Molecular Determinants of Metabolic Syndrome (Metsyn)

Project Leaders
Prof. Markku Savolainen, M.D., Ph.D.
, Biocenter Oulu and Department of Internal Medicine, University of Oulu and Oulu University Hospital
Prof. Karl-Heinz Herzig, M.D., Ph.D., Biocenter Oulu and Department of Physiology, Institute of Biomedicine, University of Oulu and Oulu University Hospital
Prof. Marjo-Riitta Järvelin, M.D., M.Sc., Ph.D., Centre For Life-Course Health Research, Biocenter Oulu, Oulu University Hospital
Faculty of Medicine, University of Oulu

Background and Significance

Cardiovascular disease (CVD) is the leading cause of death globally, representing around 30% of all deaths worldwide and nearly half of all deaths in Europe (WHO Statistics, 2008). Over the past 30 years mortality from CVD has declined steadily in the developed western economies but recent dramatic increases in the prevalence of obesity, type 2 diabetes (T2D) and metabolic syndrome (MetSyn) are, however, reversing this positive trend. Multiple factors through the life-course have been related to the risk of MetSyn (Fig. 1). Our recent work shows that determinants of early growth and growth patterns are associated with inflammatory markers and MetSyn phenotypes. There is increasing evidence that inflammatory mechanisms have an important role in the initiation and progression of CVDs, and there may be an important link between CVDs and clustering of MetSyn phenotypes (Fig. 1). Altogether, our work suggests that systemic low-grade inflammation may lie on the causal pathway involving impaired foetal growth, growth patterns and body mass from childhood, and adverse cardiometabolic health. However, the disease mechanisms and its components are still poorly understood. Consequently, there is urgent need for further exploration of human life-course data, and for molecular-level studies on the underlying pathophysiological mechanisms. These approaches are key to the identification of risk groups, for early disease prevention and treatment. This work is enormously enhanced by our recent 46- to 48-year follow-up data collection in the Northern Finland Birth Cohort (NFBC) 1966, and extended experimental work.

Our life-course studies on the Northern Finland Birth Cohort are strongly supportive of the fact that systemic low-grade inflammation may lie on the causal pathway towards MetSyn (Sovio et al. 2013). Key mechanisms behind obesity-related disorders include NFkB-dependent production of pre-inflammatory adipokines, Toll-like receptor (TLR) expression, increased oxidative stress and inflammasome activation. Macrophages can invade from the blood stream and induce inflammatory responses through pathogen- or damage-associated molecular patterns (PRRs) (Rathinam et al. 2012). Inflammatory cells can represent up to 40% of all cells in adipose tissue (Weisberg et al. 2003). In addition to macrophages, mast cells are present in adipose tissue, playing a central role in the inflammatory process (Zhang & Shi 2012, Theoharides et al. 2011).

Figure 1. Systemic low-grade inflammation might negatively influence foetal growth, growth patterns and body mass from childhood, to adverse adult cardiometabolic health.

Impairment of the high-density lipoprotein cholesterol (HDL-C) level and the quality of HDL particles is another hallmark in the definition of MetSyn. Alteration of HDL metabolism and that of other lipoproteins exerts a strong and independent risk as regards the onset of coronary heart disease (CHD), and, in particular, early-onset and familial CHD. Inflammation has a substantial effect on the quality and quantity of HDL. A recent study based on genetic instrumental variables is now raising an important debate on the causal pathways to explain the role of HDL and HDL-related biomarkers in the prevention of atherosclerosis and warrants further studies. These include not only the other major lipid and apolipoprotein components but also minor bioactive lipid molecules residing in the HDL particles. Furthermore, a large number of molecules circulating more or less firmly bound to HDL particles may contribute to the anti-atherogenic potential of HDL via antioxidative and anti-inflammatory effects or cholesterol transport capacity. Therefore, we urgently need novel ways to assess the anti-atherosclerotic potential of HDL. One of these concerns reverse cholesterol transport (RCT), where HDL particles remove cholesterol from the arterial wall and transport it to the liver. The first important step in RCT is the outflow (efflux) of cholesterol from cells into the HDL particles. The composition of HDL particles seems be a more important determinant of their anti-atherogenic properties than the amount of HDL-C. However, the effects of different HDL particle compositions on cholesterol efflux have not been studied in detail.

