In these large cohorts, 6.4% of women and 4.1% of men had RLS according to the diagnostic criteria recommended by the International RLS Study Group, and the prevalence increased progressively with increasing BMI and waist circumference. The association was independent of age, smoking status, anxiety score, use of antidepressant, and presence of a number of chronic diseases. A similar association was found between obesity in early adulthood (age 18 or 21) and RLS prevalence in mid-life or later (age 40 years and higher), suggesting that obesity is a risk factor for the development of RLS.
Although the influence of obesity on RLS may be modest, the implication of these results may be substantial as obesity is a modifiable factor which is becoming increasingly prevalent in the United States. Strengths of the study include the population-based design and adjustment for a number of potential confounders. Multiple markers of adiposity were employed in the current analyses and generated similar results. Further, in a variety of sensitivity analyses, we observed similar significant dose-response relationship between obesity and RLS.
An association between obesity and a higher RLS prevalence has been seen in most studies,7,12,13
but not all.19
In a cross-sectional study including 1,803 men and women aged 18 years or older, each increase of 5 kg/m2
BMI was associated with a 31% increased likelihood of having RLS.7
In another cross-sectional study conducted in five European countries (n = 18,890), the crude OR for RLS was 1.22 (95% CI: 1.0, 1.5) for BMI of > 27 vs 20–25 kg/m2
In a Korean population (n = 9,939), a significant association between BMI and RLS was seen among women (OR = 1.2 for BMI >25 vs ≤25 kg/m2
) but not among men (OR = 1.1).13
The mechanisms through which obesity is associated with RLS are likely to be multiple. Cardiovascular diseases are associated with an increased risk of both obesity and RLS,3
and it has been suggested that vascular pathology may contribute to RLS.20
However, exclusion of participants with cardiovascular diseases had a minimal effect on our results, suggesting that other factors mediate the relation between obesity and RLS. Results from several investigations suggest that the dopaminergic system in the CNS may be affected in both obesity and RLS. In a case-control study, obese individuals (n = 10, BMI >40 kg/m2
) had a significantly lower number of striatal dopamine D2
receptors, as measured by PET and (C-11) raclopride, than controls (p
< 0.01), and among obese individuals the number of dopamine receptors was inversely correlated with BMI.11
These findings were supported by observations from animal studies where obese rats had lower D2
Genetic studies have shown a link between obesity and variants of dopamine metabolism-relevant genes, such as MAOA and MAOB.23
Further, in some longitudinal studies individuals with higher levels of body fat, as measured by BMI and midlife triceps skin-fold thickness, have been found to have a higher risk of PD,24,25
although this finding was not confirmed in other investigations, including the HPFS.26
Obesity and RLS could share some unknown common causes. Although we excluded participants with diabetes in the analyses, obesity could also be an indictor of undiagnosed diabetes, and some individuals with RLS could have undiagnosed diabetic neuropathy. However, the effects of undiagnosed diabetes on the observed obesity–RLS relationships should be moderate, as the number of these participants should be relatively small. Further experimental studies are needed to explore biologic mechanisms underlying the potential roles of obesity in RLS.
A limitation of our study is that misreporting of BMI or waist circumference could cause misclassification, but because of the very strong correlation between self-reported and measured obesity indicators,15
error from this source is most likely minimal. Moreover, the diagnosis of RLS was based on self-report, and some degree of diagnostic error is thus likely. However, a validation study showed a relative good sensitivity (87.5%) and specificity (96%) of the three-question set of RLS diagnosis, which is used in the current study, compared with the physician diagnoses.4,27
Further, confounding by genetic risk factors for RLS28,29
cannot be excluded, but it is unlikely to fully explain the results of our study because there is no evidence that risk alleles for RLS are related to obesity. We were also unable to directly adjust for status of iron deficiency, another well-known risk factor of RLS, because we did not collect this information in our cohorts. However, further adjusting for surrogates for iron status, including use of iron-specific supplements and number of blood donations, which was found to be a strong determinant of ferritin concentration in a subsample of participants in the HPFS,30
did not materially change the observed significant associations between obesity and higher risk of RLS.