Gender‐dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplasty

Abstract

The G-protein Gas is involved in the physiology and pathophysiology of bone. Especially, Gas is a key regulator of interleukin-6, which is a potent promoter of aseptic loosening. We hypothesized that the common single nucleotide polymorphism GNAS1 T393C could also affect time to aseptic loosening. Caucasian patients were genotyped for the GNAS1 T393C polymorphism. Time and median time to aseptic loosening were analyzed for dependency on GNAS1 genotypes. Time and median time were not significantly associated with genotypes. Additional analysis corrected for gender revealed, that the TT genotype was associated with significantly longer time (p ¼ 0.048) as well as median time ( p ¼ 0.022) to aseptic loosening in female patients. In contrast to the findings in females, male TT genotype carriers had significantly shorter time ( p ¼ 0.018) and median time ( p ¼ 0.023) to aseptic loosening. Compared with TT genotype carriers heterozygous patients had a 6.25-fold lower risk with a hazard ratio of 0.160 ( p ¼ 0.016) and male patients carrying the CC genotype had an 11-fold lower risk with a hazard ratio of 0.088 ( p ¼ 0.006) in multivariate analysis. The present study suggests a significant gender-dependent role of the T393C polymorphism in aseptic loosening. The apparently contradictory results in women and men and the finding that the GNAS1 T393C genotype is an independent factor for time to aseptic loosening in male patients assigned this polymorphism as an interesting target for further investigations in bone diseases. ß

Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project

“…Interestingly, ADRB1 and ADRB2 alleles are associated with differential gender responses in blood pressure [38], and in rats these genes interact with sex hormones in a differential manner [39]. The GNAS gene was associated with different responses to hip arthroplasty [40]. While allele frequency differences between the sexes may not be frequent when they occur this may be an indicator of potential gene-gender interactions for future research.…”

Do We Need Gender-specific Total Joint Arthroplasty?

“…This work led to some orthopaedic device manufacturers developing ''gender-specific'' total knee prostheses in an attempt to provide more options for the surgeon and patient (such as incorporating more sizes, differing aspect ratios, altered trochlear grooves, and other features). Additionally, as a greater understanding of the variability of hip and knee anatomy has been attained [2,9,40,49], implants have been redesigned with more modularity in their systems.…”

Reply

“…Indeed, we addressed these limitations in our article. 1 We are aware that multiple factors can influence the time to loosening, that is, inconvenient implants, surgical inexperience, low grade sepsis but it is also known that Il-6 is a key factor in particle induced osteolysis and might be a potential target for further investigations like we did. 2 This study is one of the first studies analyzing the impact of genetic background in relation to time to aseptic loosening.…”