Unraveling obesity-related genes may hold clue to RA risk, role of inflammation
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America’s weight problem is well known to rheumatologists, with a mounting body of evidence depicting the negative impact of obesity on disease outcomes for patients with rheumatic and autoimmune diseases.
However, more than only a compounding factor for worse outcomes and impaired treatment responses, obesity may itself provide a risk factor for onset of rheumatic diseases. Prior studies have suggested that obesity is risk factor for rheumatoid arthritis and lupus development; claims now supported by an analysis of genetic data from nearly a million patients that indicate that RA risk may carry a correlation with genetically predicted BMI.
Xia Jiang, PhD, of the department of clinical neuroscience at the Karolinska Institute in Stockholm, and Bowen Tang, MSc, of the department of medical epidemiology and biostatistics, and colleagues, aimed to examine whether genetic characteristics associated with obesity can elevate RA risk.
The genetic correlation analysis was conducted using genome-wide genetic data from more than 850,000 individuals of European descent.
Specifically, data from the largest genome-wide association study provided the researchers with findings for BMI (n = 806,810), waist‐to‐hip ratio (n = 697,734) and waist-to-hip ratio adjusted for BMI (n = 694,649), along with findings for 14,361 patients with RA and 43,923 controls.
To assess causal overlap — which the researchers defined as genetic correlation between pairs of traits — cross‐trait linkage disequilibrium score regression and ‐HESS were performed. The researchers assessed for causal relationships pertaining to obesity-related exposures. In addition, they analyzed for overall relationships and gender-specific relationships.
Results from the overall analysis showed a “negligible” genetic correlation between the three obesity-related traits and RA. However, several locations on chromosome 6 — positions 28‐29M, 30‐35M, 50‐52M — did, in fact, significantly correlate with RA. The researchers suggested that this demonstrates a “shared genetic basis” between obesity and RA, according to the findings.
Other results showed that for each standard deviation increment (4.8 kg/m2) in genetically predicted BMI, RA risk accordingly increased (OR = 1.22; 95% CI, 1.09‐1.37). Sensitivity analyses failed to impact this association. Moreover, the correlation was seen in both men (OR = 1.22; 95% CI, 1.04‐1.44) and women (OR = 1.19; 95% CI, 1.04‐1.36).
Despite these links, the researchers failed to draw causal correlations between RA and waist-to-hip ratio (OR = 0.98; 95% CI, 0.84‐1.14) or waist-to-hip ratio adjusted for BMI (OR = 0.90; 95% CI, 0.79‐1.04).
Healio Rheumatology sat down with Jiang and Tang to discuss the overall findings, the impact of gender on RA incidence as a function of weight and the extent to which chromosome 6 represents a frontier in assessment of RA incidence and pathogenesis.
Q. What does this link between BMI and RA tell us about the disease mechanisms behind RA (and possibly other rheumatic diseases)?
A. While the underlying mechanisms linking these two disorders remain to be understood, several possible pathological mechanisms have been proposed by previous studies. For example, obesity has long been considered as a chronic low-grade proinflammatory state, where fat cells secret adipokines that functions in the regulation of inflammation and autoimmunity. Moreover, fat tissues localized at joints, such as articular adipose or infrapatellar fat pad, produces inflammation-related factors — including interleukin (IL)-6, IL-8 and adipokines — which intensifies pathological rheumatoid activities of fibroblast-like synoviocytes.
Q. Conversely, there was no association in the waist-to-hip ratio parameters. Do you have any thoughts on why BMI, and not waist-to-hip ratio, may have impacted RA risk?
A. The reasons are twofold. Indeed, visceral fat is the main driver of the low-grade proinflammatory status caused by obesity, yet compared to waist-hip ratio, body mass index better predicts excess fat mass (r = 0.94) and abdominal visceral fat (r = 0.71). The negative results in waist-to-hip ratio might be due to the fact that this parameter does not capture visceral fat. Moreover, fat tissues localized at joints such as articular adipose or infrapatellar fat pad also underpin the development of RA by secreting inflammation-related factors, and these fat parameters are not reflected by waist-to-hip ratio. Our results do not necessarily mean that abdominal visceral fat is not important in the development of RA.
Q. Could you address the fact that the association between BMI and RA was seen in both men and women?
A. Our sex-specific analysis found that genetically predicted BMI affects RA comparably in men and women. Our results should be interpreted with caution. Due to a high genetic correlation of BMI shared between men and women, it is challenging to obtain sex-specific genetic variants. Moreover, for RA, unfortunately the meta-genome-wide association study was performed without adjustment for sex. Further studies are needed to confirm our findings when sex specific genome-wide association study results in RA become available.
Q. Do these findings provide rheumatologists with any possible prevention strategies?
A. Yes, our findings suggest that body weight management might be an effective strategy for RA prevention. Body weight is a modifiable trait that can be altered by many lifestyle changes including diet, exercise, sleep pattern, stress management and more.
Q. Are we able to extrapolate these findings beyond those of European ethnicity? Is it likely that the findings would be similar?
A. Our analysis included individuals of European ancestry; the genetic findings can therefore only be interpreted for this particular ethnicity. However, effects of obesity on risk for RA are likely shared between ethnicities. Future genetic studies, however, should be conducted involving other ethnicities.
Q. Could you discuss the association between RA and chromosome 6?
A. The most important gene complex on chromosome 6 concerning risk for RA and other autoimmune diseases is in the region coding for the human leucocyte antigen (HLA) genes. HLA genes have critical functions in presentation of antigens by antigen-presenting cells to T lymphocytes, and our finding of a significant genetic correlation between BMI and RA on chromosome 6 therefore indicates a link between these two disorders and HLA-dependent immune functions.
Q. Is there a likelihood that similar relationships exist between obesity and other inflammatory diseases?
A. Current Mendelian randomization studies have provided important implications regarding the association between obesity and other inflammatory diseases. Genetically predicted BMI is associated with increased level of circulating inflammation/proinflammation markers including C-reactive protein and leptin, as well as a heightened risk of inflammatory diseases including psoriasis, asthma and multiple sclerosis.
Q. Finally, how could/should this impact clinical practice for clinicians treating RA?
A. Our study is about disease onset; we found an increased risk of RA when BMI was predicted to be high based on an individual’s genetics. The current data are of direct clinical importance mainly in efforts to prevent development of RA. Similar interesting studies will be performed concerning prognosis of disease development and response to therapy in patients who already manifest RA.
For more information:
Xia Jiang, PhD, and Bowen Tang, MSc, can be reached at the Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm; email: xia.jiang@ki.se; bowen.tang@stud.ki.se.
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