Overview

Pathogenicity: Alzheimer's Disease : Risk Modifier
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr6:41161469 G>A
Position: (GRCh37/hg19):Chr6:41129207 G>A
dbSNP ID: rs143332484
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to CAT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The rs143332484 (R62H) variant was identified as a significant risk modifier for Alzheimer’s disease in a cohort of European-American descent (odds ratio 2.36, p = 2.36 X 10^-4) (Jin et al., 2014) and in a cohort from the Alzheimer’s Disease Sequencing Project (odds ratio 1.44, p = 0.001) (Song et al., 2017), while several other studies of European and American subjects did not find an association between the R62H variant and AD (Benitez et al., 2013; Borroni et al., 2014; Cuyvers et al., 2014; Guerreiro et al., 2013; Jonsson et al., 2013; Pottier et al., 2013; Thelen et al., 2014). However, a three-stage case-control study of 48,343 AD cases and 36,790 controls provided strong evidence for an association between the R62H variant and AD risk in Caucasians (odds ratio 1.67, p = 1.55 X 10^-14) (Sims et al., 2017).

This variant did not associate with AD risk specifically in African-Americans, possibly due to its very low frequency (Jin et al., 2015).

Whether the R62H variant influences the clinical presentation and/or progression of AD is not known.

In a group of individuals without dementia, levels of soluble TREM2 in cerebrospinal fluid did not differ between R62H carriers (N=10, CDR 0-0.5) and non-carriers (N=95, CDR 0) (Piccio et al., 2016).

The R62H variant did not associate with frontotemporal dementia in three European cohorts (Borroni et al., 2014; Cuyvers et al., 2014; Thelen et al., 2014).

Neuropathology

Post-mortem samples from AD patients carrying the R62H variant displayed reduced microglial coverage of amyloid plaques (Krasemann et al., 2017) and an increased accumulation of autophagosomes in microglia (Ulland et al., 2017) compared to samples from patients with the reference allele.

Biological Effect

The arginine-to-histidine substitution in TREM2 appears to impair ligand binding and subsequent TREM2-mediated processes.

The R62H variant does not alter protein conformation or cell-surface expression, although it may cause subtle changes in protein stability (Kober et al., 2016). This variant exhibited reduced binding to lipoproteins in cell-free assays (Yeh et al., 2016). Uptake of acetylated low-density lipoprotein particles was reduced in HEK293 cells that expressed the R62H variant compared with cells expressing wild-type TREM2, and monocyte-derived macrophages from R62H carriers showed reduced uptake of LDL-Aβ complexes compared with cells derived from age-, gender-, ethnicity- matched controls homozygous for the common allele (Yeh et al., 2016). The R62H mutation somewhat reduced activation in response to purified phospholipids in a reporter cell line engineered to turn on GFP expression when TREM2 is engaged (Song et al., 2017).

The soluble fragment (sTREM2) produced by proteolytic processing of the R62H variant was slightly less effective than wild-type sTREM2 in stimulating microglial production of pro-inflammatory cytokines and in promoting microglial survival after trophic factor withdrawal (Zhong et al., 2017).

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References

Paper Citations

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Further Reading