Overview

Pathogenicity: Alzheimer's Disease : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr6:41159805 C>T
Position: (GRCh37/hg19):Chr6:41127543 C>T
dbSNP ID: rs2234255
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to TAC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3
Research Models: 2

Findings

Variant rs2234255 (H157Y) was associated with an increased risk for Alzheimer’s disease (AD) in a Han Chinese cohort (odds ratio: 11.01, p = 0.02) (Jiang et al., 2016). Studies of Caucasian (Cuyvers et al., 2014; Ghani et al., 2016; Guerreiro et al., 2013; Jin et al., 2014), Japanese (Miyashita et al., 2014), and African-American (Jin et al., 2015) cohorts failed to detect an association between this variant and AD. However, a meta-analysis of the studies cited above resulted in a significant association (7,102 cases, 7,408 controls, odds ratio 3.65, p = 0.002) (Jiang et al., 2016). Subsequently, the H157Y variant was reported to be associated with AD in a cohort composed of subjects enrolled in the Alzheimer’s Disease Sequencing Project (5575 cases, 4808 controls, odds ratio: 4.7, p = 0.01) (Song et al., 2017), while a large case-control study in Caucasians did not meet the investigators’ threshold for a statistically significant association, p < 10^-4 (18,077 cases, 16,097 controls, p = 0.046) (Sims et al., 2017).

No association between H157Y and frontotemporal dementia was found in a Belgian cohort (Cuyvers et al., 2014).

Neuropathology

Neuropathological characterization of individuals carrying the H157Y variant is currently lacking.

Biological Effect

Two independent groups have reported that soluble TREM2 (sTREM2) is generated by protease cleavage after amino acid 157, and that the histidine-to-tyrosine substitution results in increased shedding of sTREM2 (Schlepckow et al., 2017; Thornton et al., 2017). The matrix metalloprotease ADAM10 had been identified previously as one of the sheddases responsible for the generation of sTREM2 (Kleinberger et al., 2014), and both groups confirmed that this enzyme also cleaved the variant form. While one group reported an increase in the level of TREM2 C-terminal fragments (CTF) in the variant, as might be expected to accompany an increased rate of cleavage (Thornton et al., 2017), the other group observed less CTF in lysates of cells expressing H157Y, suggesting enhanced degradation of CTFs (Schlepckow et al., 2017).

The H157Y mutation reduced activation in response to phospholipid ligands in 2B4 T cells engineered to turn on GFP expression when TREM2 was engaged (Song et al., 2017) and also decreased phagocytosis of pHrodo-E.Coli by HEK Flp-in cells expressing the variant (Schlepckow et al., 2017), compared with cells that expressed wild-type TREM2.

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References

Paper Citations

1. Jiang T, Tan L, Chen Q, Tan MS, Zhou JS, Zhu XC, Lu H, Wang HF, Zhang YD, Yu JT. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. Epub 2016 Mar 3 PubMed.
2. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, BELNEU consortium. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.
3. Ghani M, Sato C, Kakhki EG, Gibbs JR, Traynor B, St George-Hyslop P, Rogaeva E. Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016 Jun;42:217.e7-217.e13. Epub 2016 Mar 21 PubMed.
4. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
5. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.
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7. Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, Lincoln S, Krishnan S, Kachadoorian M, Reitz C, Mayeux R, Wingo TS, Lah JJ, Levey AI, Murrell J, Hendrie H, Foroud T, Graff-Radford NR, Goate AM, Cruchaga C, Ertekin-Taner N. TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
8. Jiang T, Hou JK, Gao Q, Yu JT, Zhou JS, Zhao HD, Zhang YD. TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects. Curr Neurovasc Res. 2016;13(4):318-320. PubMed.
9. Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE, Colonna M. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017 Apr;13(4):381-387. Epub 2016 Aug 9 PubMed.
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Further Reading