The second approach of choice, to identify arthritis regulating genes for drug development, is population genetic studies by linkage association and positional cloning. With this method, genes of utmost importance for the disease development will be identified regardless of the level of expression, tissue specificity or time of expression. With positional cloning, totally new pathways for disease regulation can be discovered and genes previously not annotated or barely studied in another context can be discovered to be of relevance in the disease.
One drawback of these studies lies in the amount of individuals that have to be included in the investigation and the time it takes to analyse the linkage before positional cloning of individual genes can take place. For example it has been estimated that between 1,000-2,000 sibling pairs will be necessary to identify susceptibility genes with moderate effect [26, 27]. Due to these difficulties, few single genes have been identified from the large number of QTL (Quantitative Trait Loci) that have been identified to control RA. Positional cloning in humans is also hampered by genetic heterogeneity and lack of more individuals that are needed to confirm linkages and make the final localisation of individual disease causative genes.
Besides HLA, which has been identified in association studies and been estimated to account for one third of the inherited susceptibility of RA [28, 29], no other loci of significant contribution to RA has been detected despite several linkage analyses performed in human patient studies [30-33]. Multifactorial environmental influence, genetic and phenotypic heterogeneity together with the impracticality of obtaining individual samples in high enough number makes the majority of human linkage analyses of complex diseases predestined to end short of significant disease-associated chromosomal loci [34, 35]. Another major cumbersome problem that human geneticists have to face when dissecting complex traits is the impracticality to proceed further once a significant loci has been identified. The need for additional informative individuals might be an overwhelming obstacle as it is necessary to obtain additional samples within the same ethnic group as the original study . Despite these difficulties there have been some occasions of successful identifications of autoimmunity regulating genes in humans [37-39], but overall it is difficult to identify genes in complex human diseases . Furthermore, if a significant genetic association is identified, it is needed to identify candidate genes for positional cloning. Positional cloning approaches will most often demand additional large numbers of patient family members to identify single predisposing genes.
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