1Johanna Sandling, 1,2Johan Sundström, 1Lovisa Lovmar, 3Leif Andersson, 1Lars Lind, 1Ann-Christine Syvänen
1Medical Sciences, Uppsala University, Uppsala, Sweden, 2Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden, 3Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
The insulin-like growth factors (IGFs) influence muscle growth and are known to stimulate myogenic differentiation. In the case of IGF2 normally only the paternal allele is expressed. Genetic analysis of a paternally expressed quantitative trait locus (QTL) for muscle mass and size of the heart in pigs revealed a single nucleotide polymorphism (SNP) within the IGF2 locus as responsible for the QTL (Van Laere et al. Nature 425, 832-836; 2003). This quantitative trait nucleotide (QTN) is located in a CpG island in intron 3 of the IGF2 gene which is highly conserved between species. The single base-pair substitution at the pig QTN was found to abolish the interaction with a so far unidentified nuclear factor thereby altering the levels of IGF2 mRNA expression in muscle several-fold.
We have investigated whether polymorphisms in IGF2 are associated to heart muscle phenotypes also in humans. We tested three SNPs located within the conserved CpG island of IGF2 intron 3 for association to left ventricular characteristics in a population based cohort of 475 elderly Swedish men. Two of the SNPs showed significant association to echocardiographic parameters. One of them was associated to ejection fraction (p=0.008, n=341) and the other was associated to relative left ventricular wall thickness (p=0.014, n=379). The same tendency was also observed for absolute left ventricular wall thickness.
The high degree of cross-species conservation of the CpG island supports the idea that this intronic region harbors functional elements. Based on in silico prediction the polymorphisms are located in putative transcription factor binding DNA motifs. We are currently investigating the effect of these SNPs on transcription factor binding. Replication of the results in an independent population-based cohort consisting of 1000 Swedish men and women is also underway. Our result suggests that comparative genomics may be used as a shortcut to elucidate the genetic background of complex traits in humans.
Johanna Sandling and Johan Sundström contributed equally to this work
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