Toll-like receptor 4 (TLR4) polymorphisms in ruminants: A review of genetic associations with health, reproduction, and production traits.

Toll-like receptor 4 (TLR4), a fundamental component of the innate immune system, has been identified as a significant candidate gene for enhancing health, productivity, and reproduction in livestock. This review synthesizes and analyzes genetic association studies of TLR4 in cattle, buffaloes, sheep, and goats, assessing its significance in economically important traits. Significant evidence associates TLR4 mutations with resistance to mastitis-mainly through associations with somatic cell score-and susceptibility to several infectious diseases, including paratuberculosis (PTB), infectious bovine keratoconjunctivitis (IBK), and digital dermatitis. Moreover, TLR4 polymorphisms are significantly associated with reproductive performance metrics such as calving interval, days open, and postpartum health, in addition to milk production parameters including yield, fat, and protein content. Notably, specific polymorphisms such as TLR4c.-226 G>C and c.2021 C>T in cattle show recurring pleiotropic associations, positioning them as promising candidates for marker-assisted selection. A persistent theme is that haplotype-based analyses typically produce more reliable associations than single nucleotide polymorphisms, highlighting the significance of genetic context. Data typically reveal population- and breed-specific variability, emphasizing the importance of local genetic structure. Although TLR4 exhibits substantial pleiotropic potential for genomic selection, notable deficiencies persist, especially in functional validation and studies involving small ruminants. Future studies should emphasize functional genomics to establish causality, conduct extensive multi-breed genome-wide studies, and employ integrated systems biology methodologies. This will facilitate the effective application of TLR4 in breeding programs designed to produce animals that are more disease-resistant, reproductively efficient, and adaptable to climate change.