

Association between serum zinc and later development of metabolic syndrome in middle aged and older men: The Kuopio Ischaemic Heart Disease Risk Factor Study.

Nutrition 2017 May 20;37:43-47. Epub 2016 Sep 20.

University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland. Electronic address:

Objective: The aim of this study was to investigate associations of serum zinc with incident metabolic syndrome and its components in middle-aged and older Finnish men.

Methods: An 11-y prospective follow-up study conducted among 683 men from the Kuopio Ischaemic Heart Disease Risk Factor Study who were 42 to 60 y old at baseline in 1984 to 1989. The main outcome was incident metabolic syndrome, defined by the National Cholesterol Education Program (NCEP) criteria. Other outcomes were the individual components of the NCEP metabolic syndrome: Fasting blood glucose, serum triacylglycerols, serum high-density lipoprotein (HDL) cholesterol, hypertension, and waist circumference.

Results: During the average follow-up of 11 y, 139 men (20.4%) developed metabolic syndrome. Those in the highest tertile of serum zinc had 84% higher risk (95% confidence interval 12 to 201%, P trend across tertiles = 0.015) to develop metabolic syndrome compared with those in the lowest tertile, after adjustment for several potential confounders. The association between serum zinc and incident metabolic syndrome was attenuated by adjustment for waist circumference, serum HDL cholesterol, or hypertension. Serum zinc was also directly associated with higher waist circumference and hypertension and inversely associated with HDL cholesterol at the 11 y examinations.

Conclusions: We found a direct association between serum zinc and incidence of metabolic syndrome in middle-aged and older eastern Finnish men. Further studies are warranted to explore the mechanisms.
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http://dx.doi.org/10.1016/j.nut.2016.09.004DOI Listing
May 2017

Serum dihomo-γ-linolenic acid level is inversely associated with the risk of depression. A 21-year follow-up study in general population men.

J Affect Disord 2017 Apr 16;213:151-155. Epub 2017 Feb 16.

Department of Psychiatry, Kuopio University Hospital, P.O. Box 100, 70029, KYS, Kuopio, Finland. Electronic address:

Background: Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation.

Methods: A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42-60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation.

Results: An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36-0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618).

Limitations: Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting.

Conclusions: Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear.
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http://dx.doi.org/10.1016/j.jad.2017.02.022DOI Listing
April 2017

Association of follicle-stimulating hormone levels and risk of type 2 diabetes in older postmenopausal women.

Menopause 2017 Jul;24(7):796-802

1Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 2Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland 3Department of Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland 4Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.

Objective: Recent studies of perimenopausal women have observed associations of follicle-stimulating hormone (FSH) levels with markers of insulin resistance, independent of estradiol. Whether FSH is related to type 2 diabetes (T2D) in older women who have completed the menopause transition remains unknown. We assessed the association of FSH levels with diabetes and measures of insulin resistance among 588 postmenopausal Finnish women.

Methods: Study participants were aged 53 to 73 years and not using hormone therapy at baseline (1998-2001) when FSH was measured. Prevalence of T2D was assessed at baseline, along with fasting insulin and glucose levels. Incident T2D, and insulin and glucose levels were assessed 7 to 9 years later at follow-up examination.

Results: After adjustment for age, estradiol, body mass index, smoking, lipids levels, and other factors, women with higher FSH (>50 IU/L) had a lower prevalence of T2D (odds ratio 0.49, 95% confidence interval [CI] 0.28-0.86) than women with lower FSH. Each 1 unit increase in FSH level was associated with a significant 1.9% lower risk of T2D (95% CI 0.966-0.997, P = 0.02). Higher FSH was associated with marginally significant lower incidence of T2D at follow-up (hazard ratio 0.53, 95% CI 0.27-1.02). Baseline FSH levels were inversely correlated with fasting insulin and glucose levels at both baseline and follow-up visits (all P < 0.05). After adjustment, FSH was modestly associated with fasting insulin at baseline (P = 0.01) and at follow-up (P = 0.11).

Conclusions: Higher postmenopausal FSH levels were associated with lower prevalent and incident T2D and fasting insulin levels. These findings warrant replication in larger prospective studies.
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http://dx.doi.org/10.1097/GME.0000000000000834DOI Listing
July 2017

Association of dietary cholesterol and egg intakes with the risk of incident dementia or Alzheimer disease: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2017 02 4;105(2):476-484. Epub 2017 Jan 4.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and

Background: There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ɛ4 (APO-E4), a major risk factor for dementia.

Objective: We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland.

Design: A total of 2497 dementia-free men, aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses.

Results: During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11).

Conclusions: Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance.
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http://dx.doi.org/10.3945/ajcn.116.146753DOI Listing
February 2017

Low serum 25-hydroxyvitamin D is associated with higher risk of frequent headache in middle-aged and older men.

