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

Markku Laakso,Johanna Kuusisto,Alena Stančáková,Teemu Kuulasmaa,Päivi Pajukanta,Aldons J Lusis,Francis S Collins,Karen L Mohlke,Michael Boehnke

doi:10.1194/jlr.o072629

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.

Highlights

The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005–2010
We found that interleukin 1 receptor antagonist (IL-1RA) levels were associated with liver inflammation and alanine aminotransferase (ALT), independent of obesity, alcohol consumption, and insulin resistance in the METSIM study
We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD genome-wide association study (GWAS) loci, and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index (TBC1D30, KANK1, PAM) in 8,229 nondiabetic participants of the METSIM study

Summary

Ethics approval

The Ethics Committee of the University of Eastern Finland and Kuopio University Hospital approved the METSIM study, and this study was conducted in accordance with the Declaration of Helsinki. Others, have identified several nongenetic biomarkers (amino acids, ketone bodies, noncholesterol sterols, fatty acids) associated with the risk of T2D that improve the prediction for the conversion to diabetes beyond and above the classical risk factors for this disease (obesity, age, family history of diabetes, etc.) These findings need to be replicated in other ethnic groups and in women. Several studies, including the METSIM cohort, have shown that common [40,41,42,43] and low-frequency/rare variants assayed by the exome array [44, 45] are associated with fasting or 2 h glucose concentrations [46, 47]. GCKR regulates glucose metabolism, and lipoprotein and ketone body metabolism, and demonstrates that deep phenotyping offers a tool to identify new functions for the genes of interest

Summary point

Findings

CONCLUSIONS