Genetic variability at the leptin receptor (LEPR) locus is a determinant of plasma fibrinogen and C-reactive protein levels

Objective: Cellular and animal studies suggest that leptin has proinflammatory and prothrombotic effects that could link increased adipose mass directly to atherogenesis. To investigate this hypothesis, we examined the effect of genetic variability at the leptin receptor (LEPR) locus on the plasma levels of fibrinogen and CRP-two markers of inflammation and susceptibility to atherosclerosis. Methods and results: Linkage disequilibrium analysis of 71 single-nucleotide polymorphisms (SNPs) spanning the LEPR locus revealed four haplotype blocks that could be tagged by 11 SNPs. In 630 healthy Caucasian individuals, variability in block #4 was significantly associated with plasma fibrinogen (p = 0.005), accounting for 3% of its variance (r² = 0.030). The same block was also associated with CRP levels (p = 0.049, r² = 0.022). The effect was strongest for two of the SNPs in this block. At rs3790432, fibrinogen was 10% higher in minor allele homozygotes than in major allele homozygotes and intermediate in heterozygotes (p = 0.015). At rs1805096, it was 5% higher (p = 0.007) and CRP 32% higher (p = 0.011) in major allele homozygotes than in minor allele carriers. This pattern of association was also evident in the haplotype analysis. Conclusions: Association of leptin receptor variability with inflammatory traits supports the hypothesis that leptin may play a role in atherogenesis.