Toll-like Receptor 4 (TLR4) Polymorphisms in Ruminants: A Review of Genetic Associations with Health, Reproduction, and Production Traits.

TLR4 polymorphisms show pleiotropic associations with mastitis resistance, reproduction, and milk production in ruminants.

This review synthesizes genetic association studies examining Toll-like receptor 4 (TLR4) polymorphisms across ruminant species, including cattle, buffaloes, sheep, and goats, evaluating their relevance to health, reproductive, and production traits. TLR4, a critical component of the innate immune system, has emerged as a promising candidate gene for livestock improvement programs. Key findings demonstrate that TLR4 mutations are significantly associated with mastitis resistance, as measured by somatic cell score, and with susceptibility to economically important infectious diseases including paratuberculosis, infectious bovine keratoconjunctivitis, and digital dermatitis. Reproductive performance metrics—including calving interval, days open, and postpartum health—also show meaningful associations with TLR4 variants. Milk production parameters such as yield, fat content, and protein content exhibit additional associations, demonstrating the gene's pleiotropic nature. Specific polymorphisms, notably c.-226 G>C and c.2021 C>T, appear repeatedly across studies and are highlighted as strong candidates for marker-assisted selection. The review underscores that haplotype-based analyses consistently outperform single SNP approaches, and that population- and breed-specific genetic context substantially influences outcomes. Critical gaps remain, particularly in functional validation studies and research involving small ruminants. The authors advocate for future functional genomics investigations, large-scale multi-breed genome-wide association studies, and systems biology approaches to translate these genetic associations into effective breeding programs aimed at improving disease resistance, reproductive efficiency, and climate adaptability.

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