Association of ENPP1 gene polymorphisms with hand osteoarthritis in a Chuvasha population

Osteoarthritis (OA) is the most common form of arthritis and is among the leading causes of disability throughout the world. It is a multifactorial disorder with multiple risk factors contributing to its onset and progression, such as age, genes, hormones, and lifestyle [1]. The most common form of OA is that of the hand [2].Evidence of a genetic influence on OA originates from various studies, including those on family history and familial clustering, twin studies, and examination of rare monogenic disorders. Estimates of the heritability of OA have ranged from 27% to 65% [3-5]. A number of candidate genes have been implicated by association studies in the pathology of OA. Among them are the genes for the vitamin D receptor [6], collagen type II [7], and the estrogen receptor-α [8]. However, these genes can explain only a small part of the genetic component. Up to now, the pathogenesis of OA is poorly understood. Anatomical, physiological, and immunological processes seem to be involved. With a disease as complex in etiology as OA, all of the possible structural and functional susceptibilities make it hard to make an educated guess about the involvement of a particular gene. In such a situation, the analysis of a rare monogenic disorder with an overlapping phenotype may give a clue to the right gene or pathway.Recently, we identified the genetic defect in patients with generalized arterial calcification of infancy (MIM#208000) [9]. In addition to calcifications of great and medium-sized arteries, periarticular calcifications and inflammation of the wrists and ankles were observed in many patients [10,11]. We found numerous disabling mutations in the gene coding for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in these patients [9,12]. This enzyme regulates soft-tissue calcification and bone mineralization by generating inorganic pyrophosphate (PPi), a solute that triggers cell differentiation and serves as an essential physiological inhibitor of hydro