Genetic Susceptibility in Dry Eye Disease: Immunogenetic Evidence, Current Limitations, and Future Directions

Dry eye disease is a multifactorial disorder which is heterogeneous in nature, caused by interactions among ocular surface abnormalities, systemic diseases, environmental factors and host susceptibility. The inherited variation related to the pathophysiology of dry eye disease is not very well characterized, but known mechanisms include inflammation, tear film instability, neurosensory dysfunction and lacrimal and meibomian gland changes. Studies exploring the contribution of genetics suggest that dry eye disease (DED) and specific ocular surface endophenotypes are heritable. Candidate-gene and human leukocyte antigen association studies have reinforced contributions from pathways associated with innate and adaptive immunity, inflammatory regulation and neural function, and glandular homeostasis, but many associations require replication in larger, more diverse populations. Genome-wide association studies and biobank-based assessments have recently begun to shed light on the polygenic architecture of Dry Eye Disease (DED) and its genetic overlap with other related conditions worldwide. This paper evaluates critically the current evidence on DED heritability, candidate susceptibility genes, HLA associations, genome-wide signals, polygenic risk models and genetic pleiotropy. It will cover how transcriptomic, epigenomic, and single-cell approaches can link inherited susceptibility loci to disease-relevant cell states and molecular pathways across the ocular surface unit, including the cornea, conjunctiva, lacrimal gland, and meibomian glands. The study would stress phenotypic heterogeneity, ancestry-related limitations, and inconsistent diagnostic definitions. In the end, we will evaluate opportunities and existing constraints in the incorporation of genomic information with clinical endophenotypes and environmental exposures to support risk stratification, biomarker discovery, identification of therapeutic targets, and the development of future ocular surface precision medicine.