The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases

Abstract

The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005-2010. The aim of the study is to investigate nongenetic and genetic factors associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and >2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors. The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits.

Keywords: METSIM; cardiovascular risk factors; coronary artery disease; metabolic disease; type 2 diabetes.

Fig. 1.

Description of the cross-sectional and longitudinal METSIM study. The cross-sectional study included 10,197 Finnish men, aged from 45 to 73 years. Phenotyping included several laboratory measurements in fasting, an OGTT, and proton NMR measurements from all participants. DNA-based genotyping includes OmniExpress for common and exome chip for low-frequency and rare variants, exome and genome sequencing, DNA methylation analysis in adipose tissue, and gut microbiome sequencing. Adipose tissue biopsies have been taken from 1,410 participants, RNA sequencing performed for 795 participants and RNA expression determined for 770 participants. The protocol of the follow-up study is identical to the cross-sectional study, and so far 6,496 individuals have participated in the follow-up. Additionally, all participants have registry follow-up allowing information on morbidity, mortality, and drug treatment to be obtained.

Fig. 2.

Roles of described genes in G protein signaling [small G protein signaling modulator 2 (SGSM2), MAP kinase activating death domain (MADD), TBC1 domain family member 30 (TBC1D30), and KN motif and ankyrin repeat domains 1 (KANK1)] have been shown to regulate or function in G protein signaling. GTP-binding proteins (G proteins) are characterized by their ability to bind and hydrolyze GTP and include members of Rab, Rac, Rho, Rap, and other families. G proteins are active when bound to GTP, but inactive when bound to GDP. Guanine nucleotide exchange factors (GEFs) catalyze the dissociation of GDP and the binding of GTP, thus promoting to active G protein state. When bound to GTP, G proteins remain active briefly and can activate G proteins by promoting GTP hydrolysis and a return to the inactive state. Adapted from (9).

Fig. 3.

A roadmap for the genome and phenome analyses in the METSIM study. The whole-genome sequencing and extensive phenotyping are ongoing. Phenotyping includes metabolomics, proteomics, epigenomics, adipose tissue transciptomics, and microbiome analysis. The interaction between the genome and phenome will be extensively investigated as well as the interaction between the genome and lifestyle/environmental factors and aging. Prediction models will be developed using the Mendelian randomization approach by using genetic variants to estimate the causal contribution of a given risk marker to the risk of a given disease (especially T2D and CAD).

Fig. 4.

The number of the METSIM participants having data on adipose tissue RNA sequencing (N = 795), adipose tissue methylation (N = 758), and gut microbiota (N = 532) in relation to mass spectrometry-based metabolomics (N = 2,292). About 90% of participants who have RNA sequencing and methylation results and about 50% of participants who have microbiota analyses also have metabolomics data.