15.011 Health2000 GenMets-subsample
(5.3.2009/ Genetiikkaryhmä 3.3.2009)

Vesa Olkkonen, Leena Peltonen et al. ( ks. liite lopussa)
KATO/GETY/National Institute for Health and Welfare and FIMM, Institute for Molecular Medicine Finland
Biomedicum, P.O.Box 104, 00251 Helsinki
Tel. 020-6108286; GSM 045-6334065; e-mail vesa.olkkonen@thl.fi

Background Families of proteins with homology to the carboxy-terminal ligand binding domain of oxysterol binding protein (OSBP) are present in eukaryotic organisms from S. cerevisiae to man, and are suggested to function in various cellular processes such as lipid metabolism, intracellular lipid transport, membrane trafficking, and cell signaling [1, 2]. In humans, the gene family consists of 12 members, which are denoted OSBP-like genes (OSBPL), while the encoded proteins are called either OSBP-like (OSBPL) or OSBP-related proteins (ORP).

In the present study we assessed whether allelic diversity of the OSBPL2, OSBPL9, or OSBPL10 genes contributes to extreme serum lipid levels in Finnish families ascertained for low HDL-cholesterol or familial combined hyperlipidemia (FCHL), common dyslipidemias associated with increased risk of premature coronary heart disease. Variants (SNPs) of OSBPL10 displayed suggestive linkage and association with HDL-cholesterol and triglyceride levels, indicating that variation in OSBPL10 may contribute to the low serum HDL-cholesterol and high triglyceride concentrations in these families. RNA interference experiments in cultured human hepatoma cells suggested action of the encoded protein, ORP10, as a regulator of cellular lipid biosyntheses and apolipoprotein B-100 (apoB100) secretion.

The work was submitted to the Journal of Molecular Medicine (JMM), the reviewers of which were not satisfied with the strength of the genetic evidence, the highest linkage LOD score being 2.4, for >90th percentile triglyceride levels in the combined low-HDL and FCHL families, a majority of the reported LOD scores being below 2. A reviewer suggested that we should study possible association of the OSBPL10 SNPs with extreme end lipid traits in a general population sample. Ida Lindqvist did this for the NFBC study material, with no significant associations found.

Proposal We find it likely that, even though no association of OSBPL10 SNPs with extreme end lipid traits was found in the NFBC material, such positive findings could be achieved in the Health2000 GenMets subsample. This study sample is already selected and may contain some of the same genetic predisposition that is present in the Finnish dyslipidemia family materials mentioned above. This analysis would thus represent a replication of our initial findings in an independent study sample, and could very well become decisive for the acceptance of our publication in JMM. The OSBPL10 gene position in chr. 3p23 did not come up in the preliminary analysis of the GenMets genotype dataset, so use of the data in our candidate gene study would definitely not harm the goals of the actual GenMets study.

In this analysis we would like to sort the GenMets subjects into ones with extremely high triglyceride (>90th or 95th percentile) or low HDL (<5th or 10th percentile) levels and the rest, and carry out association analysis of the 102 SNPs in the OSBPL10 gene and its flanking regions with these dichotomized extreme end lipid traits. If positive findings are made, these would be included in our manuscript as a Figure or a Table depicting the association p values, to support our earlier weak genetic evidence.

1. Fairn GD, McMaster CR (2008) Emerging roles of the oxysterol-binding protein family in metabolism, transport, and signaling. Cell Mol Life Sci 65: 228-236 2. Yan D, Olkkonen VM (2008) Characteristics of oxysterol binding proteins. Int Rev Cytol 265: 253-285

Liite (täsmennys kirjoittajaluetteloon):

Julia Perttilä1,2*, Krista Merikanto1*, Jussi Naukkarinen1, Nicolas W. Martin1,3, Ida Lindqvist1, Kimmo Tanhuanpää4, Vinciane Grimard5, Marja-Riitta Taskinen6, Christoph Thiele3, Ismo Virtanen2, Vesa M. Olkkonen1,2, and Leena Peltonen1,7,8,9

ADDITIONAL AUTHORS FROM THE GENMETS GROUP: Veikko Salomaa, Markus Perola, Antti Jula (if permission to study the material is granted)
1 National Public Health Institute and FIMM, Institute for Molecular Medicine Finland, Biomedicum, P.O.Box 104, FI-00251, Helsinki, Finland
2 Institute of Biomedicine/Anatomy, P.O.Box 63, University of Helsinki, FI-00014, Helsinki, Finland
3 Queensland Institute of Medical Research, 300 Herston Road, Brisbane 4029, Australia
4 Light microscopy unit, Institute of Biotechnology, FI-00014 Univ. of Helsinki, Finland
5 Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany
6 Department of Medicine, Division of Cardiology, Helsinki University Hospital and Biomedicum, Haartmaninkatu 8, FI-00290, Helsinki, Finland
7 The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
8 Department of Medical Genetics, University of Helsinki, FI-00014, Helsinki, Finland
9 The Broad Institute, Boston, Massachusetts 02142, USA