Neurobiology of Aging 36 (2015) 546.e9e546.e13

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TREM2 analysis and increased risk of Alzheimer’s disease Deana Finelli a, Sara Rollinson a, Jenny Harris a, Matthew Jones a, b, Anna Richardson a, b, Alex Gerhard a, b, Julie Snowden a, b, David Mann a, Stuart Pickering-Brown a, * a b

Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK Institute of Brain, Behaviour and Mental Health, Salford Royal Hospital NHS Foundation Trust, Salford, UK

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 July 2014 Accepted 1 August 2014 Available online 27 August 2014

Important insights into the pathogenic mechanism of Alzheimer’s disease (AD) have arisen from the identification of genetic risk factors. Recently, a variant in the TREM2 gene (rs75932628), causing a C-to-T base-pair change that results in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein, has been associated with an increased risk of AD. We, therefore, genotyped samples from a cohort of 474 AD patients and 608 healthy controls, from the northwest region of the UK, using allelic discrimination assays, to replicate the results of the previous studies. We show a significant association of the T allele of the rs75932628 variant of TREM2 with AD (allelic odds ratio 11.08, 95% confidence interval 2.55e48.09, and Yates’ corrected p value ¼ 0.000146). TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management. Ó 2015 Elsevier Inc. All rights reserved.

Keywords: TREM2 Alzheimer’s disease Risk factor

1. Introduction Alzheimer’s disease (AD) is characterized clinically by a decline in cognitive function and pathologically by 2 hallmark lesions amyloid plaques and tau neurofibrillary tangles (Kidd, 1964; Terry, 1963). Despite extensive research, the pathologic mechanism underlying the disease remains unclear, and as such treatment options are limited. The genetic basis of AD is complex. Currently, mutations in 3 genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), are widely accepted to cause early-onset autosomal dominant AD. However, the genetic basis of late-onset AD is poorly understood. Variations in multiple genes have been hypothesized to confer disease risk, and until recently, the ε4 allele of the apolipoprotein E (APOE) gene was the main known genetic risk factor. In the last decade, Genome-Wide Association Studies have identified numerous susceptibility regions in late-onset cases (Harold et al., 2009; Hollingworth et al., 2011; Lambert et al., 2009; Naj et al., 2011; Seshadri et al., 2010), which include variants at many new loci (Escott-Price et al., 2014; Lambert et al., 2013). However, allelic odds ratios (ORs) reported for these variants range from 1.1 to 1.5, which is significant but modest compared with ORs reported for the ε4 allele of APOE.

* Corresponding author at: Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester M139PT, UK. Tel.: þ44 (0)161 275 1341; fax: þ44 (0)161 275 3938. E-mail address: [email protected] (S. Pickering-Brown). 0197-4580/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.001

Recently, a variant in the TREM2 gene (rs75932628) was identified as a novel risk factor for late-onset AD in 2 independent studies (Guerreiro et al., 2013a; Jonsson et al., 2013), and this has since been replicated by other further studies in different populations (Benitez et al., 2013; Giraldo et al., 2013). An association of rs75932628 with early-onset AD has also been recently reported (Pottier et al., 2013). TREM2 is located on chromosome 6 and encodes the triggering receptor expressed on myeloid cells 2 protein (Paloneva et al., 2002). The rs75932628 variant involves a C-to-T base-pair change resulting in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein. Interestingly, homozygous mutations in TREM2 resulting in a loss of protein function are known to cause Nasu-Hakola disease, a disease characterized by the development of bone cysts and early-onset dementia (Bianchin et al., 2004). In the present study, we have attempted to replicate the association of the rs75932628-T variant of TREM2 with AD in a British population. 2. Methods 2.1. Study population Participants were recruited from the northwest region of the UK, through the Cerebral Function Unit at Salford Royal Hospital. Ethical approval for the study was granted by the Newcastle and North Tyneside Research Ethics Committee. The study group consisted of

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474 patients with probable AD and 608 neurologically normal (spouse) controls. In the AD group (51% male, 49% female), age of onset ranged from 42 to 85 years (mean 61.4  standard deviation [SD] years). In the control group (39% male, 61% female), age when sampled ranged from 26 to 78 years (mean age of 50.9  SD years).

