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

Eun-Kyung Suk1, Ida Malkin2, Stefan Dahm3, Leonid Kalichman2, Nico Ruf1, Eugene Kobyliansky2, Mohammad Toliat16, Frank Rutsch4, Peter Nürnberg156* and Gregory Livshits2

Author Affiliations

1 Gene Mapping Center, Max Delbrück Center for Molecular Medicine, Berlin, Germany

2 Human Population Biology, Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel

3 Bioinformatics Section, Max Delbrück Center for Molecular Medicine, Berlin, Germany

4 Department of Pediatrics, University Medical School Münster, Germany

5 Institute of Medical Genetics, Charité – University Hospitals of Berlin, Germany

6 Cologne Center for Genomics and Institute for Genetics, University of Cologne, Germany

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Arthritis Research & Therapy 2005, 7:R1082-R1090  doi:10.1186/ar1786

Published: 13 July 2005


Periarticular calcification is a common attendant symptom of generalized arterial calcification of infancy, a rare Mendelian disorder caused by mutations of the gene coding for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This prompted us to perform a family-based association study to test the hypothesis that genetic variation at the ENPP1 locus is involved in the etiology of osteoarthritis of the hand. The study population comprised 126 nuclear families with 574 adult individuals living in small villages in the Chuvasha and Bashkirostan autonomies of the Russian Federation. The extent of osteoarthritis was determined by analyzing plain hand radiographs. The outcome of a principal component analysis of osteoarthritis scores of a total of 28 joints of both hands was used as a primary phenotype in this study. Maximum likelihood estimates of the variance component analysis revealed a substantial contribution of genetic factors to the overall trait variance of about 25% in this homogeneous population. Three short tandem repeat (STR) polymorphisms – one intragenic and two flanking markers – and four single-nucleotide polymorphisms were tested. The markers tagged the ENPP1 locus at nearly equal intervals. We used three different transmission disequilibrium tests and obtained highly significant association signals. Alleles of the upstream microsatellite marker as well as several single-nucleotide polymorphism haplotypes consistently revealed the association. Thus, our data highlights variability of ENPP1 as an important genetic factor in the pathogenesis of idiopathic osteoarthritis.