Replication of association of the D-repeat polymorphism in asporin with osteoarthristis

Abstract

Rodriguez-Lopez and colleagues [1] describe a replication study of our previous association between osteoarthritis (OA) and asporin [2]. The authors were unable to find this association in the Spanish population and question the association we found in the Japanese population. Their report also contains an interpretation of two previous papers on the same topic [3,4] that differs from those of the original study authors. We have concerns about their interpretation of data and about the conclusions drawn. It is not surprising that an association of a gene with a disease is found in some populations but not in others. Such diversity has been established for many common complex diseases with several explanations [5]. In this particular case, one explanation is the difference in the inclusion criteria used to recruit study participants. Whereas we recruited symptomatic OA patients with supporting radiographic evidence, Rodriguez-Lopez and colleagues used joint replacement surgery as inclusion criteria (Table ​(Table11). Table 1 Association studies of asporin and osteoarthritis Another explanation is ethnic diversity, which is apparent in the very different allelic frequencies between the Spanish and Japanese populations. We question the authors' generalization of the three European populations (Spanish, Greek and UK) as 'European Caucasian', given the diverse frequencies of asporin alleles in the three populations [1,3,4] (Table ​(Table2),2), as well as their history and geography. The Spanish population in particular is distinct from the others; for example, the frequency of the common allele, Asp13 (D13), in the Spanish control groups shows statistically significant differences (p = 0.00088 versus UK; p = 0.021 versus Greek). The allelic frequency in hip OA also is very different. Table 2 Allelic frequencies of D13 and D14 repeats of asporin in osteoarthristis However, it is notable that in studies of knee OA for all three European populations, the allelic frequency of D13 is decreased and that of D14 is increased in the case group – the same trend observed in our Japanese study (Table ​(Table2).2). In all four populations, the odds ratios exceed 1. Given that the deviation of the odds ratio is random, the probability for its occurrence by chance is (1/2)4 = 1/16, which is substantially low. If we combine data for all three European populations, the association becomes significant (p = 0.030; odds ratio 1.26, 95% confidence interval 1.02 to 1.56). We believe that this estimation is valid because the inclusion criteria are the same, provided that the ethnicity is consistent as the Spanish group itself proposed. If so, the association of asporin has been replicated in the European Caucasian population. The low odds ratio given above suggests that the Spanish study might be under-powered to detect the low-risk gene. It remains under-powered even when we postulate the moderate risk (power = 0.56 to 0.71 at a relative risk of 1.4 to 1.5 [6]). OA is a serious disease with global impact, and it has proven refractory to genetic (etiologic) study. The questions raised by Rodriguez-Lopez and colleagues [1] provide further incentive to build common platforms for phenotype definition, inclusion criteria, genotyping and analytical methods, and to unite the ethnically diverse resources available for study. Such efforts would increase the accuracy and power of the research for our 'common' enemy.