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Am J Hum Genet. Feb 2007; 80(2): 383–386.
PMCID: PMC1785353

Genetic Association Analysis of RHOB and TXNDC3 in Osteoarthritis

To the Editor:

In the May 2006 issue of The American Journal of Human Genetics, Mahr et al.1 reported an association with osteoarthritis (OA [MIM 165720]) for a SNP (rs49846015) located immediately 5′ of the coding region of RHOB (on chromosome 2p24.1 [MIM 165370]) and for a SNP (rs4720262) located immediately 5′ of the coding region of TXNDC3 (on chromosome 7p14.1 [MIM 607421]). RHOB codes for a GTP-binding protein whereas TXNDC3 codes for a thioredoxin protein. The association study by Mahr et al. was performed with 171 patients with OA (74% females) who had undergone joint-replacement surgery (68% knee and 32% hip) and with 182 healthy control subjects (66% females), all of European white ethnicity. Possession of a copy of the G allele of rs49846015 was an OA risk factor (P=.0007), as was possession of the T allele of rs4720262 (P=.0007).

To assess the robustness of these associations, we have genotyped the SNPs in our collection of >1,500 case patients with OA (mean age 65 years; age range 56–85 years) and >700 age-matched control subjects (mean age 69 years; age range 55–89 years). As in the study by Mahr et al.,1 our case patients were ascertained by joint-replacement surgery (hip, knee, or hip and knee) due to severe end-stage OA. Our control subjects had no signs or symptoms of arthritis or joint disease (pain, swelling, tenderness, or restriction of movement). All case patients and control subjects were individuals from the United Kingdom who are of white European ethnicity. Further details about the ascertainment of our case patients and control subjects have been published elsewhere.2 Ethical approval for our study was obtained from the appropriate ethics committees, and informed consent was obtained from each individual studied.

When planning our investigation, we noted that rs49846015 was absent from dbSNP. A correspondence with Sandra Mahr (personal communication) revealed that rs585017 was the correct accession number for this SNP. rs585017 and rs4720262 were genotyped by mass spectrometry (homogeneous MassARRAY system [Sequenom]), and the genotype and allele distributions in case and control groups were compared using standard χ2 analysis-of-contingency tables. Tables Tables11 and and22 list the results for rs585017 and rs4720262, respectively. Both SNPs were in Hardy-Weinberg equilibrium in the case and control groups. There were no significant differences (all P values >.05) in genotype or allele frequencies for either SNP between the case and control groups. This was also the case when the data were stratified by sex, with male case patients compared with male control subjects and female case patients compared with female control subjects.

Table 1.
Association of RHOB SNP rs585017 between Our Case Patients with OA and Control Subjects
Table 2.
Association of TXNDC3 SNP rs4720262 between Our Case Patients with OA and Control Subjects

The frequency of the G allele of rs585017 in our study is comparable to that in the study by Mahr et al.,1 with a frequency of 27.4% in our control group and 23.9% in Mahr et al.'s control group (P=.20). However, the frequency of the T allele of rs4720262 shows a highly significant difference between the two studies, with a frequency of 28.8% in our control group and 13.4% in Mahr et al.'s control group (P<.0005). In dbSNP, the T allele of rs4720262 is listed as having a frequency of 31.2% in the AFD-EUR panel (23 unrelated American individuals of European descent and one sample from a human variation panel of 50 whites) and a frequency of 21.7% in a HapMap-CEU panel (30 mother-father-child trios from the CEPH collection of Utah residents with northern and western European ancestry). Our T-allele frequency of 28.8% is between these two dbSNP-reported frequencies, whereas the T-allele frequency of 13.4% reported by Mahr et al. is substantially lower than both database frequencies. This implies that the control frequencies reported for this SNP by Mahr et al. may not accurately reflect the true frequency of this SNP in Europeans of white ancestry.

To assess the power of our study, we conducted power calculations by using Quanto, version 1.5,3,4 with the following options: an unmatched case-control study design, a population risk of severe OA of 5%, a significance level of 0.05, a G-allele frequency of 23.9% for rs585017, a T-allele frequency of 13.4% for rs4720262, and a log-additive inheritance mode. The allele frequencies and the inheritance mode were selected to agree with the results of Mahr et al. Table 3 lists, for each comparison, the minimum odds ratio (OR) detectable with 80% power for our study. We calculated an OR of 2.05 for the association with rs585017 and an OR of 2.26 for the association with rs4720262 from the results reported by Mahr et al. All the ORs given in table 3 are lower than these values, indicating that the sample sizes used in our study are more than adequate to detect the ORs previously observed by Mahr et al. In fact, the power to detect an OR of 2.05 for the association with rs585017 was [gt-or-equal, slanted]99.7% for all comparisons, and the power to detect an OR of 2.26 for the association with rs4720262 was [gt-or-equal, slanted]99.6% for all comparisons.

Table 3.
The Minimum Detectable ORs for Our Analysis under the Log-Additive Model with Power [gt-or-equal, slanted]80% and a Significance Level of 5%

Overall, our study does not replicate the previous findings of an association between OA and the RHOB SNP rs585017 and the TXNDC3 SNP rs4720262. Our study was adequately powered to detect an association comparable to that reported by Mahr et al., and we avoided potential confounding factors by using the same disease ascertainment (joint replacement of the hip or knee) and the same ethnic group (Europeans of white ethnicity) used in the original study. As more studies are reported, an accurate estimation of the effect of these two SNPs on OA susceptibility will become apparent.

Web Resources

Accession numbers and URLs for data presented herein are as follows:

dbSNP, http://www.ncbi.nlm.nih.gov/projects/SNP/ (for rs585017 and rs4720262)
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for osteoarthritis, RHOB, and TXNDC3)
Quanto, http://hydra.usc.edu/gxe (for power calculations)

References

1. Mahr S, Burmester G-R, Hilke D, Göbel U, Grützkau A, Häupl T, Hauschild M, Koczan D, Krenn V, Neidel J, et al (2006) Cis- and trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet 78:793–803 [PMC free article] [PubMed]
2. Mustafa Z, Dowling B, Chapman K, Sinsheimer JS, Carr A, Loughlin J (2005) Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population. Arthritis Rheum 52:3502–3506 [PubMed] [Cross Ref]10.1002/art.21399
3. Gauderman WJ (2002) Sample size requirements for matched case-control studies of gene environment interaction. Stat Med 21:35–50 [PubMed] [Cross Ref]10.1002/sim.973
4. Gauderman WJ (2003) Candidate gene association studies for a quantitative trait, using parent offspring trios. Genet Epidemiol 25:327–338 [PubMed] [Cross Ref]10.1002/gepi.10262

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