The “fused-toe” or the fat-mass and obesity-associated FTO gene (Dina et al. 2007, Frayling et al. 2007) is the most prevalent genetic variant as regards human BMI (Speliotes et al.  2010, Yang et al. 2012). It may provide a missing link in the developmental regulation of energy metabolism (Sebert et al. 2014). The question of whether or not the obesity-associated gene FTO is key in obesity development in humans, and the underlying molecular mechanisms are very poorly understood. Current knowledge suggests a role of the FTO protein in the demethylation of RNA in relation to energy-sensing pathways. The physiological function of the protein and the mechanisms associating weight gain and RNA demethylation demand further attention. Our group is conducting research in Fto knock-out mice to further comprehend the process through which FTO predisposes individuals to weight gain.

Recent Progress

Our consortium posits a primary role of pro-inflammatory pathways (Fig. 1) in setting up the risk of a myriad of disorders associated with metabolic syndrome. In 2016 the group made major advances in each of our three projects.

Project 1: Life-course Epidemiology.

We have i) acquired new data to characterise further the pathways, ii) performed research in the genomic determinants of the early risk for obesity and T2D, and iii) explored the genetics and the pathophysiology of HDL composition and function. Briefly, while analysing the factors associated with the changes in metabolic health in mid-age in the NFBC, we have further intensified our work on phenotyping the cohort deeply. An essential aspect of the life-course origin of health and diseases is interplay between genetic build-up and the epigenetic program. DNA methylation is suggested to play a major role in modulating the individual risk of obesity and T2D (Chambers J.C. et al. 2015). It might at the same time bio-mark environmental insults and be informative as regards new discoveries. In 2015, we were able to intensify the measure of DNA methylation in the NFBC and we further organised our teams to analyse the role of early stress in setting up the intermediary risk factor (inflammation, metabolomics) and clinical end-points (obesity, type 2 diabetes) (Academy project EGEA). In the Horizon 2020 call, our application PHC-01-2014, “Understanding the dynamic determinants of glucose homeostasis and psychosocial capability to promote healthy and active ageing (DynaHEALTH)” was approved for funding at the beginning of 2015. In addition to this effort we have intensified our research into the genomics of early growth, exemplified by our track record with the EGG (early growth genetics) and GIANT consortium.

Our previous genome-wide linkage scan revealed six loci showing suggestive evidence of linkage in connection with HDL-C level regulation in families collected from Northern Finland (Kangas-Kontio, T. et al. Eur. J. Hum. Genet 2010). Whole-exome sequencing was used to perform detailed analysis of these linkage regions and also additional genomic regions associated with HDL-C, other lipid traits and CHD in large genome-wide association studies. Deeper genotyping of these regions uncovered multiple inherited alleles possibly contributing to the increased risk of CHD in these families. Large population-specific cohorts will enable reliable replication of the results. It is estimated that protein-coding genes harbour about 85% of the mutations with great effects on disease-related traits (Majewski, J. et al. J. Med. Genet. 2011), which makes whole-exome sequencing an effective tool to screen rare genetic variants contributing to disease risk. Finland is ideal for the first generation of large-scale medical sequencing studies, focused on discovering high-impact rare variants and demonstrating their impact on disease (Zuk, O. et al. Proc. Natl. Acad. Sci. USA 2014). Finnish allele frequency distribution shows a paucity of singleton variants, compared with other European populations (Lim, E. T. et al. PLoS Genet. 2014), and a relative overabundance of variants in the 0.5–5% range. The latter is particularly marked for those variants that are most likely deleterious. We have reported that plasma levels of antibodies against oxidized LDL are inherited but not associated with HDL-cholesterol levels in families with early-onset CHD (Paavola, T. et al. Atherosclerosis 2012; Makinen, V. P. et al. J. Intern. Med. 2013). To study the functional role of HDL in reverse cholesterol transport (RCT), a mechanism presumed to protect against CHD, we have investigated how different HDL subclasses derived from CHD patients vs. control subjects mediate RCT from THP-1 cells. In this functional study, early-onset CHD, metabolic syndrome and low HDL-C levels were associated with impaired HDL2-mediated RCT. Combination of low level and poor quality of HDL2 was observed with the cardiometabolic disease of the study subjects, but the phospholipid content could not explain the impaired efflux (Paavola T et al. PLoS One 2017).

Project 2: Contribution of inflammation to features of metabolic syndrome.

Recently, we have been investigating if there are quantitative associations between amounts and intensities of physical activities (PA) on NMR biomarkers and changes in skeletal muscle gene expressions in subjects with high risk for type 2 diabetes (T2D).