Sci Rep 2017 01 3;7:39697. Epub 2017 Jan 3.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Vitamin D has been suggested to have a role in various neurovascular diseases, but the data regarding headache is inconclusive. Our aim was to investigate the associations between serum 25-hydroxyvitamin D [25(OH)D], a marker for vitamin D status, and risk of frequent headache. The study population consisted of 2601 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) from eastern Finland, aged 42-60 years in 1984-1989. The cross-sectional associations with prevalence of self-reported frequent headache (defined as weekly or daily headaches) were estimated with multivariable-adjusted odds ratios. The average serum 25(OH) concentration was 43.4 nmol/L (SD 18.9, min-max 7.8-136.1 nmol/L). A total of 250 men (9.6%) reported frequent headache. The average serum 25(OH)D concentration among those with frequent headache was 38.3 nmol/L (SD 18.8) and 43.9 nmol/L (SD 18.9) among those without frequent headache, after adjustment for age and year and month of blood draw (P for difference <0.001). After multivariable adjustments, those in the lowest vs. the highest serum 25(OH)D quartile had 113% (95% CI 42, 218%; P for trend <0.001) higher odds for frequent headache. In conclusion, low serum 25(OH)D concentration was associated with markedly higher risk of frequent headache in men.
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http://dx.doi.org/10.1038/srep39697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206741PMC
January 2017

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies.

JAMA Intern Med 2016 08;176(8):1155-66

Department of Odontology, Umeå University, Umeå, Sweden.

Importance: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers.

Objective: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD.

Data Sources: A global consortium of 19 studies identified by November 2014.

Study Selection: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD.

Data Extraction And Synthesis: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes.

Main Outcomes And Measures: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI).

Results: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses.

Conclusions And Relevance: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.
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http://dx.doi.org/10.1001/jamainternmed.2016.2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183535PMC
August 2016

Molecular evaluation of vitamin D responsiveness of healthy young adults.

J Steroid Biochem Mol Biol 2017 11 6;174:314-321. Epub 2016 Jun 6.

School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. Electronic address:

Vitamin D has via its metabolites 25-hydroxyvitamin D (25(OH)D) and 1α,25-dihydroxyvitamin D (1,25(OH)D) direct effects on the transcriptome and the epigenome of most human cells. In the VitDbol study we exposed 35 healthy young adults to an oral vitamin D dose (2000μg) or placebo and took blood samples directly before the supplementation as well as at days 1, 2 and 30. Within 24h the vitamin D intake raised the average serum levels of both 25(OH)D and 1,25(OH)D by approximately 20%. However, we observed large inter-individual differences in these serum levels, reflected by the average ratios between 25(OH)D and 1,25(OH)D concentrations ranging from 277 to 1365. Interestingly, average serum parathyroid hormone (PTH) levels increased at day 1 by some 10% but then decreased within the following four weeks to levels 5% below baseline. In peripheral blood mononuclear cells (PBMCs) that were isolated at the same time points we determined vitamin D-modulated chromatin accessibility by FAIRE-qPCR at selected genomic loci. This method is well suited to evaluate both short-term and long-term in vivo effects of vitamin D on the epigenome of human subjects. The differential vitamin D responsiveness of the VitDbol study participants was determined via individual changes in their PTH levels or chromatin accessibility in relation to alterations in 25(OH)D concentrations. This led to the segregation of the subjects into 14 high, 11 mid and 10 low responders. In summary, the vitamin D responsiveness classification provides additional information compared to a vitamin D status assessment based on single 25(OH)D serum measurements. The study was registered at Clinicaltrials.gov (NCT02063334).
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http://dx.doi.org/10.1016/j.jsbmb.2016.06.003DOI Listing
November 2017

Gender difference in type 2 diabetes and the role of body iron stores.

Ann Clin Biochem 2017 Jan 28;54(1):113-120. Epub 2016 Sep 28.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Finland.

Background Studies of gender difference in type 2 diabetes have been inconclusive. We investigated gender difference in type 2 diabetes and the contribution of body iron, as assessed by serum ferritin to this difference. Methods We performed cross-sectional ( n = 1707) and prospective ( n = 1506) analyses in males and females aged 53-73 years in 1998-2001. Type 2 diabetes diagnosis was determined by questionnaire, blood glucose measurements and record linkage to type 2 diabetes registers. Gender difference in type 2 diabetes and serum ferritin contribution to the difference was examined in multivariable logistic and Cox regression models. Gender difference in fasting plasma glucose and insulin and homeostasis model assessment of insulin resistance was examined in linear regression analysis. Results In the cross-sectional analysis, a total of 201 type 2 diabetes cases were observed (males = 111 [55.2%] vs. female = 90 [44.8%], P = 0.032), and in adjusted models, males had higher odds of type 2 diabetes (OR = 1.61, 95% CI 1.10 to 2.34); higher fasting plasma glucose (β = 0.28, 95% CI 0.15 to 0.41), fasting plasma insulin (β = 0.73, 95% CI 0.26 to 1.19) and homeostasis model assessment of insulin resistance (β = 0.11, 95% CI 0.04 to 0.17). In the prospective analysis, males had increased risk of type 2 diabetes (HR = 1.46, 95% CI 1.03 to 2.07). With serum ferritin introduction (100  µg/L, log-transformed) into the models, the type 2 diabetes prevalence (OR = 1.35, 95% CI 0.91 to 1.99) and incidence (HR = 1.38, 95% CI 0.96 to 1.97) were appreciably attenuated. Conclusions These data suggest a gender difference in type 2 diabetes, with a higher prevalence and increased type 2 diabetes risk in males. Body iron explains about two-fifths and one-fifth of the gender difference in type 2 diabetes prevalence and incidence, respectively.
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http://dx.doi.org/10.1177/0004563216646397DOI Listing
January 2017

