Does a Genetic Variant in FOXO3A Predict a Milder Course of Rheumatoid Arthritis?

The severity of rheumatoid arthritis (RA) is variable between patients, and the processes underlying these interindividual differences are scarcely understood. Although it has been observed that the severity of joint destruction is heritable (1), and several identified genetic risk factors have been replicated in independent cohorts (2,3), a large part of the total genetic effect is still unexplained. Unraveling the biologic processes that determine the course of RA increases our comprehension of disease progression and may convey novel targets for focused therapies. Lee et al reported a milder disease course in patients carrying the FOXO3A minor allele (G) of rs12212067 (4). That candidate gene study addressed genetic variants in the immune pathways of interleukin-2 (IL-2) and IL-7 and was initially performed in patients with Crohn’s disease. It was observed that the rs12212067 minor allele was associated with higher transcription of FoxO3 in blood monocytes after lipopolysaccharide stimulation and with down-regulation of tumor necrosis factor (TNF ) and other proinflammatory cytokines and up-regulation of IL-10. The relevance of FoxO3 in disease outcome was supported by associations with more severe malaria and less severe joint damage in patients with early RA. FoxO3 is a transcription factor that is involved in the regulation of immune cell homeostasis (5). Increased expression of FoxO3 in polymorphonuclear cells has been described in RA (6). The results described by Lee et al are promising, because identification of predictors of interindividual differences in disease outcome is the Holy Grail of personalized medicine. This finding therefore requires replication in independent cohorts. The challenges within the field of RA severity are that large longitudinal cohorts with well-characterized data are scarce, and that cohorts of patients who were treated in an era when disease-modifying antirheumatic drugs (DMARDs) were less potent and strategies were not guided by the Disease Activity Score (DAS) are rare (7). We examined rs12212067 in FOXO3A in relation to the severity of RA in multiple cohorts; the majority of patients studied were treated in the era before the introduction of biologic agents and DAS-guided therapy. The main outcome of our study was radiographic progression. Five independent data sets were studied, comprising a total of 2,300 patients with RA and 5,512 radiographs. RA was defined according to the American College of Rheumatology 1987 revised criteria (8). All patients gave informed consent, and approval was obtained from the local medical ethics committees. The Leiden Early Arthritis Clinic (EAC) cohort comprised 597 patients with early RA, all of whom were included between 1993 and 2006 (9). At baseline and at yearly followup visits over 7 years, a total of 3,143 sets of radiographs of the hands and feet were obtained. These radiographs were scored according to the Sharp/van der Heijde (SHS) method (10) by one reader in chronologic order (within-reader intraclass correlation coefficient [ICC] 0.91). The initial treatment strategy differed for different inclusion periods: patients included in 1993–1995 were initially treated with nonsteroidal antiinflammatory drugs, patients included in 1996–1998 were initially treated with hydroxychloroquine or sulfasalazine, and patients included in 1999–2006 were promptly treated with methotrexate (9). The Umeå cohort consisted of 459 patients with early RA from Sweden, in whom RA was diagnosed between 1996 and 2010 (11). A total of 868 sets of radiographs of the hands and feet obtained at baseline and year 2 were scored using the Larsen method (12), as described previously (11). All patients were initially treated with methotrexate or sulfasalazine. Treatment with biologic agents during the 2-year followup period was uncommon (5.7%). The North American Rheumatoid Arthritis Consortium (NARAC) study group comprised 384 unrelated patients in whom RA was diagnosed between 1953 and 2002 (13). One set of radiographs of the hands was available for each patient. The radiographs were scored according to the SHS method (ICC 0.99). The Wichita cohort consisted of 101 patients from a single practice in Wichita, Kansas, in whom RA was diagnosed between 1963 and 1999 (14). Radiographic evaluations were not performed at protocolized time points; 358 sets of hand radiographs were obtained during the first 15 years after disease onset. These were scored in a known time order, using the SHS method (ICC 0.98). The National Data Bank for Rheumatic Diseases (NDB) cohort comprised 759 patients from the US and Canada, in whom RA was diagnosed between 1944 and 1999 (15). One set of radiographs of the hands was available for each patient. The radiographs were scored using the SHS method (ICC 0.98). The patients in the 3 North American cohorts were treated in an era when biologic agents were uncommon. Genotyping in the Leiden EAC, Umeå, Wichita, and NDB cohorts was performed using the Illumina ImmunoChip according to the manufacturer’s protocols, as previously described (2,16), and data for rs12212067 located on chromosome 6 were extracted. In the NARAC cohort, genotyping was performed using Illumina HapMap 500 BeadChips (13,17). Data for rs12212067 were not available in the NARAC group, but data for a perfect proxy for this variant (rs11153120) were retrieved (r 1.00). In all data sets, the radiographic scores were logtransformed before analyses to approximate a normal distribution. In each data set, the relative progression rate in patients with the rs12212067 minor allele was estimated, using patients with the common genotype as reference. An additive model was used. For the analyses in the cohorts with multiple measurements per patient (Leiden EAC, Umeå, and Wichita), a multivariate normal regression analysis was performed, with radiographic damage as the response variable (18). For the data sets with one radiographic measurement per patient (NARAC and NDB), the estimated yearly progression rate (the total SHS divided by the number of disease-years at the time of radiography) was studied. Details on the statistical methodology and adjustment factors are available in Supplementary Methods (available on the Arthritis & Rheumatology