Highlights 2009:
A genome-wide association study identifies three loci associated with mean platelet volume
PD Dr. med. Christa Meisinger, MPH; christa.meisinger@helmholtz-muenchen.de; +49-(0)821/34642-12
Angela Döring; doering@helmholtz-muenchen.de; +49-(0)89-3187-4153
Keywords:
Mean platelet volume, genome wide association study, WDR66, ARHGEF3, TAOK1.
Central statement:
In a genome wide association study (KORAF3-500K), the most significant SNPs associated with mean platelet volume mapped within WDR66, ARHGEF3 and TAOK1, three genes which could modify the process of platelet formation.
Highlight:
Mean platelet volume (MPV) is increased in myocardial and cerebral infarction and is an independent and strong predictor for post-event morbidity and mortality.
In a genome wide association study (KORAF3-500K), MPV was strongly associated with 3 common single nucleotide polymorphisms (SNPs): rs7961894 located within intron 3 of WDR66 on chromosome 12q24.31, rs12485738 upstream of the ARHGEF3 on chromosome 3p13-p21, and rs2138852 located upstream of TAOK1 on chromosome 17q11.2.
These findings were replicated in another GWAS from the UK and in two population-based samples from Germany. In a combined analysis including 10,048 subjects the SNPs had P values of 7.24 x 10-48 for rs7961894, 3.81 x 10-27 for rs12485738, and 7.19x10-28 for rs2138852, respectively.
The three quantitative trait loci together accounted for 4-5% of the variance in MPV.
In depth sequence analysis of WDR66 in 382 samples from the extremes revealed 20 new variants and a haplotype with three coding SNPs and one SNP at the transcription start site associated with MPV (P=6.8x10-5). In addition, expression analysis indicated a direct correlation of WDR66 transcripts and MPV.
All three genes are plausible biological candidates which could modify the process of platelet formation: It is hypothesized that WD-repeat proteins, which are present in all eukaryotes but not in prokaryotes, are involved in the regulation of cellular functions ranging from signal transduction and transcription regulation to cell cycle control and apoptosis. ARHGEF3 (XPLN) encodes the rho guanine-nucleotide exchange factor 3 (RhoGEF3), which activates RhoGTPases, which play an important role in many cellular processes like regulation of cell morphology, cell aggregation, cytoskeletal rearrangements, and transcriptional activation. TAOK1 encodes the TAO kinase 1 peptide a microtubule affinity-regulating kinase which has been identified recently as an important regulator of mitotic progression, required for both chromosome congression and checkpoint induced anaphase delay.
Identification of primary genetic determinants of MPV may not only enhance the understanding of platelet activation and function, but may also provide a focus for several novel research avenues.
Publication:
Christa Meisinger, Holger Prokisch, Christian Gieger, Nicole Soranzo, Divya Mehta, Dieter Rosskopf, Peter Lichtner, Norman Klopp, Jonathan Stephens, Nicholas A Watkins, Panos Deloukas, Andreas Greinacher, Wolfgang Koenig, Matthias Nauck, Christian Rimmbach, Henry Völzke, Annette Peters, Thomas Illig, Willem H Ouwehand, Thomas Meitinger, H.- Erich Wichmann, Angela Döring. A genome-wide association study identifies three loci associated with mean platelet volume. Am J Hum Genet 2009; 84(1):66-71.
Abstract
Taking account of the HMGU mission:
Analyzing genetic determinants of human health requires an interdisciplinary effort. The group identified three loci associated with mean platelet volume. This work may provide a focus for several novel research avenues.