Study suggests a link between the protein-coding gene TREM2 and obesity in females

By Dr. Priyom Bose, Ph.D.Reviewed by Emily Henderson, B.Sc.Jan 11 2023

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a membrane protein expressed on immune cells and associated with neurodegenerative diseases, such as Alzheimer’s disease. Several studies have indicated the importance of TREM2 in cancer, metabolic, and neurodegenerative diseases.

A recent Scientific Reports study has investigated the link between TREM2 expression and human obesity, based on two large public datasets, namely, the UK Biobank (UKB) and the Genotype-Tissue Expression (GTEx) project.

Study: TREM2 has a significant, gender-specific, effect on human obesity. Image Credit: kurhan / Shutterstock

Background

Using the transcriptional single-cell sorting technique, TREM2 was detected in lipid-associated macrophages present in adipose tissues. Another study revealed that TREM2 knockout mice developed metabolic symptoms, such as hyper-cholesterolemia, adipocyte hypertrophy, glucose intolerance, and body fat accumulation. 

An animal-based study discovered a novel subpopulation of macrophages expressing a high level of TREM2 in the kidney of obese mice. Interestingly, these were matched to macrophages expressing high levels of TREM2 in obese humans. 

The role of TREM2 in cancer has been recently elucidated. This study determined TREM2 to be a biomarker of tumor-associated macrophages in cancers. A high level of expression of TREM2 in macrophages has been associated with a poor survival rate. It was observed that blocking TREM2 led to an enhancement of anti-tumor response in mice. 

Very little epidemiological evidence has been documented related to the role of TREM2 in human obesity. Nevertheless, a small study based on fifteen participants with diabetes and obesity revealed high TREM1 and reduced TREM2 expression in blood and several tissues.

About the Study

As stated above, data was obtained from the GTEx portal, a public resource used to study tissue-specific gene expression. Samples were obtained from 54 healthy tissue sites across nearly 1,000 individuals, and BMI data were obtained from dbGAP. Single nucleotide polymorphism (SNP) and BMI data were also obtained from 481,271 participants registered in the UKB. 

Study Findings

The GTEx bulk tissue gene expression profile for TREM2 indicated that this membrane protein is mainly expressed in the lungs, brain, and nerve tissues. Among the 54 different types of tissues assessed, subcutaneous and visceral adipose tissues ranked 12th and 20th, respectively, in terms of normal TREM2 expression levels.

Out of the 54 tissues, six exhibited a significant correlation between the TREM2 expression level and the BMI of participants. Both subcutaneous and visceral adipose tissues exhibited the most significant and highest correlation. This correlation was more prominent in males compared to females.

Based on the UKB cohort, the current study identified a coding SNP (rs2234256 SNP, L211P) in TREM2, which significantly affects BMI. Compared to 74 other SNP previously shown to affect BMI, the currently identified one exhibited the highest effect. SNP rs2234256 is a missense coding SNP in TREM2, which causes a change from Leucine to Proline at amino acid 211.

In the UKB, rs2234256 is present in a minor, non-negligible frequency, i.e., 0.87% for heterozygotes and 0.04% for homozygotes. A stronger association between TREM2 expression level in adipose tissue and BMI was found in males compared to females; however, the effect of rs2234256 was only found in females. These two effects have been associated with different phenomena. More specifically, the former expression was linked to the expression of wild-type genes in adipose tissues, which affected BMI, and the latter was associated with the effect of a specific coding SNP mutation in heterozygotic and homozygotic carriers.

Conclusions

The current computational study is based on large voluntary public databases that contain selection bias and several confounders. In addition, the correlations shown in this study cannot prove causality. Despite these limitations, the present study revealed that TREM2 is an important gene associated with neurodegenerative disease, metabolic diseases, and obesity.