The polymorphism rs6918289 located in the downstream region of the TREM2 gene is associated with TNF-α levels and IMT-F

International audienceTriggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response, and influences negatively on TNF-α expression levels. Genetic epidemiology studies have identified polymorphisms located in the TREM2 gene associated with neurodegenerative and chronic inflammatory diseases. TREM2 levels have been observed to affect plasma levels of TNF-α and plaque stability in symptomatic and asymptomatic patients with carotid stenosis. In this study, we investigated polymorphisms located in the TREM2 gene region and association with TNF-α levels and the intima media thickness of the femoral artery. The discovery population from the STANISLAS Family Study comprised of 809 individuals, whereas the replication population utilized an independent cohort of French origin (n = 916). Our results suggest that the minor allele (T) of SNP rs6918289 is positively associated with elevated plasma levels of TNF-α in discovery and replication populations (P = 0.0026, SE = 0.04 and P = 0.023, SE = 0.09, respectively), including femoral artery thickness in the discovery cohort (P = 0.026, SE = 0.009). Results indicate that rs6918289 may be considered as a risk factor for inflammatory diseases and could be used in stratified medicine with patients diagnosed with chronic inflammatory-related conditions, such as atherosclerosis

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

<div><p>High levels of TREM-1 are associated with cardiovascular and inflammatory diseases risks and the most recent studies have showed that <i>TREM-1</i> 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 <i>TREM-1</i> 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 <i>TREM-1</i> 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 <i>TREM-1</i>, 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.</p></div

Statistical associations of the 10 polymorphisms studied with the serum levels of TREM-1 and mRNA levels according to the different inheritance models.

<p>P-value thresholds for TREM-1 protein levels are P<0.005 for the discovery population and P<0.05 for the replication population. P-value threshold for mRNA levels is <0.025.</p

Effects of the polymorphism rs2234246 located within the <i>TREM-1</i> gene on the serum levels of the studied selectin molecules.

<p>MAF = Minor allele frequency of the rs2234246. Cutoff value of significance: 0.016 in discovery and 0.05 in replication population.</p

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

<p>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.</p

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

<p>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.</p

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

<p>Specific transcription factor binding sites for the minor allele T of the SNP rs2234246.</p

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

<p>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.</p

Demographic and clinical characteristics of the individuals.

<p>Demographic and clinical characteristics of the individuals.</p