DNA was extracted from whole frozen blood. Cells were lysed with 0.86% ammonium chloride and subsequently washed in cell lysis buffer (20 mM Tris, 5 mM EDTA, pH 7.5, 0.003% Tween 20). Cells were suspended in a proteinase K buffer plus sodium dodecyl sulfate mixture and digested overnight at 37  C after the addition of proteinase K. DNA was then extracted using the phenol:chloroform method. Equal volumes of phenol and chloroform were added to the samples, and mixtures were separated into aqueous and organic phases by centrifugation. After final chloroform wash, DNA was precipitated from the aqueous phase by the addition of 2.5 volumes of 96% ethanol. DNA pellets were collected by centrifugation and washed in 70% ethanol. Pellets were then dissolved in 300 mL volumes of Tris EDTA (TE). DNA concentration was measured using NanoDrop technology, and samples were normalized to 10 ng/mL solutions before being plated on 96-well plates. 2.3. Genotyping Samples were genotyped for the rs75932628-T single-nucleotide polymorphism (SNP) (the R47H variant) using allelic discrimination assays. Primer sequences were GGCAGGATTTTTGTCTGTTTAGGT (forward) and CACACAGACGCCCAAAACAT (reverse). Allelic discrimination assays were performed using an ABI Prism 7900HT Sequence Detection System. Data were analyzed using SDS software version 2.3 from Applied Biosystems. For quality control purposes, 6 samples were additionally genotyped by the Sanger method, and sample duplicates were included on plates. 2.4. Statistics For single-variant analysis, ORs and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression adjusting for age and sex using Stata (version 9), using the most common variant as the baseline. 3. Results The rs75932628 polymorphism was more frequent in AD than in controls. In AD, 462 patients (97.5%) bore wild-type sequences, 7 (1.5%) were heterozygous, and 5 (1%) were homozygous, for the mutation. In controls, 606 (99.7%) patients were wild type, with only 2 individuals (0.3%) being heterozygous and none homozygous, for the mutation. Analysis of genotypes in cases versus controls using logistic regression showed a significant association of the rs75932628 polymorphism with AD (see Table 1). Carriers who Table 1 Allelic discrimination resultsdassociation of genotype with AD Genotype

Controls

Cases

OR

95% CI

p

CC CT TT CT þ TT

606 2 0 2

462 7 5 12

1.0 4.59

0.95e22.20

0.058

7.87

1.75e35.34

0.007

(97.47) (1.48) (1.05) (2.53)

Allele

Controls

Cases

OR

95% CI

p Value (Yates)

C T

1214 (99.84) 2 (0.16)

931 (98.2) 17 (1.79)

1.0 11.08

2.55e48.09

0.000146

Analysis of the frequency of C and T alleles in controls versus cases is shown. The T allele represents the rs75932628 polymorphism. Key: AD, Alzheimer’s disease; CI, confidence interval; OR, odds ratio.

2.2. DNA extraction and preparation

(99.67) (0.33) (0) (0.33)

Table 2 Association of the T allele with AD

Candidates with the CT genotype are heterozygous, TT genotype are homozygous, and CC genotype are wild types, for the R47H mutation. When rs75932628 heterozygotes and homozygotes are combined, a higher OR is reported. Key: AD, Alzheimer’s disease; CI, confidence interval; OR, odds ratio.