In the principal component analysis after a 3-month intervention PA was associated with beneficial biomarker changes in a factor containing several VLDL and HDL subclasses and lipids (P= -0.01). Division of PA into quartiles demonstrated significant changes in NMR biomarkers in the 2nd 4th quartiles compared to the 1st quartile representing PA of less than 2850 daily steps (P=0.0036). Mediation analysis of body weight loss on physical activity-related reductions in lipoproteins showed that the effects of PA was 5.7 times greater than on body weight reduction. In a subset study in highly active subjects’ gene expressions of oxidative fiber markers, Apo D, G0/G1 S 2, controlling insulin signaling and glucose metabolism were significantly increased.

Slow walking exceeding 2895 steps/day attenuated several circulating lipoprotein lipids and the effects were mediated rather by PA than weight loss indicating that lower thresholds for PA exists for long term prevention of cardio-metabolic diseases and in sedentary and overweight subjects with abnormal glucose tolerance.

In addition, we could observe strong associations with fiber supplementations with food intake (mice and man) and lower vitamin D levels in patients with colorectal cancer compared to the controls. Interestingly, among the patients mismatch repair deficiency, serrated morphology and high body mass index associated with lowest serum 25(OH)D levels.

In terms of inflammation, vitamin D deficiency detected upon ICU admission was not associated with 90-day mortality in patients with severe sepsis or septic shock. In severe sepsis and septic shock, a vitamin D deficiency upon ICU admission was not associated with increased mortality. Compared to patients with sufficient vitamin D, patients with deficient vitamin D more frequently exhibited diabetes, elevated C-reactive protein levels, and hospital-acquired infections upon ICU admission, and they more frequently developed acute kidney injury.

Project 3: Obesity, adipogenesis and the role of Fto

In our studies, we use Fto-knock-in-first mouse model to study the effects of Fto in vivo. The mouse model contains a lacZ-reporter gene that visualizes the expression of Fto in different tissues and organs (Fig. 2).

Figure 2. Pictures of whole organs dissected from wild-type (left) and heterozygous Fto-G10 (right) mice stained with X-gal for β-gal expression. a) brain, b) muscle, c) bowel (with pancreas on the right-hand side), d) epididymal adipose tissue, e) spleen, f) embryo at the age of 11.5 dpc.

We have found that Fto deficiency protects mice from diet-induced obesity, which was confirmed by reduced adipocyte size (Ronkainen et al. 2015). Metabolic and behavioural parameters were unaltered in Fto-deficient mice. The expression of genes regulating adipogenesis was higher and adipokine production altered in the white adipose tissue of Fto-deficient mice. The expression of Irx3 (iroquois homeobox) was elevated in Fto-deficient mice after high-fat feeding, which was not seen in wild-type mice. Our study demonstrates that Fto has a role in adipose tissue which modifies the response of white adipose tissue to high-fat feeding. Fto deficiency increases the expression of genes related to adipogenesis, preventing adipocytes from becoming hypertrophic after a high-fat diet. In addition, in our current research we are analysing interaction with the dietary environment to characterise precisely how exposure to an obesogenic environment may condition the activity of FTO (Fig. 3A). Our findings support the role of gene–gene interaction (i.e. Fto with Irx3) in adipose tissue in connection with a high-fat diet.

Figure 3. Proposal for the altered response of Fto-knockout white adipose tissue to high-fat feeding. The physiological response to a high-fat diet in wild-type mice causes Fto to decrease the levels of genes related to adipogenesis, such as Pparg, Rxra and Cebpa, promoting adipocyte hypertrophy and obesity, with unfortunate consequences. When Fto is absent, levels of Pparg, Rxra and Cebpa remain elevated even after a high-fat diet, which prevents adipocytes from becoming hypertrophic and maintains adiponectin production.

Many miRNAs regulate the adipogenesis related gene expression and FTO participates in the regulation of certain miRNAs. Our recent results indicate that the adaptation to high-fat diet in the scWAT and BAT of the Fto-KO mice occurs via miRNAs (Fig. 3B), such as miR-130b, miR-155 and miR-378 (Ronkainen J et al. 2016).

Future Goals

We aim to identify inflammatory pathways from early life leading to MetSyn, by using an integrated systems approach in human epidemiological and clinical data, molecular mechanistic studies and application of causal analytical approaches. We will continue to explore the genetic determinants of MetSyn phenotypes by considering life-course exposures (exposomics).

