Contribution of putative genetic factors and candidate gene variants to inter-individual variation of circulating fractalkine (CX3CL1) levels in a large UK twins' sample

Objective: Soluble fractalkine (sFRACT) is involved in the pathogenesis of several clinical diseases. Our major objective was to determine to what extent its variation is governed by genetic factors and whether this genetic variation could be attributable to SNPs in five candidate genes: CX3CL1, CX3CR1, ADAM10, ADAM17 and AREG. Methods: Plasma levels of sFRACT and 38 SNPs, with minor allele frequency >0.1 were examined in a large twin sample drawn from the general UK population. The discovery sample included 3306 middle-aged females: 1172 MZ twins and 2134 DZ twins. A replication sample of 1675 twins was used to validate the major association results obtained in genetic association analysis in the discovery sample. We implemented variance component analysis to estimate contribution of putative genetic, (including above SNPs) and environmental factors to sFRACT variation. Results: sFRACT was found not to vary with either age or BMI. Putative genetic factors (heritability) explained 43.6±3% of the total variation of plasma sFRACT levels. However, we found no evidence of association between sFRACT and any of the examined SNPs, despite having >85% power to detect an association of just 1% of the variance explained. The results in the discovery and replication samples were in good agreement suggesting these findings are real. Conclusion: Our results suggest involvement of genetic factors to inter-individual variation of sFRACT levels in a general human population. However, further studies are required to determine genetic polymorphisms affecting sFRACT variation.