Through a large-scale association study with subsequent functional researches, the Japanese group have demonstrated a convincing association between the
CALM1 core promoter polymorphism and Japanese hip OA. The well clarified role Ca
2+-calmodulin signal played in chondrogenesis and normal cartilage phenotype maintaining, together with the results of the microarray analysis [
7] showing higher levels of
CALM1 expression both in hip and knee OA, have interested us in assessing whether this genetic polymorphism is also associated with OA in a Chinese Han population. However, we failed to find any positive result. Before the present study, this potential association had also been studied in UK Caucasian populations [
11,
12], yielding no positive findings either in hip or knee OA patients. Together, these studies highlight the complexity and diversity of genetic contributions to such a multifactorial disease as OA.
The "T" allele and "TT" genotype frequencies of controls in present study were very similar to those in the original study of the Japan group but different to those in the UK study [
12]. The "T" allele even seemed to be the major allele in UK Caucasians instead of the allele "C" which was dominant in both the present and the Japanese studies, indicating a heterogenous nature of this polymorphism between Asians and UK Caucasians. The different ethnic background and the potential linkage disequilibrium (LD) of the -16C/T locus with some other more relevant allele or alleles within the CALM1 gene that differ in different populations, may be one of the most likely explanations for the failure to replicate the association of -16C/T with OA susceptibility in UK Caucasians.
Recently, several population-based association studies for other OA susceptibility genes have shown consistent results in the Japanese and Chinese Han populations [
13,
16]. Populations from neighboring regions may have greater similarities in genome for the fact that they share more recent common ancestors. Therefore, their allele frequencies are more highly correlated, a pattern that is commonly manifested as a cline of allele frequencies [
17]. All these together had encouraged us to expect a positive association of -16C/T polymorphism in our population-based study, except for the fact that there is an obvious difference in clinical phenotype of OA patients between the present and the original Japanese studies -the different joint site affected, which may account for the inconsistent results of the two studies. It is becoming more apparent that the nature of OA genetic susceptibility is likely to vary between different joint sites [
18]. In the RHOB and TXNDC3 studies, different associations were detected for the different affected joint sites [
19‐
21]. A relatively small population size might have prevented from seeing the association. The proportion of genetic contribution of certain polymorphic locus to OA susceptibility may be influenced by other local environmental factors such as anatomical and biomechanical effects, and by some joint-specific genetic factors most of which were postulated to be involved in cell signalling and signal transduction [
18,
22]. Interestingly,
CALM1 is only one member of the
CALM family by which mammalian CaM is encoded. The
CALM family includes three nonallelic genes
CALM1,
CALM2 and
CALM3 located on chromosomes 14q24-q31, 2p21.1-p21.3 and 19q13.2-q13.3, respectively, but all these three genes encode an identical 148 amino acid protein CaM [
23]. However, the transcriptional activity and the proportion of each gene contributing to the local mRNA pools seem to differ during cell differentiation processes or in different biochemical microenvironments [
24,
25]. Thus, the other two
CALM genes that are more functionally active in the knee joint might have decreased the extent to which the
CALM1 OA risk is manifest. To make our study more complete and comparable, it is necessary to collect enough samples of hip OA despite of the very much lower prevalence [
26], and assess the association between this polymorphism and hip OA in the same Chinese population.
Moreover, Hoaglund [
27] has recently made a comment on the ascertainment criteria used for the patient enrollment in the Japanese association study and has suggested that the
CALM1 core promoter polymorphism may be associated with Japanese congenital hip disease causing secondary hip OA rather than primary hip OA. Colleagues in our department are now trying to identify this hypothesis by assessing the association in patients of developmental dysplasia of the hip (DDH) which may represent a severe phenotype of congenital hip disease.