The intergenic SNPs rs599839 and rs646776 have been identified through GWAs as novel genetic markers for two complex and related traits, serum lipid levels and CAD. In the present study, performed in the SHEEP, a large Swedish population, we confirmed the association of these two genetic variants with serum lipid levels; however we have not observed a direct association between these two genetic variants and the risk of non-fatal MI. We have therefore tested the hypothesis that the interaction between these two SNPs and serum lipid levels contributed to the risk of non-fatal MI in the SHEEP.
The analysis of the association of genetic variants with complex phenotypes may largely vary among different populations. Genes do not have large effect on complex traits and differences in the definition of the trait under investigation as well as the genetic structure of the loci may create large differences in the association results. Although the lack of association in the SHEEP population might partly reflect a reduced power in the association analysis as compared to the analysis of genetic association in large international consortia, several other factors should be taken into account. In the populations formerly investigated different criteria have been used to identify to cases, the phenotype under investigation was either CAD
] or early myocardial infarction in patients with at least one first degree relative with premature CAD
] and the matching criteria for the controls were sometimes incompletely described
]. In the current study, only MI patients who survived at least 28
days after the MI event have been included and the referent population has been matched according to age, sex and residential area. Therefore lack of direct association of 1p13 variants with MI in the SHEEP might be related to the differences in the definition of cases as well as to the controls selection. In addition, differences in the genetic structure of the populations under investigation may hamper the replication of genetic associations. With regard to the chromosome 1p13 locus we have observed that in the SHEEP the pairwise LD value between rs599839 and rs646776 is different from the one currently reported in the Hapmap Consortium (
) for the European population (r2
0.51 observed vs 0.87 reported). These data speak in favor of a different genetic structure of this locus in the Swedish population and are consistent with the hypothesis raised by evolutionary geneticists stating that European populations have a composite genetic structure due to recent gene selection events (10 000-20 000
years ago) that might have changed pairwise LD values
]. In addition, the G allele frequency at rs599839 in the SHEEP (17%) is lower than previously reported in former studies (23%)
] and in the European panel of the HapMap (33%). Such findings underscore the importance of the knowledge of the locus structure when analysing the effect of genetic variants on a phenotype even within populations of the same ethnicity
] and may well explain discrepancies in the genetic effect of even truly genetic susceptibility variants
In the SHEEP, the risk of MI was increased in the presence of high ApoB serum levels and presence of the rare allele at rs599839, and to a lesser extent of the rare allele at rs647767, was found to antagonize the increased risk due to the exposure to high ApoB serum levels, as shown by the results of the interaction analysis. Although we cannot provide proof of a biological mechanism, this interpretation is in line with the results of the original GWAs studies, where the protective effect of 1p13 was observed in populations where the proportion of cases with dyslipidemia ranged from 76 to 80%
] and was therefore higher than the proportion reported in the SHEEP that is about 40%.
The analysis of interaction represents a powerful tool to integrate genetic association data into the complexity of multifactorial traits
]. In the present study we have utilized the biological method to analyze the effect of the interaction between genetic variants at 1p13 and serum lipid levels because they participate in the same causal mechanism that leads to MI. The elucidation of the mechanisms underlying interactions between genetic variants and environmental factors or, as in the present study exposure that may be modulated by pharmacological interventions, might have important implication in the assessment of the individual cardiovascular risk as well as in the clinical practice. Exposure to a specific agent may in fact have more or less detrimental effect in different genotype groups if an interaction between the genotype and the exposure exists
]. In this perspective gene environment interaction analyses hold the promise to contribute to a better understanding of the effect of genetic variants on the risk of cardiovascular diseases.
The association with reduced serum lipid levels was evident only in men. A gender specific association of genetic variants with MI and intermediate phenotypes has already been reported in the SHEEP
] and may reflect the selective effect of risk factors in men and women
Several limitations of the present study should be acknowledged. The choice of the SNPs to be investigated in the present studies relies on published data and does not include the other two tagSNPs, rs4970834 and rs611917, at chromosome1p13. The interaction analyses may be hard to interpreter and require large study population to achieve a sufficient power, therefore the replication of our findings in a larger and independent population is warranted.