The new areas of research are to investigate whether the early exposome is associated with specific methylation marks, as molecular-level indicators of the impact of environment, and whether these marks are associated with later-life metabolic outcomes. The results obtained will be further applied in experimental work.

We hypothesize that factors secreted from adipocytes and/or other cells in adipose tissue are responsible for the inflammatory state and activated macrophages/mast cells. Low concentrations of 25(OH)D (as a model substance) are associated with adverse metabolic phenotypes via increased cytokine/altered adipokine production, which might be reversed by high 25(OH)D levels. These mechanisms will be investigated in vivo and in vitro, including under hypoxic conditions, and the downstream targets elucidated.

The main aim of our work with lab animals will be to characterize the role of Fto in the early epigenetic programming of obesity in the fetal and early postnatal period. We will define the underlying molecular programming of inflammation- and oxidative stress-related pathways in key organs, including the hypothalamus and adipose tissues, to characterize the underlying pathways and the pathophysiological responses in terms of regulation of body weight and other pro-inflammatory functions. Furthermore, inflammation via stress responses will affect crosstalk in insulin-sensitive tissues. Changes in the environment, physical or perceived, are coordinated in the body by the hypothalamic-pituitary-adrenal (HPA) axis to maintain homeostasis which, via a coordinated neuroendocrine response communicates with all tissues modulating metabolic responses.

Publications 2016-

Ala-Kokko T, Mutt SJ, Nisula S, Koskenkari J, Liisanantti J, Ohtonen P, Poukkanen M, Pettilä V, Herzig KH and the FINNAKI study group. Vitamin D deficiency on admission is not associated with 90 day mortality in patients with severe sepsis or septic shock. Ann Med 48(1-2):67-75, 2016.

Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, et al (incl Herzig KH, Järvelin MR). The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet 48(10):1171-84, 2016.

Eising E, Huisman SM, Mahfouz A, Vijfhuizen LS, Anttila V, et al (incl Järvelin MR). Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas. Hum Genet 135(4):425-39, 2016.

Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, et al (incl Järvelin MR). Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48(8):856-66, 2016.

Gormley P, Anttila V, Winsvold BS, Palta P, et al (incl Järvelin MR). Corrigendum: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48(10):1296, 2016.

Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, et al (incl Järvelin MR). Genome-wide associations for birth weight and correlations with adult disease. Nature 538(7624):248-252, 2016.

Kamakura R, Kovalainen M, Leppäluoto J, Herzig KH, Mäkelä KA. The effects of group and single housing and measuring physiological and behavioral parameters using automated monitoring system on stress levels in male mice. Physiol Reports 4(3), 2016.

Kaminska D, Käkelä P, Venesmaa S, Ilves I, Herzig KH, Kolehmainen M, Karhunen L, Kuusisto J, Gylling H, Laakso M, Pihlajamäki J. Regulation of alternative splicing in human obesity loci. Obesity 24(10):2033-7, 2016.

Kanoni S, Masca NG, Stirrups KE, Varga TV, Warren HR, et al (incl Järvelin MR). Analysis with the exome array identifies multiple new independent variants in lipid loci. Hum Mol Genet 25(18):4094-4106, 2016.

Kantomaa MT, Tikanmäki M, Kankaanpää A, Vääräsmäki M, Sipola-Leppänen M, Ekelund U, Hakonen H, Järvelin MR, Kajantie E, Tammelin TH. Accelerometer-Measured Physical Activity and Sedentary Time Differ According to Education Level in Young Adults. PLoS One 11(7):e0158902, 2016.

Kiviniemi AM, Perkiömäki N, Auvinen J, Herrala S, Hautala AJ, Ahola R, Tammelin T, Tulppo MP, Järvelin MR, Korpelainen R, Huikuri HV. Lifelong Physical Activity and Cardiovascular Autonomic Function in Midlife. Med Sci Sports Exerc 48(8):1506-13, 2016.

Larsen SC, Ängquist L, Moldovan M, Huikari V, Sebert S, Cavadino A, Ahluwalia TS, Skaaby T, Linneberg A, Husemoen LLN, Toft U, Pedersen O, Hansen T, Herzig KH, Jarvelin MR, Power C, Hyppönen E, Heitmann BL, Sørensen TIA. Serum 25-hydroxyvitamin D status and longitudinal changes in weight and waist circumference: influence of genetic predisposition to adiposity. PloS One 11(4):e0153611, 2016..

