Jaana Leiviskä

Metabonomic, transcriptomic, and genomic variation of a population cohort

Comprehensive characterization of human tissues promises novel insights into the biological architecture of human diseases and traits. We assessed metabonomic, transcriptomic, and genomic variation for a large population‐based cohort from the capital region of Finland. Network analyses identified a set of highly correlated genes, the lipid–leukocyte (LL) module, as having a prominent role in over 80 serum metabolites (of 134 measures quantified), including lipoprotein subclasses, lipids, and amino acids. Concurrent association with immune response markers suggested the LL module as a possible link between inflammation, metabolism, and adiposity. Further, genomic variation was used to generate a directed network and infer LL modules largely reactive nature to metabolites. Finally, gene co‐expression in circulating leukocytes was shown to be dependent on serum metabolite concentrations, providing evidence for the hypothesis that the coherence of molecular networks themselves is conditional on environmental factors. These findings show the importance and opportunity of systematic molecular investigation of human population samples. To facilitate and encourage this investigation, the metabonomic, transcriptomic, and genomic data used in this study have been made available as a resource for the research community.

Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study.

Objective: To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. Methods: A dementia-free sample of 271 subjects aged 65–79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. Results: The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04–1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965–0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ϵ4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01–1.39) for tHcy and 0.977 (0.958–0.997) for holoTC. Adjusting for holoTC attenuated the tHcy–AD link (OR changed from 1.16 to 1.10, 95% CI 0.96–1.25). The holoTC–AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968–1.000). Addition of folate did not change any of the results. Conclusions: This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy–AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated.

Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study

Abstract.  Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hänninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H & Kivipelto M (Aging Research Center, Karolinska Institutet, Stockholm, Sweden; KI Alzheimer’s Disease Research Center (KI‐ADRC), Karolinska Institutet, Stockholm, Sweden; National Institute for Health and Welfare (THL), Helsinki, Finland; University of Eastern Finland, Institute of Clinical Medicine, and University Hospital, Kuopio, Finland). Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 2012; 271: 204–212.

Role of serum cytokines tumour necrosis factor-α and interleukin-6 in the association between body weight and periodontal infection

AIM To study the role of serum cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) as potential mediators in the association between body weight and periodontal infection among an adult population. MATERIAL AND METHODS This study was based on a subpopulation of the Health 2000 Health Examination Survey, which included dentate non-diabetic, non-rheumatic subjects, aged between 45 and 64 years, who had never smoked and whose serum levels of TNF-alpha and IL-6 were analysed and whose periodontal status was clinically determined (effective n=425). The number of teeth with periodontal pockets of 4 mm or more and the number of teeth with periodontal pockets of 6 mm or more were used as outcome variables. Relative risks and 95% confidence intervals were estimated using Poisson regression models. RESULTS Serum IL-6, but not TNF-alpha associated with teeth with deepened periodontal pockets. Multivariate models showed that IL-6, but not TNF-alpha, could mediate the effect of body weight on periodontium. CONCLUSION In this population of non-diabetic and non-rheumatic subjects, who had never smoked, serum IL-6 was associated with periodontal infection. The results suggest that serum IL-6 could be one mediating factor that connects body weight and periodontal infection.

Blood microRNA profile associates with the levels of serum lipids and metabolites associated with glucose metabolism and insulin resistance and pinpoints pathways underlying metabolic syndrome The cardiovascular risk in Young Finns Study

Since metabolic syndrome (MetS) is a collection of cardiovascular risk factors involving multiple signaling systems, we related the metabolic abnormalities associated with MetS with circulating microRNA profiles to pinpoint the affected signaling pathways. The blood microRNA profile, genome wide gene expression and serum NMR metabolomics were analyzed from 71 participants of the Young Finns Study. We found nine microRNAs that associated significantly with metabolites connected to MetS. MicroRNA-144-5p concentration correlated with glucose levels, hsa-1207-5p with glycosylated hemoglobin and hsa-miR-484 with metabolites related to insulin resistance. Hsa-miR-625-3p correlated with cholesterol levels, hsa-miR-1237-3p and hsa-miR-331-3p expression with certain fatty acids levels and hsa-miR-129-1-3p, -129-2-3p, and -1288-3p with glycerol levels. The down-regulated targets of miR-1207-5p and -129-2-3p were enriched in PI3K and MAPK pathways and 8 out of the 12 enriched pathways were down-regulated in individuals with MetS. In conclusion microRNAs associated with several aspects of MetS, possibly regulating glucose and lipid metabolism.

Association of Serum 25-Hydroxyvitamin D with Lifestyle Factors and Metabolic and Cardiovascular Disease Markers: Population-Based Cross-Sectional Study (FIN-D2D)