Serum n-6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2016 05 23;103(5):1337-43. Epub 2016 Mar 23.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and

Background: The role of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations.

Objectives: We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations.

Design: The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y and free of T2D at baseline in 1984-1989. T2D was assessed by self-administered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations.

Results: During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend < 0.001) and higher concentrations of total n-6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend < 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend < 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of γ-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomo-γ-linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend < 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04).

Conclusions: Higher serum total n-6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D.
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http://dx.doi.org/10.3945/ajcn.115.128629DOI Listing
May 2016

Serum long-chain omega-3 polyunsaturated fatty acids and risk of orthostatic hypotension.

Hypertens Res 2016 Jul 25;39(7):543-7. Epub 2016 Feb 25.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) from fish have been shown to lower blood pressure. However, there is little information about the association with orthostatic hypotension, for which hypertension is a risk factor. We investigated the associations between serum long-chain omega-3 PUFAs and orthostatic hypotension in 1666 middle-aged or older men and women free of cardiovascular disease (CVD), diabetes or hypertension in 1998-2001 in the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. We also investigated the associations with mercury exposure, a major source of which is fish, and which has been associated with higher CVD risk in KIHD. Orthostatic hypotension was defined as decrease in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 1 min of standing. Orthostatic hypotension was found in 146 participants (8.8%). The mean serum concentrations were 1.67% (s.d. 0.92) for eicosapentaenoic acid, 0.79% (s.d. 0.16) for docosapentaenoic acid (DPA) and 2.78 (s.d. 0.92) for docosahexaenoic acid of all serum fatty acids. The mean pubic hair mercury concentration was 1.5 μg g(-1) (s.d. 1.6). We did not find statistically significant associations between the serum long-chain omega-3 PUFAs or pubic hair mercury and risk of orthostatic hypotension, except for DPA. Those in the highest vs. the lowest serum DPA tertile had multivariate-adjusted 41% lower odds for orthostatic hypotension (95% confidence interval 7-63%, P-trend=0.02). Serum long-chain omega-3 PUFAs or mercury exposure were not associated with the risk of orthostatic hypotension, except for the inverse association with DPA.
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http://dx.doi.org/10.1038/hr.2016.19DOI Listing
July 2016

Associations of egg and cholesterol intakes with carotid intima-media thickness and risk of incident coronary artery disease according to apolipoprotein E phenotype in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2016 Mar 10;103(3):895-901. Epub 2016 Feb 10.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and.

Background: In general populations, the effects of dietary cholesterol on blood cholesterol concentrations are modest. However, the relation is stronger in those with an ɛ4 allele in the apolipoprotein E gene (APOE). There is little information on the association between cholesterol intake and the risk of coronary artery disease (CAD) among those with the ApoE4 phenotype.

Objective: We investigated the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with carotid intima-media thickness and the risk of incident CAD in middle-aged and older men from eastern Finland.

Design: The study included 1032 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on common carotid artery intima-media thickness (CCA-IMT) were available for 846 men. Dietary intakes were assessed with 4-d food records. Associations with incident CAD and baseline CCA-IMT were analyzed by using Cox regression and ANCOVA, respectively.

Results: The ApoE4 phenotype was found in 32.5% of the men. During the average follow-up of 20.8 y, 230 CAD events occurred. Egg or cholesterol intakes were not associated with the risk of CAD. Each 1 additional egg (55 g)/d was associated with a multivariable-adjusted HR of 1.17 (95% CI: 0.85, 1.61) in the ApoE4 noncarriers and an HR of 0.93 (95% CI: 0.50, 1.72) in the ApoE4 carriers (P-interaction = 0.34). Each 100-mg/d higher cholesterol intake was associated with an HR of 1.04 (95% CI: 0.89, 1.22) in the ApoE4 noncarriers and an HR of 0.95 (95% CI: 0.73, 1.25) in the ApoE4 carriers (P-interaction = 0.81). Egg or cholesterol intakes were also not associated with increased CCA-IMT.

Conclusion: Egg or cholesterol intakes were not associated with increased CAD risk, even in ApoE4 carriers (i.e., in highly susceptible individuals).
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http://dx.doi.org/10.3945/ajcn.115.122317DOI Listing
March 2016
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