Leder L, Kolehmainen M, Narverud I, Dahlman I, Myhrstad M, et al (incl Herzig KH, Savolainen MJ). Effects of a healthy Nordic diet on gene expression changes in peripheral blood mononuclear cells in response to an oral glucose tolerance test in subjects with metabolic syndrome: a SYSDIET sub-study. Genes Nutr 11:3, 2016.

Lehne B, Drong AW, Loh M, Zhang W, Scott WR, Tan ST, Afzal U, Schulz R, Scott J, Järvelin MR, Elliott P, McCarthy MI, Kooner JS, Chambers JC. Erratum to: A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies. Genome Biol 17(1):73, 2016.

Linna H, Suija K, Rajala U, Herzig KH, Karhu T, Jokelainen J, Keinänen-Kiukaanniemi S, Timonen M. The association between impaired glucose tolerance and soluble CD40 ligand: a 15-year prospective cohort study. Aging Clin Exp Res 28(6):1243-1249, 2016.

Karppinen P, Oinas-Kukkonen H, Alahäivälä T, Jokelainen T, Keränen AM, Salonurmi T, Savolainen M. Persuasive user experiences of a Health Behavior Change Support System: A 12-month study for prevention of metabolic syndrome. Int J Med Inform 96:51-61, 2016.

Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G; Social Science Genetic Association Consortium., Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Gale CR, Deary IJ. Genetic variants linked to education predict longevity. Proc Natl Acad Sci U S A 113(47):13366-13371, 2016.

Mason WA, January SA, Chmelka MB, Parra GR, Savolainen J, Miettunen J, Järvelin MR, Taanila A, Moilanen I. Cumulative contextual risk at birth in relation to adolescent substance use, conduct problems, and risky sex: General and specific predictive associations in a Finnish birth cohort. Addict Behav 58:161-6, 2016.

Minelli C, Dean CH, Hind M, Couto Alves A, Amara AFS, et al (incl Järvelin MR). Association of Forced Vital Capacity with the Developmental Gene NCOR2. PlosOne 11(2): e0147388, 2016.

Narverud I, Myhrstad MCW, Herzig KH, Karhu T, Dahl TB, Halvorsen B, Ulven SM, Holven KB. Lack of Effects of a Single High-Fat Meal Enriched with Vegetable n-3 or a Combination of Vegetable and Marine n-3 Fatty Acids on Intestinal Peptide Release and Adipokines in Healthy Female Subjects. Front Nutr 3:38, 2016.

Olli K, Saarinen M, Forssten S, Madetoja M, Herzig KH, Tiihonen K. Independent and combined effects of lactitol, polydextrose and Bacteroides thetaiotaomicron on postprandial metabolism and body weight in rats fed a high-fat diet. Front Nutr 3:15, 2016.

Okbay A, Baselmans BM, De Neve JE, Turley P, Nivard MG, et al (incl Järvelin MR). Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet 48(6):624-33, 2016. Corrigendum: 48(8):970 and 48(12):1591, 2016.

Okbay A, Beauchamp JP, Fontana MA, Lee JJ, Pers TH, et al (incl Järvelin MR). Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533(7604):539-42, 2016.

Palaniswamy S, Williams D, Järvelin MR, Sebert S. Vitamin D and the Promotion of Long-Term Metabolic Health from a Programming Perspective. Nutr Metab Insights 8(Suppl 1):11-21, 2016.

Parmar PG, Taal HR, Timpson NJ, Thiering E, Lehtimäki T, et al (incl Järvelin MR). International GWAS Consortium Identifies Novel Loci Associated with Blood Pressure in Children and Adolescents. Circ Cardiovasc Genet 9(3):266-78, 2016.

Perkiömäki N, Auvinen J, Tulppo MP, Hautala AJ, Perkiömäki J, Karhunen V, Keinänen-Kiukaanniemi S, Puukka K, Ruokonen A, Järvelin MR, Huikuri HV, Kiviniemi AM. Association between Birth Characteristics and Cardiovascular Autonomic Function at Mid-Life. PLoS One 11(8):e0161604, 2016.

Rannikko I, Jääskeläinen E, Miettunen J, Ahmed AO, Veijola J, Remes AM, Murray GK, Husa AP, Järvelin MR, Isohanni M, Haapea M. Predictors of Long-Term Change in Adult Cognitive Performance: Systematic Review and Data from the Northern Finland Birth Cohort 1966. Clin Neuropsychol 30(1):17-50, 2016.

