Genetic susceptibility to OPLL

Abstract

Introduction Ossification of the posterior longitudinal ligament of the spine (OPLL) is a pathological condition of the paravertebral ligament that causes ectopic bone formation possibly through an endochondral Ossification process. OPLL is a common disorder among Japanese and throughout Asian populations but is uncommon in Caucasian populations. The incidence of this disorder in Japan is reported to be 2%-4% in the general population over 30 years of age (see Chapter 4). Although multiple etiologies for OPLL must be considered, evidence from studies of twins and siblings strongly indicate that a certain proportion of the cases of this common disorder are genetically determined. OPLL has long been recognized as a disease of unknown etiology, but identifi cation of genetic susceptibilities would clarify the biometabolic pathway that leads to the development of ectopic bone formation, thereby eventually leading to a full understanding of OPLL. Since the fi rst edition of this book was published, there has been signifi cant progress in the identifi cation of genetic susceptibilities to OPLL by several research groups. In this chapter, I discuss how we can approach the genetic factors of OPLL and how and to what extent the susceptibility genes are involved in the etiology of OPLL. Various research groups have applied different strategies to approach the question of genetic susceptibility, such as genetic linkage analysis and positional cloning, an association study with candidate genes, and gene discovery from an OPLL mouse model (Fig. 1) [1]. Each approach has advantages and disadvantages. For the genetic linkage-based approach, family recruitment is the major diffi culty because numerous members of the nuclear family are needed to perform a robust nonparametric linkage analysis for such a complex disease as OPLL. However, if a certain genetic component exists, the linkage-based approach followed by positional (candidate) cloning is the standard and most promising method. The candidate gene association approach is a direct method for detecting the causality. In general, the biopathway related to a complex disease cannot be explicitly determined; therefore, selecting a candidate gene depends on the researcher?s knowledge, and its success relies on luck. Naturally occurring animal models would be applied not only for detecting the causality in the animal but also for detecting the causality in the human counterpart. The results of this approach should be highly probable if the model animal shares a common etiological background with the human disease, which is indeed diffi cult to predict. In fact, despite enormous efforts, most of the causalities of animal models do not correlate with those of the human diseases. Because of the complexities of OPLL, continuous efforts by cooperative groups also supported by the Investigation Committee on Ossification of the Spinal Ligaments are needed and may provide complete understanding of OPLL in the near future. © 2006 Springer.