rs3732378

This study examined the functional role of CX3CR1 in developmental dysplasia of the hip (DDH) using a CX3CR1 knockout mouse model. CX3CR1 ablation resulted in 5-17% larger acetabular diameter in knockout mice at both 5 and 8 weeks of age, and significantly larger gaps between femoral head and acetabulum (21.5-45.4%, p≤0.037) at 8 weeks. Gait analysis revealed multiple abnormalities in knockout mice consistent with hip osteoarthritis, including increased stance width, step angle variability, and altered gait symmetry. These findings provide functional evidence supporting the role of the rs3732378 CX3CR1 variant (Thr188Met) in DDH susceptibility.

A prospective nested case-control study pooled from five large cohorts examining 15 CX3CR1 SNPs (including T280M and V249I) in 1,110 AMD cases (369 neovascular AMD) and 2,532 controls. No significant associations with AMD were found for the candidate variants T280M (RR=0.87, P=0.074) or V249I (RR=1.01, P=0.82) after multiple comparisons correction. Some CX3CR1 variants showed nominal associations with neovascular AMD in recessive models (rs2669845 RR=3.10 P=0.035, rs9868689 RR=0.31 P=0.017, rs2853707 RR=0.48 P=0.050), with possible gene-environment and gene-gene interactions identified.

A 72-member, four-generation family with developmental dysplasia of the hip (DDH) was studied using genomewide linkage analysis and whole exome sequencing. A 2.61 Mb candidate region on chromosome 3p (38.7-41.31 Mb) was identified with LOD score 3.31. Whole exome sequencing of four severely affected family members revealed a shared nonsynonymous variant rs3732378 (C>T) in CX3CR1 causing a threonine-to-methionine substitution at position 280 in the transmembrane domain (predicted deleterious by PolyPhen-2 and SIFT), which was present in all affected individuals.