Ried JS, Jeff M J, Chu AY, Bragg-Gresham JL, van Dongen J, et al (incl Järvelin MR). A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat Commun 7:13357, 2016.

Ronkainen J, Mondini E, Cinti F, Cinti S, Sebért S, Savolainen MJ, Salonurmi T. Fto-Deficiency Affects the Gene and MicroRNA Expression Involved in Brown Adipogenesis and Browning of White Adipose Tissue in Mice. Int J Mol Sci 17(11), 2016.

Ruiz M, Goldblatt P, Morrison J, Porta D, Forastiere F, Hryhorczuk D, Antipkin Y, Saurel-Cubizolles MJ, Lioret S, Vrijheid M, Torrent M, Iñiguez C, Larrañaga I, Bakoula C, Veltsista A, van Eijsden M, Vrijkotte TG, Andrýsková L, Dušek L, Barros H, Correia S, Järvelin MR, Taanila A, Ludvigsson J, Faresjö T, Marmot M, Pikhart H. Impact of Low Maternal Education on Early Childhood Overweight and Obesity in Europe. Paediatr Perinat Epidemiol 30(3):274-84, 2016.

Schumann G, Liu C, O'Reilly P, Gao H, Song P, et al (incl Herzig KH, Järvelin MR). KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci U S A 113(50):14372-14377, 2016.

Surendran P, Drenos F, Young R, Warren H, Cook JP, et al (incl Järvelin MR). Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet 48(10):1151-61, 2016.

Tikanmäki M, Tammelin T, Sipola-Leppänen M, Kaseva N, Matinolli HM, Miettola S, Eriksson JG, Järvelin MR, Vääräsmäki M, Kajantie E. Physical Fitness in Young Adults Born Preterm. Pediatrics 137(1):1-10, 2016.

Uimari O, Auvinen J, Jokelainen J, Puukka K, Ruokonen A, Järvelin MR, Piltonen T, Keinänen-Kiukaanniemi S, Zondervan K, Järvelä I, Ryynänen M, Martikainen H. Uterine fibroids and cardiovascular risk. Hum Reprod 31(12):2689-2703, 2016.

Vavuli S, Salonurmi T, Loukovaara S, Nissinen A, Savolainen MJ, Liinamaa MJ. Elevated levels of plasma IgA autoantibodies against oxidized LDL found in proliferative diabetic retinopathy but not in nonproliferative retinopathy. J Diabetes Res, 2016:2614153, 2016.

Williams DM, Palaniswamy S, Sebert S, Buxton JL, Blakemore AI, Hyppönen E, Järvelin MR. 25-Hydroxyvitamin D Concentration and Leukocyte Telomere Length in Young Adults: Findings From the Northern Finland Birth Cohort 1966. Am J Epidemiol 183(3):191-198, 2016.

Würtz P, Cook S, Wang Q, Tiainen M, Tynkkynen T, Kangas AJ, Soininen P, Laitinen J, Viikari J, Kähönen M, Lehtimäki T, Perola M, Blankenberg S, Zeller T, Männistö S, Salomaa V, Järvelin MR, Raitakari OT, Ala-Korpela M, Leon DA. Metabolic profiling of alcohol consumption in 9778 young adults. Int J Epidemiol 45(5):1493-1506, 2016.

Väyrynen JP, Jagalur Mutt S, Herzig KH, Klintrup K, Mäkelä J, Markus J Mäkinen MJ, Tuomisto A. Decreased preoperative serum 25-Hydroxyvitamin D levels in colorectal cancer are associated with systemic inflammation and serrated morphology. Sci Rep 6:36519, 2016.

Väyrynen JP, Kantola T, Väyrynen SA, Klintrup K, Bloigu R, Mäkelä J, Karhu T, Herzig KH, Karttunen TK, Tuomisto A, Mäkinen MJ. The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer. Int J Cancer 139(1):112-21, 2016.

Cichonska A, Rousu J, Marttinen P, Kangas AJ, Soininen P, Lehtimäki T, Raitakari OT, Järvelin MR, Salomaa V, Ala-Korpela M, Ripatti S, Pirinen M. metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis. Bioinformatics 32(13):1981-9, 2016.

Kettunen J, Demirkan A, Würtz P, Draisma HHM, Haller T, Rawal R, et al (incl Järvelin MR) . Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun 23;7:11122, 2016.

