New Genetic Links Between LILRB2 and Pathological Myopia

Pathological myopia (PM) is a significant cause of irreversible blindness, particularly prevalent in East Asian populations. Research led by Professor Yi Shi and her team at the Sichuan Academy of Medical Sciences focused on uncovering the genetic factors that contribute to this condition. Their recent Genome-Wide Association Study identified the LILRB2 gene (Leukocyte immunoglobulin-like receptor subfamily B member 2) as a novel genetic risk factor. Using experimental mouse models, they demonstrated that increased expression of this gene’s protein causes eye structure changes consistent with human pathological myopia, providing important clues as to why this condition disproportionately affects certain populations.

Why Myopia Is a Significant Concern for East Asian Populations

Myopia, commonly known as nearsightedness, is widespread, but pathological myopia is a more severe and progressive form. Unlike typical myopia, which can often be corrected with lenses, PM is characterized by extreme elongation of the eyeball, with axial length exceeding 26 mm (normal axial length is usually below 24 mm). This elongation leads to thinning of critical eye tissues including the retina, sclera, and choroid, resulting in complications such as lacquer cracks, choroidal neurovascularization, retinal detachments, and staphylomas¹.

The high prevalence of PM particularly in East Asian and Middle Eastern populations suggests a strong genetic contribution. Understanding these genetic risks can help explain the uneven geographic distribution of the disease and open paths to early detection or intervention.

Revealing Genetic Targets in Myopia Through Two-Stage genome-wide association studies

Genome-wide association studies enable researchers to compare millions of genetic variants, single nucleotide polymorphisms (SNPs), across individuals to identify differences associated with diseases². Previous work uncovered many loci linked to general myopia, but fewer have been definitively connected to the pathological form.

To address this, Professor Shi’s team conducted a two-stage genome-wide association study. Stage 1, the discovery phase, analyzed around 750,000 SNPs in patients with PM and healthy controls from Sichuan, China. The most promising five SNPs identified were then tested in stage 2, in additional cohorts from Shanghai, Japan, and Guangzhou, ensuring robustness of the findings. Both stages of the study restricted PM patients to those with axial lengths over 26 mm, enhancing the confidence of the results.

Among many candidates, the region on chromosome 19q13.42 stood out: the LILRB2 gene emerged as a novel risk locus. Notably, carriers of specific alleles, such as rs367070 and rs13345069, showed a significantly higher likelihood of developing PM.

Functional insights into LILRB2’s role in PM

After identifying LILRB2, the team explored how LILRB2 might contribute to PM. Peripheral blood samples showed increased expression of LILRB2 protein in PM patients, especially in CD14+ monocytes. In human eyes, LILRB2 localized to retinal vessels, the choroid, and retinal ganglion cells, and it was also present in widely used ocular cell lines.

To test causality, the researchers investigated Pirb (paired Ig-like receptor B), the mouse homolog of LILRB2. They found that Pirb is expressed in critical ocular tissues including the sclera, retina, and choroid. Using two established mouse models of myopia, form deprivation and lens-induced, they induced myopia and confirmed its development through measurements of refractive error utilizing Striatech’s Photorefractor system, alongside axial length assessments. Both myopia models exhibited elevated Pirb expression in ocular tissues, supporting the gene’s functional role in myopia progression.

Building on this, they employed an adeno-associated virus (AAV) to deliver Pirb into the subretinal space of mice bilaterally. Using Striatech’s Keratometer, they confirmed that the injection itself did not affect corneal radius or curvature. Overexpression of Pirb, on the other hand, triggered hallmark PM changes: axial elongation, increased refractive error, and thinning of the choroidal and retinal pigment epithelium (RPE) layers, mirroring human disease progression.

Fatty Acid Metabolism Impairment underlying Myopia Pathogenesis

They next conducted RNA sequencing on the eye tissues to identify molecular pathways altered by LILRB2/Pirb overexpression. Fatty acid metabolism emerged as significantly disrupted, with reduced uptake, transport, and processing of fatty acids in the mouse eyes. Histological examination revealed accumulation of triglycerides within the choroid and retina.

These metabolic disturbances were corroborated in human-derived HUVEC and RPE cell lines genetically modified to overexpress LILRB2, resulting in increased intracellular fat droplets. Mechanistically, LILRB2/Pirb appears to activate the ERK-P38-JNK signaling cascade, which in turn upregulates fatty acid synthesis-related genes such as FASN and ACC1, driving lipid accumulation. The resulting buildup undermines the structural and functional integrity of the RPE and choroid, which play critical roles in oxygen supply and retinal health.

LILRB2 Discovery Opens Doors for Early Detection and Treatment of Myopia-Related Blindness

The identification of LILRB2 and its specific risk alleles enriches the genetic landscape of pathological myopia and has significant clinical implications, especially given the higher burden of PM in East Asian populations. Genetic screening for these risk variants could facilitate earlier diagnosis and intervention strategies tailored to high-risk individuals.

Moreover, the link between LILRB2 overexpression and fatty acid metabolism dysfunction opens new avenues for exploring therapeutic targets. Modulating lipid metabolic pathways or intervening on the ERK-P38-JNK signaling axis could hold promise in mitigating the progression of PM.

Continued research is essential to further elucidate how genetic and environmental factors converge on these molecular pathways, with the ultimate goal of preventing blindness from pathological myopia in vulnerable populations.

Source material:

1. Jonas JB, Jonas RA, Bikbov MM, Wang YX, Panda-Jonas S. Myopia: Histology, clinical features, and potential implications for the etiology of axial elongation. Prog Retin Eye Res. 2023 Sep;96:101156. doi: 10.1016/j.preteyeres.2022.101156.
2. Uffelmann, E., Huang, Q.Q., Munung, N.S. et al. Genome-wide association studies. Nat Rev Methods Primers 1, 59 (2021). https://doi.org/10.1038/s43586-021-00056-9

Original article: L. Jiang,  L. Huang,  C. Dai,  R. Zheng,  M. Miyake,  Y. Mori,  S. Nakao,  K. Morino,  K. Ymashiro,  Y.-B. Miao,  Q. Li, W. Ren,  Z. Ye,  H. Li,  Z. Yang,  Y. Shi,  Genome-Wide Association Analysis Identifies LILRB2 Gene for Pathological Myopia. Adv. Sci.  2024,  11, 2308968. https://doi.org/10.1002/advs.202308968

Blog author: Emilia Kawecka, Technical University of Munich, Student Assistant at Striatech