were homozygous or heterozygous for the polymorphism had >7fold increased risk of AD compared with noncarriers (OR 7.87, 95% CI 1.75e35.33, p value ¼ 0.007). As mentioned previously, the rs759392628 variant is an SNP resulting in a C-to-T base-pair change. The frequency of the T allele was 0.16% in the control group and 1.79% in the AD group (0.88% overall). There was a significant association between the T allele of rs75932628 and AD (OR 11.08, 95% CI 2.55e48.09, Yates’ corrected p value ¼ 0.000146, Table 2). Age of disease onset was recorded in 5/7 AD patients heterozygous for the rs759392628 polymorphism, this ranging from 52 to 80 years (mean 60.8  SD years). Of the 5 patients homozygous for the polymorphism, age of onset ranged from 52 to 72 years (mean age of onset being 60.0  SD years). There was no association between the rs759392628 variant and gender. For quality control purposes, 58 samples were duplicated with 100% concordance. Additionally, 6 samples (2 wild type, 2 heterozygous, and 2 homozygous) were directly genotyped by the Sanger method with results matching those of the allelic discrimination assay. 4. Discussion The rs759392628 variant in TREM2 was originally identified as a risk factor for late-onset AD by 2 independent groups (Guerreiro et al., 2013a; Jonsson et al., 2013). Although this association has been replicated (Benitez et al., 2013; Giraldo et al., 2013), there is still a debate as to how much risk this genetic variation confers (Bertram et al., 2013). Present results further validate the association of rs759392628 variant of TREM2 with AD in a British population. The additive OR of 7.87 (95% CI 1.75e35.34, p ¼ 0.007) for the association of the rs759392628 allele with AD is higher than that of the previous reports (Guerreiro et al., 2013a; Jonsson et al., 2013). In one of these studies, an OR of 5.05 (95% CI 2.7 7e9.16, p ¼ 9.0  109) was reported (Guerreiro et al., 2013a). In the other, an OR of 2.26 (95% CI 1.71e2.98, p ¼ 1.13  108) was reported, but this association was significantly higher (OR 4.66, 95% CI 2.38e9.14, p ¼ 7.39  106) when the control population was limited to cognitively intact candidates of 85 years and older (Jonsson et al., 2013). In our control group, ages ranged from 26 to 78 years (mean age 50.9 years). In our control population, the rs759392628-T allele was rare, with a frequency of 0.16%, similar to that reported in the previous studies (Guerreiro et al., 2013a; Jonsson et al., 2013) where the minor allelic frequency was reported to be 0.12% in an American population, 0.19% in a German population, 0.15% in a Dutch population, and 0.16% in a Norwegian population (Jonsson et al., 2013). However, our result is significantly lower than the minor allelic frequency of 0.63% reported in an Icelandic population (Benitez et al., 2013; Jonsson et al., 2013). In a recent study in a Spanish population, the T allele was not present in any of the controls (Benitez et al., 2013). The rs759392628 variant of TREM2 has been claimed, in a French cohort, to be a risk factor for early-onset AD and late-onset disease, with a reported OR of 4.07 (95% CI 1.3e16.9, p ¼ 0.009) (Pottier et al., 2013). In our sample population, most carriers who were either heterozygous or homozygous for the mutation were younger than 65 years, supporting the findings that the rs759392628 variant of

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TREM2 may also be a risk factor for early-onset disease, although we did not have enough carriers in our cohort to effectively assess the effects of heterozygosity or homozygosity on age of disease onset. Nonetheless, these appeared similar with a mean age of disease onset in heterozygotes and homozygotes being 60.8 and 60 years, respectively. Although rare, the risk of AD conferred by the rs759392628 variant of TREM2 has an effect size similar to that of the ε4 allele of APOE. Major insights into the pathogenic mechanism of AD have come from the identification of genetic susceptibilities and the elucidation of their phenotypic consequences. Thus, analysis of the function of TREM2 and the effects of the rs759392628 mutation may provide further insight into the disease mechanisms that result in AD. Homozygous mutations in TREM2 resulting in a loss of protein function classically give rise to a syndrome characterized by early-onset dementia and bone cysts (Paloneva et al., 2002) known as Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, although interestingly not all homozygous mutations in TREM2 associated with NasuHakola disease present with cognitive decline and behavioral changes and associated bone abnormalities (Guerreiro et al., 2013b). Mutations in TREM2 have also been reported to cause early-onset dementia without bone cysts in a Lebanese family (Chouery et al., 2008). Mutations in TREM2 underlying Nasu-Hakola disease have also been associated with memory deficits in heterozygous individuals of an Italian family (Montalbetti et al., 2005). Therefore, the association of TREM2 mutations with dementia (with or without bone cysts) suggests an important role of the TREM2 protein in cognitive function. The TREM2 gene encodes the triggering receptor expressed on myeloid cells 2 protein. The TREM2 protein is an innate immune receptor expressed on the surface of myeloid cells (Neumann and Takahashi, 2007). It is a glycoprotein consisting of a transmembrane region, short cytoplasmic region, and an immunoglobulin-like extracellular domain (Colonna, 2003). TREM2 associates with the protein DAP12 (also known as TYROBP) to form a receptor-signaling complex that activates immune responses (Neumann and Takahashi, 2007). Mutations in DAP12 have been found to underlie some cases of Nasu-Hakola disease, emphasizing the shared functional roles of TREM2 and DAP12 (Paloneva et al., 2002). As mentioned previously, the rs759392628 SNP is highly conserved and is predicted to be damaging. The substitution of arginine for histidine (R47H mutation) occurs within the extracellular component of TREM2 and so is likely to affect the capacity of TREM2 to bind to its natural ligands and function as a receptor (Jonsson et al., 2013). TREM2 protein is located on the surface of immature dendritic cells, osteoclasts, and microglia (Colonna, 2003). In immature dendritic cells, TREM2 triggers maturation by activating the protein tyrosine kinase extracellular signal-regulated kinase (ERK) via DAP12 (Bouchon et al., 2001). TREM2 is also crucial to the differentiation of monocytic precursors into mature osteoclasts (Cella et al., 2003). Lack of functional TREM2 protein in patients with Nasu-Hakola disease results in the inability of monocytes to differentiate into mature osteoclasts (Cella et al., 2003). In such cases, aggregates of immature osteoclasts are formed that display abnormalities in bone resorption. The differentiation of precursor cells into mature osteoclasts is blocked in DAP12 knockout mice (Kaifu et al., 2003). In the central nervous system, TREM2 and DAP12 are expressed in microglial cells (Sessa et al., 2004). In a mouse model of AD, TREM2 localizes to microglial cells around both plaques and neurones (Guerreiro et al., 2013a). However, TREM2 has been found to be more highly expressed in microglial cells surrounding amyloid plaques than in plaque-free tissue in an animal model of AD (Frank et al., 2008).