Wang Q, Würtz P, Auro K, Morin-Papunen L, Kangas AJ, Soininen P, Tiainen M, Tynkkynen T, Joensuu A, Havulinna AS, Aalto K, Salmi M, Blankenberg S, Zeller T, Viikari J, Kähönen M, Lehtimäki T, Salomaa V, Jalkanen S, Järvelin MR, Perola M, Raitakari OT, Lawlor DA, Kettunen J, Ala-Korpela M. Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence. Int J Epidemiol 45(5):1445-1457, 2016.

Wang Q, Würtz P, Auro K, Mäkinen VP, Kangas AJ, Soininen P, Tiainen M, Tynkkynen T, Jokelainen J, Santalahti K, Salmi M, Blankenberg S, Zeller T, Viikari J, Kähönen M, Lehtimäki T, Salomaa V, Perola M, Jalkanen S, Järvelin MR, Raitakari OT, Kettunen J, Lawlor DA, Ala-Korpela M. Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence. BMC Med 14(1):205, 2016.

Würtz P, Wang Q, Niironen M, Tynkkynen T, Tiainen M, Drenos F, Kangas AJ, Soininen P, Skilton MR, Heikkilä K, Pouta A, Kähönen M, Lehtimäki T, Rose RJ, Kajantie E, Perola M, Kaprio J, Eriksson JG, Raitakari OT, Lawlor DA, Davey Smith G, Järvelin MR, Ala-Korpela M, Auro K. Metabolic signatures of birthweight in 18 288 adolescents and adults. Int J Epidemiol 45(5):1539-1550, 2016.

Würtz P, Wang Q, Soininen P, Kangas AJ, Fatemifar G, Tynkkynen T, Tiainen M, Perola M, Tillin T, Hughes AD, Mäntyselkä P, Kähönen M, Lehtimäki T, Sattar N, Hingorani AD, Casas JP, Salomaa V, Kivimäki M, Järvelin MR, Davey Smith G, Vanhala M, Lawlor DA, Raitakari OT, Chaturvedi N, Kettunen J, Ala-Korpela M. Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase. J Am Coll Cardiol 67(10):1200-10, 2016.

Berry DJ, Dutton J, Fraser WD, Järvelin MR, Hyppönen E. Harmonization Study Between LC-MS/MS and Diasorin RIA for Measurement of 25-Hydroxyvitamin D Concentrations in a Large Population Survey. J Clin Lab Anal, epub ahead of print, 2016.

2017 -

Abass K, Koiranen M, Mazej D, Tratnik JS, Horvat M, Hakkola J, Järvelin MR, Rautio A. Arsenic, cadmium, lead and mercury levels in blood of Finnish adults and their relation to diet, lifestyle habits and sociodemographic variables. Environ Sci Pollut Res Int 24:1347-1362, 2017.

Ibarra A, Olli K, Pasman W, Hendriks H, Alhoniemi S, Raza GS, Herzig KH, Tiihonen K. Effects of polydextrose with breakfast or with a midmorning preload on food intake and other appetite-related parameters in healthy normal-weight and overweight females: An acute, randomized, double-blind, placebo-controlled, and crossover study. Appetite 110:15-24, 2017.

Metcalf SA, Jones PB, Nordstrom T, Timonen M, Mäki P, Miettunen J, Jääskeläinen E, Järvelin MR, Stochl J, Murray GK, Veijola J, Khandaker GM. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study. Brain Behav Immun 59:253-259, 2017.

Sanders AE, Jain D, Sofer T, Kerr KF, Laurie CC, Shaffer JR, Marazita ML, Kaste LM, Slade GD, Fillingim RB, Ohrbach R, Maixner W, Kocher T, Bernhardt O, Teumer A, Schwahn C, Sipilä K, Lähdesmäki R, Männikkö M, Pesonen P, Järvelin M, Rizzatti-Barbosa CM, Meloto CB, Ribeiro-Dasilva M, Diatchenko L, Serrano P, Smith SB. GWAS Identifies New Loci for Painful Temporomandibular Disorder. J Dent Res96(3):277-284, 2017.

Tikanmäki M, Tammelin T, Kaseva N, Sipola-Leppänen M, Matinolli HM, Hakonen H, Ekelund U, Eriksson JG, Järvelin MR, Vääräsmäki M, Kajantie E. Objectively Measured Physical Activity and Sedentary Time in Young Adults Born Preterm - The ESTER Study. Epub ahead of print, 2017.

Wahl S, Drong A, Lehne B, Loh M, Scott WR, et al (incl Järvelin MR). Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541(7635):81-86, 2017.

