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

Introduction Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response. Moreover, TREM2 levels have been observed to affect plasma levels of TNF-α and... [ view full abstract ]

Introduction

Triggering receptor expressed on myeloid cells 2 (TREM2) is known for its anti-inflammatory properties during the immune response. Moreover, 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 their association with TNF-α levels and the intima media thickness of the femoral artery in healthy individuals.

Methods

Discovery population consisted of 139 healthy children from the STANISLAS Family Study (SFS). Five readily available SNPs located in TREM-2 region (rs7748777, rs6918289, rs7759295, rs9357347 and rs6915083 available in the genome-wide scan IlluminaHuman CNV370-Duo array) were analyzed for associations with TNF-α levels, using the R package GWAF (Genome-Wide Association/Interaction Analysis and Rare Variant analysis with Family Data). After performing initial association analysis, the polymorphism rs6918289 was de novo genotyped in 393 adults and 277 more children of SFS and in an independent replication population (n=916). De novo genotyping of rs6918289 was conducted by Laboratory of the Government Chemist (LGC) using a PCR-based KASP assay. The association of the rs6918289 with TNF-α plasma levels was assessed separately in the total individuals of SFS (children and adults combined; n=809) and in the replication population (n=916). A sub-group of 350 individuals, consisting of adults and children from the SFS population was used to identify associations between intima media thickness of the femoral artery (IMT-F) and rs6918289.

Results

Our results suggest that the minor allele (T) of the rs6918289 is positively associated with elevated plasma levels of TNF-α in the discovery population (P=0.0026, β=0.13, SE=0.04) (Figure 1). Similar results were found in the replication population  (P=0.023, β=0.202, SE=0.09). Additionally, rs6918289 was associated with IMT-F in the discovery cohort (P=0.026, β=0.02, SE=0.009).

Figure 1: Mean values of TNF-α levels according to the different genotypes of rs6918289 (GG vs TG vs TT) in the STANISLAS population. Thin bars show SE.

Discussion

These results indicate that rs6918289 may be considered as a risk factor for inflammatory diseases and could be used in personalized medicine for patients diagnosed with chronic inflammatory-related conditions such as atherosclerosis.