Objectives Low serum 25-hydroxyvitamin D (25OHD) level has been associated with an increased risk of several chronic diseases. Our aim was to determine lifestyle and clinical factors that are associated with 25OHD level and to investigate connection of 25OHD level with metabolic and cardiovascular disease markers. Design In total, 2868 Finnish men and women aged 45–74 years participated in FIN-D2D population-based health survey in 2007. Participants that had a serum sample available (98.4%; n = 2822) were included in this study. 25OHD was measured with chemiluminescent microparticle immunoassay method. Results The mean 25OHD level was 58.2 nmol/l in men (n = 1348) and 57.1 nmol/l in women (n = 1474). Mean 25OHD level was lower in the younger age groups than in the older ones (p<0.0001 both in men and women). This study confirmed that low physical activity (p<0.0001 both in men and women), smoking (p = 0.0002 in men and p = 0.03 in women) and high BMI (p<0.0001 in women) are factors that independently associate with low 25OHD level. Of the metabolic and cardiovascular disease markers high triglyceride concentration (p = 0.02 in men and p = 0.001 in women) and high apolipoprotein B/apolipoprotein A1 ratio (p = 0.04 in men and p = 0.03 in women) were independently associated with low 25OHD level. Conclusions Higher age did not predict lower 25OHD level in this study population of aged 45–74 years which may derive from a healthy life-style of “active pensioners”. Low physical activity and smoking came up as independent lifestyle factors associated with low 25OHD level. Defining the molecular mechanisms behind the associations of 25OHD with low physical activity and smoking are important objective in future studies. The association of 25OHD with BMI, high triglyceride concentration and apolipoprotein B/apolipoprotein A1 ratio may be related to the role of vitamin D in inflammation, but more detailed studies are needed.

Systematic error of serum triglyceride measurements during three decades and the effect of fasting on serum triglycerides in population studies.

BACKGROUND An uncontrolled systematic error in serum biomarkers may be a serious problem when comparing their trends both within and between populations. The aim of the study was to assess which factors are responsible for systematic errors in the measurement of serum triglycerides (Tg) and the effect of fasting on serum triglycerides in Finnish population surveys. METHODS Data on precision and accuracy during 30 years for serum triglycerides were documented from participation in 492 rounds of five different external quality assessment (EQA) programs. Data on fasting and health status from questionnaires were combined from three population surveys comprising 27,131 participants. RESULTS The mean annual accuracy (bias) of the Tg methods from all EQAs during 1978-2007 was -1.54% (95% CI -2.25, -0.83). The mean relative change in triglyceride concentration per fasting hour was -3.7% (95% CI -4.2, -3.1) in all subjects. A minimum serum Tg concentration was seen in men and women who had fasted for at least 8 and 7 h, respectively. CONCLUSIONS The mean bias in serum Tg analyses has been very small throughout the 30-year period. Fasting has a considerable effect on triglyceride levels, but they can be converted either to fasting or non-fasting levels using specific factors.

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.

Modifying effects of alcohol on the postprandial glucose and insulin responses in healthy subjects

BACKGROUND Moderate alcohol consumption associates with lower risk of type 2 diabetes, but in postprandial studies, alcohol induced impaired insulin sensitivity. The measurement of the glycemic index (GI) for beer has been considered challenging because of its low carbohydrate content. Therefore, imputed GI values from 36 to 95 on the basis of carbohydrate-rich beverages have been used for beer in epidemiologic studies. OBJECTIVES We investigated the acute effects of alcohol on glucose and insulin responses and measured GIs and insulinemic indexes (IIs) of nonalcoholic and alcoholic beers. DESIGN In a crossover design, 10 healthy volunteers were served beer with 4.5% alcohol by volume, nonalcoholic beer, and a glucose solution with alcohol once and the reference glucose solution twice. Each portion contained 25 g available carbohydrate, and the beer and glucose solution with alcohol contained 21 g alcohol. Capillary blood samples were collected up to 2 h after ingestion, and the incremental AUCs (IAUCs), GIs, and IIs were calculated. RESULTS Compared with the reference glucose solution, the glucose solution with alcohol produced an 18% higher postprandial glucose IAUC (P = 0.03) and had no significant effect on the insulin IAUC. Compared with the reference glucose solution, beer had no significant effect on glucose or insulin IAUCs, and nonalcoholic beer tended to reduce the glucose IAUC (P = 0.06) but not the insulin IAUC. GIs of beer and nonalcoholic beer were 119 and 80, and IIs were 130 and 88, respectively. CONCLUSIONS Alcohol increases the postprandial glucose response, probably through impaired insulin sensitivity. GI values published for alcohol-containing beers have underestimated the true glycemic effects.

Associations of the Baltic Sea diet with obesity-related markers of inflammation

Abstract Introduction. Inflammation is an important contributor to the development of chronic diseases. We examined whether a healthy Nordic diet, also called the Baltic Sea diet, associates with lower concentrations of inflammatory markers. Methods. We used two independent cross-sectional studies: the DILGOM study including Finnish participants aged 25–74 years (n = 4579), and the Helsinki Birth Cohort Study including individuals born at Helsinki University Central Hospital between 1934 and 1944 and who participated in a clinical examination in 2001–2004 (n = 1911). Both studies measured anthropometrics, drew blood, and assessed concentrations of leptin, high-molecular-weight adiponectin, tumor necrosis factor α, interleukin 6, and high-sensitivity C-reactive protein (hs-CRP). A food frequency questionnaire was used to measure dietary intake over the past year and calculate the Baltic Sea Diet Score (BSDS). Results. In both studies, linear regression adjusting for age, sex, energy intake, lifestyle factors, obesity, statin medication, and upstream inflammatory markers revealed an inverse association between the BSDS and hs-CRP concentrations (P < 0.01). Especially, high intake of Nordic fruits and cereals, low intake of red and processed meat, and moderate intake of alcohol contributed to the emerged association (P < 0.05). The BSDS did not associate with other inflammatory markers. Conclusion. The Baltic Sea diet is associated with lower hs-CRP concentrations.