Familial and genetic aspects of spondyloarthropathy

Continuous progress in the field of genetic biology offers new opportunities to identify the genetic factors that underlie predisposition to common disorders, also called complexes because they result from several interacting genetic and environmental determinants [1]. Among the most significant advances is the expanding field of candidate gene approach as a consequence of the full human genome sequencing progress and the increasing power of positional cloning strategies. The principle of the latter approach is to map genetic regions linked with disease (which therefore contain genes predisposing to the studied trait). Such an approach typically starts with a genome-wide scan, which compares the observed sharing of genetic markers (microsatellites) widespread along the genome among disease-affected siblings pairs (ASP) with that sharing expected in case of random distribution. Although not related to any particular gene, microsatellites are allelic markers easily genotyped by the polymerase chain reaction (PCR) technique, which allows tracking of the transmission of genetic regions from parents to offspring. Linkage of a specific genetic region with disease will translate into increased sharing between ASP of the microsatellites spanning that region. Positional cloning strategies appear to be most adapted to diseases for which the pathogenesis is still poorly understood, such as the spondyloarthropathies (SpA), and for which a systematic candidate gene approach seems an unreasonably large quest. Though this positional cloning has been successful in a number of Mendelian monogenic disorders, results in polygenic disorders have remained inconclusive, except in a few cases [2-4]. One such example of successful research concerns the identification of the IBD1/CARD15/NOD2 gene as a susceptibility gene for Crohn's disease, albeit not for ulcerative colitis [5,6]. Among difficulties inherent to the positional cloning strategy in polygenic disorders are the typically small-sized pedigrees and the large number of markers tested to span the whole genome (> 400 in general) with regard to the relatively low power of the statistics used to analyze their linkage with disease. This situation implies that the number of pedigrees required is quite large (routinely > 200 ASP), and that some of the positively mapped regions are indeed false positive and formal exclusion of any apparently negative region is virtually impossible. Mixing together a large number of pedigrees increases the formal risk of genetic heterogeneity, which might have several different causes: (1) variability produced by different types of mutations in a given gene or by additional genetic or environmental factors might result in distinct phenotypes (an example of this first situation is provided by mutations in CARD15/NOD2 gene, which predispose either to Crohn's disease [5] or to Blau syndrome [7] depending on the site of the mutation in the gene); (2) a similar phenotype can result from mutations in distinct genes controlling the same function (an example of this possibility is given by the genetic predisposition to mycobacterial infections that has been associated with mutations affecting either of the following genes: interferon [IFN-gamma receptor 1 or 2, interleukin [IL]-12B, IL-12 receptor B1, and STAT1, all of which lead to impaired IFN-gamma-mediated immunity [8]). To reduce the pitfalls of genetic research in polygenic disorders, it is necessary to carefully define the studied phenotype. Genetic heterogeneity can also be potentially reduced at the level of recruitment by limiting heterogeneity of the studied population [4]. It would be wise to answer some of the following questions before recruiting large, multiplex family cohorts: How meaningful is the studied phenotype? How strong is the evidence for genetic predisposition to the studied disease and, thereby, the chance to identify gene of medical significance (ie, a that the inflammatory bowel disease in SpA is determined by factors different than those responsible for isolated Crohn's disease.