TREM-1 SNP rs2234246 regulates TREM-1 protein and mRNA levels and is associated with plasma levels of L-selectin

Abstract

High levels of TREM-1 are associated with cardiovascular and inflammatory diseases risks and the most recent studies have showed that TREM-1 deletion or blockade is associated with up to 60% reduction of the development of atherosclerosis. So far, it is unknown whether the levels of TREM-1 protein are genetically regulated. Moreover, TREM family receptors have been suggested to regulate the cellular adhesion process. The goal of this study was to investigate whether polymorphisms within TREM-1 are regulating the variants of serum TREM-1 levels and the expression levels of their mRNA. Furthermore, we aimed to point out associations between polymorphisms on TREM-1 and blood levels of selectins. Among the 10 SNPs studied, the minor allele T of rs2234246, was associated with increased sTREM-1 in the discovery population (p-value = 0.003), explaining 33% of its variance, and with increased levels of mRNA (p-value = 0.007). The same allele was associated with increased soluble L-selectin levels (p-value = 0.011). The higher levels of sTREM-1 and L-selectin were confirmed in the replication population (p-value = 0.0007 and p-value = 0.018 respectively). We demonstrated for the first time one SNP on TREM-1, affecting its expression levels. These novel results, support the hypothesis that TREM-1 affects monocytes extravasation and accumulation processes leading to atherogenesis and atherosclerotic plaque progression, possibly through increased inflammation and subsequent higher expression of sL-selectin.

Fig 1. Mean values of sTREM-1 levels according to the different genotypes of rs2234246 (CC vs TC vs TT) in the discovery population.

Thin bars show standard errors. CC; Homozygous for the major allele of the rs2234246. TC; Heterozygous for the rs2234246. TT; Homozygous for the minor allele of the rs2234246. The significance between genotypes is showed as follows; N.S.; >0.05, * p<0.05, ** p<0.01, *** p<0.001.

Fig 2. Mean values of sTREM-1 levels according to the different genotypes of rs2234246 (CC vs TC vs TT) in the replication population.

Thin bars show standard errors. CC; Homozygous for the major allele of the rs2234246. TC; Heterozygous for the rs2234246. TT; Homozygous for the minor allele of the rs2234246. The significance between genotypes is showed as follows; N.S.; >0.05, * p<0.05, ** p<0.01, *** p<0.001.

Fig 3. Specific transcription factor binding sites for the minor allele T of the SNP rs2234246.

Fig 4. Specific transcription factor binding sites for the major allele C of the SNP rs2234246.

The consensus sequence (fixed) of the transcription factor binding sites means: S = C or G, W = A or T, R = A or G, Y = C or T, K = G or T, M = A or C, N = any base pair. The input sequence was 38pb length, centred on the SNP of interest rs2234246. Only TFBS harbouring a nucleotide in its consensus sequence in coherence with the SNP of interest were selected.