Doctoral Theses 2016

Saeid Haghighi Poodeh: Novel pathomechanisms of intrauterine growth restriction in fetal alcohol syndrome in a mouse model. Acta Universitatis Ouluensis D, 1381, 2016

Justiina Ronkainen: Role of Fto in the gene and microRNA expression of mouse adipose tissues in response to high-fat diet.Acta Universitatis Ouluensis D, 1387, 2016

Research Group Members

Project Leaders:
Marjo-Riitta Järvelin MD, PhD (Center for Life-Course Health Research (CLCHR) and Imperial College London) - Project leader
Karl-Heinz Herzig, MD, PhD, Professor - Physiology - Project leader (University of Oulu)
Markku Savolainen, MD, PhD, Professor – Internal Medicine – Project leader (University of Oulu)

Senior and Post-doctoral Investigators:
Jouko Miettunen, PhD, Professor, Statistics (CLCHR, Academy of Finland)
Sylvain Sebert, PhD, Docent - Early programming (CLCHR, DynaHEALTH)
Minna Männikkö, PhD, Docent - Genetics (CLCHR)
Dylan Williams, PhD, Post doctoral researcher - Life-course epidemiology (DynaHEALTH)
Estelle Lowry, PhD, Post doctoral researcher - Life-course epidemiology (DynaHEALTH)
Nina Rautio, PhD Post doctoral researcher - Social epidemiology (DynaHEALTH and Academy of Finland
Kari Mäkelä, PhD, Post doctoral researcher - Experimental physiology (University of Oulu)
Juhani Leppäluoto, MD, PhD; Prof emeritus hc., endocrinology, physiology (Foundations)
Miia Kovalainen, PhD, Post doctoral researcher - peptide and nutrient application (Foundations and Academy of Finland)-maternity leave at 2016
Tuire Salonurmi, PhD, Post doctoral researcher – molecular dietetic biology, transgenic mice (Oulu University Hospital, University of Oulu)
Antti Nissinen, PhD, Post doctoral researcher – immunological biology of lipids (Foundations, University of Oulu)

Ph.D. Students:
Saranya Palaniswamy, MSc (BCO)
Rozenn Nedelec, MSc (CLCHR and Foundation)
Eeva Nevala, MSc (UniOGS)
Ghulam Shere Raza, MSc (Foundation)
Toni Karhu, MSc (Foundation)
Shivaprakash J Mutt, MSc (Foundation)
Laura Niiranen, MSc (UniOGs and Foundation)
Justiina Ronkainen, MSc (BCO)
Timo Paavola, LicMed, (Foundations)
Saeid Haghighi, MSc (Foundations)

Laboratory Technicians:
Marja-Leena Kytökangas, Laboratory technician (University of Oulu)
Sari Pyrhönen, Laboratory technician (Oulu University Hospital)
Saara Korhonen, Biomedical laboratory scientist (Oulu University Hospital)

Sauli Herrala (CLCHR, DynaHEALTH)
Ville Karhunen (CLCHR, DynaHEALTH)
Eeva Varamo (CLCHR, DynaHEALTH)

Foreign Scientists, 8

National and International Activities

For group Järvelin:
Coordination and management of the DynaHEALTH research action (

Active members of:
Early Growth Genetics Consortium (EGG)
GIANT consortium
PACE consortium
CHARGE consortium

Group Members Who Spent More Than Two Weeks in Foreign Laboratories During 2016

Ville Karhunen, multiple visits at the Department of Epidemiology and Biostatistics, Imperial College London.

EU Projects (present and progress)

Principal investigator (MRJ) in EurHEALTHAgeing (European ResearcH on DevElopmentAL, BirTH and Genetic Determinants of Ageing).

Principal investigator (MRJ) in EPI-MIGRANT (Identification of epigenetic markers underlying increased risk of T2D in South Asians).

EU H2020: Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging, Grant no. 633595, 01.04.2015-31.03.2019, M-R Järvelin (Coordinator), Team members: Prof. K-H Herzig, Dr. S Sebert et al.

EU H2020-HCO-2004, Prevention and treatment of type 2 diabetes, J Chambers (PI), M-R Järvelin (Co-PI) et al. 01.02.2015-31.01.2020.  Team members Prof. K-H Herzig, Prof. S Keinänen-Kiukaanniemi et al.

Co-operation with Finnish and Foreign Companies

Co-operation with ABBOTT Nutrition and ORDESA laboratorios (as part of DynaHEALTH)

Last updated: 15.10.2018