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The activation of the TREM2/DAP12 receptoresignaling complex in microglial cells triggers cytoskeleton reorganization and phagocytosis (Takahashi et al., 2005). Overexpression of TREM2 enhances phagocytosis of apoptotic neurones by microglial cells, whereas deficiencies in TREM2 expression reduce phagocytic activity (Takahashi et al., 2005). It has also been shown that TREM2 expression parallels amyloid phagocytosis by plaque-associated microglial cells (Melchior et al., 2010). TREM2 might, therefore, play a protective role in the neurodegenerative process of AD by enhancing the clearance of neural debris and amyloid peptides. In addition to enhancing phagocytosis, TREM2 also inhibits the production of pro-inflammatory cytokines by microglial cells (Hamerman et al., 2006; Takahashi et al., 2005). Gene transcription of tumor necrosis factor and nitric oxide synthase-2 is reduced in microglial cells overexpressing TREM2 and is enhanced in TREM2deficient microglial cells (Takahashi et al., 2005). Moreover, TREM2 has been shown to inhibit the production of tumor necrosis factor triggered by toll-like and Fc receptors (Hamerman et al., 2006). In TREM2-deficient macrophages, there is an increased production of tumor necrosis factor induced by toll-like and Fc receptors (Hamerman et al., 2006). Toll-like receptoreinduced production of inflammatory cytokines is also inhibited in TREM2-deficient dendritic cells (Ito and Hamerman, 2012). Inhibition of pro-inflammatory cytokine production by TREM2 may, therefore, prevent the formation of damaging inflammatory cascades in the brain, thereby serving a neuroprotective role. Studies in APP transgenic mice have revealed that pro-inflammatory cytokines such as tumor necrosis factor and interferon-g are linked to enhanced deposition and reduced clearance of beta-amyloid peptides (Hickman et al., 2008; Yamamoto et al., 2007). This provides further evidence that TREM2 may play a protective role in AD formation by suppressing cytokine production. In a recent study, the rs759392628 TREM2 polymorphism has been associated with frontotemporal dementia and Parkinson’s disease (Rayaprolu et al., 2013). An OR of 5.06 (95% CI 1.9e13.51, p ¼ 0.0012) was reported for the association of the TREM2 variant with frontotemporal dementia. This is similar to ORs reported by the previous studies for the association of the rs759392628 variant with AD (Guerreiro et al., 2013a; Jonsson et al., 2013). The rs759392628 variant was also found to confer a significant risk of Parkinson’s disease, although the association was not as strong, with a reported OR of 3.14 (95% CI 1.1e9.03, p ¼ 0.0333) (Rayaprolu et al., 2013). In the same study, the rs759392628 variant was not associated with an increased risk of developing progressive supranuclear palsy, amyotrophic lateral sclerosis, or ischemic stroke. These findings suggest that the rs759392628 variant is not specific to AD pathology and that abnormalities in TREM2 play a more general role in the pathology of neurodegenerative processes. In conclusion, therefore, we have successfully replicated the association of the R47H variant of TREM2 with a cohort of AD patients from the northwest of England and, by implication, provided further evidence for the involvement of changes in TREM2 gene and protein as key players in the pathogenesis of AD.

Disclosure statement The authors report no conflicts of interest.

Acknowledgements This work was supported by the Medical Research Council (G0701441). All patients included in this study were recruited with the local ethical committee approval and provided informed consent.

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TREM2 analysis and increased risk of Alzheimer's disease.

Important insights into the pathogenic mechanism of Alzheimer's disease (AD) have arisen from the identification of genetic risk factors. Recently, a ...
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