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Osteoarthritis (OA) of the hip is a major cause of pain, disability and use of healthcare resources.1 Although OA is multifactorial, it is known to have significant genetic contribution and a number of studies have attempted to dissect such contribution (see2 for review).
The DOT1L gene encodes the DOT1-like histone H3 methyltransferaseis, a potentially dedicated enzyme for Wnt target gene activation in leukaemia recently shown to be associated with endochondral bone formation.3
A polymorphism (rs12982744) in DOT1L has been found to be strongly associated with minimum joint space width (minJSW) at the hip. This exact same single nucleotide polymorphism (SNP) was previously identified to be associated with increased height.4 ,5 The C allele associated with lower minJSW and lower height was associated with hip OA, although this association did not reach genome-wide significance (GWS) (OR 1.14, CI 1.06 to 1.22; p=1.5 × 10−4).3
The GWS level of p<5×10−8 is the threshold at which genetic associations are considered credible.6 The aim of our study was to prove that common genetic variation in the DOT1L gene is important in hip OA at this level of confidence.
Genetic association data for rs12982744 and hip OA were derived from the Translational Research in Europe Applied Technologies for OsteoArthritis (TREAT-OA) consortium and combined with data from the UK (arcOGEN consortium), Estonia (Estonian Genome Center of the University of Tartu) and other studies (Nottingham, GOAL).3 The total sample size was 9789 hip OA cases and 31 873 controls of which there were 4155 cases and 15 213 controls in male subjects and 5634 cases and 16 660 controls in female subjects. Summary OR was calculated using a fixed effects model. The individual study estimates and sample sizes are shown in figure 1. A full detailed description of each study cohort on recruitment, radiographic and clinical assessment is found in.7 ,8 Studies were approved by the relevant Ethics Committee and informed consent was obtained from all study participants.
The results of the meta-analysis show that in male subjects the C allele of DOT1L rs12982744 is GWS with a 17% increased risk of hip OA (OR 1.17, 95% CI 1.11 to 1.23, p=7.8×10−9) with no observed heterogeneity (I2=0). In female subjects, the OR is 1.05 (95% CI 1.00 to 1.10, p=0.04) with I2=31%. The effect size estimate is significantly different between both sexes (p=0.003) with non-overlapping CIs. For both genders combined, the p value was 8.1×10−8 (I2=35%) (figure 1). The difference in effect size between genders is not surprising considering the sexual dimorphism of this trait: men have a larger mJSW and prevalence of hip OA rises specifically in women after menopause, suggesting a role of sex hormones in the disease process.
In this large-scale meta-analysis we show that the association between a DOT1L SNP and hip OA achieves GWS in male subjects strengthening the robustness of DOT1L as a risk factor for hip OA.
This makes DOT1L a potential therapeutic target for modulation and intervention in hip OA. This is relevant since small molecular inhibitors have been developed and a phase I trial has been started (http://epizyme.com/programs/dot1l.asp).
This result also highlights the greater statistical power of quantitative endophenotypes for genetic studies.
EE and AMV contributed equally.
Contributors All authors contributed to the study design, data interpretation and the final manuscript. In addition, EE analysed the data; JvM, EE and AMV interpreted the data and prepared the manuscript; and JvM supervised the study.
Funding This work was supported by EC framework 7 programme grant 200800 TREAT-OA. EZ, KP and LS are funded by the Wellcome Trust (098051). KP is funded by Arthritis Research UK (19542). arcOGEN was funded by a special purpose grant from Arthritis Research UK (18030). The Leiden University Medical Centre, the Dutch Arthritis Association and Pfizer Inc., Groton, CT, USA support the GARP study, while genotypic work was supported by the Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917 66344 and 911-03-012), Leiden University Medical Centre, and by the ‘Centre of Medical System Biology’ and the ‘Netherlands Consortium of Healthy Aging’ in the framework of the Netherlands Genomics Initiative (NGI). Furthermore, the research leading to these results has received funding from the Dutch Arthritis Association (DAA 2010_017) and the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), and by The Netherlands Society for Scientific Research (NWO) VIDI Grant 917103521.
Competing interests None.
Ethics approval Each participating study obtained approval from the appropriate ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/