**4.7.2 Current status of the research**

348 Recent Advances in Arthroplasty

the risk for aseptic loosening (Fig. 6). Engh et al estimated that both wear and patient propensity to osteolysis might together account for 53% of the variance in total area of

Fig. 6. Functional variation in genes for cytokines (other molecules) could influence the rate of aseptic loosening via contribution to severity of bone resorption around the implant

The question is which genes (genotype) could influence the fate of implant in terms of premature aseptic loosening/ periprosthetic osteolysis (phenotype). A gene is traditionally defined as a segment of DNA encoding a protein. Single nucleotide polymorphism (SNP) is a common form of variation in the human genome implicating that a single base change in the DNA sequence could influence the amount/functionality of secreted proteins. With the sequencing of the human genome, it has been recognized that SNPs occur about once every 1000 base pairs (Dupuis and O'Donnell 2007). The key problem is *how to distinguish the gold (functional polymorphisms) from fool´s gold (unimportant variants)*. By genotyping a large number of SNPs in a large number of patients there is a good chance of detecting those that are significantly associated with the target disease. Unfortunately, epigenetic factors and further DNA sequence variants such as copy number variants create other sources of variation between individuals. In addition, there are several non-coding small regulatory molecules (e.g. miRNAs, siRNAs) that significantly influence the process of translation of

According to the number of genes participating in the pathophysiology of a disease and the size of their effect, *polygenic predisposition* assuming small/ marginal effects of many genes fits much better to the model of THA failure than the oligogenic model with two or more major gene (locus) effects. In this line, the odds ratios of 1.2 to 1.6 are required for differentiating true effects of individual genetic variants on a complex disease from the potential impact of bias (Ioannidis et al. 2006). Studies reporting weaker individual size effects are unlikely to be used for predicting a target condition; on the other hand, a combination of several even weaker genetic variants (especially at multiple loci) can increase

**4.7.1 Methods for investigating genetic susceptibility to aseptic loosening/** 

osteolysis (Engh et al. 2011).

**periprosthetic osteolysis** 

genes into effector proteins.

the chance for reasonable prediction.

Wilkinson et al were the first to publish a study on the association between polymorphisms in the gene encoding for TNF alpha and risk of periprosthetic osteolysis in THA (Wilkinson et al. 2003). After this introductory work several papers were published nominating other molecules as candidates involved in the processes of aseptic loosening/ osteolysis. Structurally and functionally, these include receptors, intracellular mediators, enzymes, cytokines and other proteins. A recently published systematic review on genetically determined susceptibility to aseptic loosening of THA, revealed several areas of potential agreement (SNPs of TNF-238A allele, IL1RA +2018C allele, polymorphisms in genes for IL-6, MMP-1 etc.), but also several sources of heterogeneity between studies, showing the need for large multi-centre prospective studies that should provide stronger evidence for genetic predisposition to THA premature failure (Del Buono et al. 2011). As a result, further progress in the field of genetic risk of aseptic loosening/ osteolysis will require both sophisticated research strategy and statistics (e.g. improved risk-analysis models) to overcome a series of challenges. Fortunately, as experience accumulates, there is increased interest of orthopaedic specialty in the outcomes of such research.
