Allergic rhinitis is a common allergic and inflammatory disease in the upper respiratory tract.1 More than 500 million people are affected by this disease worldwide, and the prevalence’s of allergic rhinitis in China and several western countries are even higher, reaching between 12 and 30%.2,3 Although the disease is not fatal, it can still cause a range of adverse effects if not effectively controlled. For example, severe allergic rhinitis may disrupt sleep, cause headaches and memory loss, trigger sinusitis and aggravate asthma.4,5 Symptoms such as the runny nose induced by the disease can also affect the patient's image when socializing, causing social fear and depression.6 However, there is no cure for allergic rhinitis, and the available medications can only relieve the symptoms.7 Therefore, in-depth research into the pathogenesis and risk factors of the disease is necessary.

It is well known that obesity is a growing global health challenge. Several studies have confirmed the correlation between obesity and the development of asthma.8,9 Because allergic rhinitis and asthma are very similar in their pathogenesis and there is a concept of “one airway, one disease”, the effect of obesity on allergic rhinitis has therefore attracted a great deal of attention globally.10 Then, an increasing number of studies have been carried out, suggesting that obesity and overweight may increase the risk of developing allergic rhinitis, and the correlation is implicated in inflammation and air pollution.11–13 However, these results are all obtained by observational studies and are susceptible to confounding factors and causal inversions. Therefore, a final conclusion still cannot be drawn.

Mendelian randomization (MR) studies are a form of genetics-based epidemiological research that allows for causal inference at the genetic level by replacing the traits under study with a series of genetic variants.14,15 Such studies can effectively make up for the deficiencies of observational studies. However, there are still no published MR studies exploring the association between obesity and allergic rhinitis at present.

Taken together, this study proposed to adopt the MR approach to explore the impact of obesity on the risk of developing allergic rhinitis at the genetic level. Considering the close association of numerous peripheral lipids, lipoproteins, apolipoproteins and adipokines with obesity, this study also used this approach to explore the association of a range of lipids and adipokines with this allergic disease at the genetic level. The findings obtained from this study were expected to increase our knowledge and understanding of the pathogenesis of allergic rhinitis.

As an allergic and inflammatory disease, the etiology and pathogenesis of allergic rhinitis are still unknown. However, genetic background is supposed to be one of the main pathogenic mechanisms. Thus, we investigated the genetic effects of obesity, lipids and adipokines on the risk of the disease using MR methods in the study, which contributed to our further understanding of the risk factors and pathogenesis of allergic rhinitis, and helped us to find suitable therapeutic targets and improve therapeutic strategies so as to reduce the incidence of this disease and improve its prognosis.

According to the IVW results in this study, although all obesity and lipid indicators cannot influence the risk of developing allergic rhinitis, the levels of two adipokines were potentially correlated with the risk of the disease. Briefly, for each SD increase in peripheral levels of IL-6 and A-FABP, the risk of developing allergic rhinitis decreased by approximately 10%–30%. Because the sensitivity analyses did not detect horizontal pleiotropy, the IVW results mentioned above were considered to be the most reliable. Moreover, the results obtained by the other two methods were directionally consistent with the IVW results, although none of them were statistically significant. Thus, MR can preliminarily confirmed the effect of IL-6 and A-FABP on the risk of allergic rhinitis. However, it should be noted that the IVW p-values for these two adipokines were only slightly lower than 0.05. More importantly, there was a design of multiple comparisons in this study. Therefore, we believed that these analyses had the potential for type I error, and therefore the Bonferroni correction was adopted. After the correction, the results showed that these two adipokines were only nominally associated with the risk of allergic rhinitis. These results were not sufficient to draw a conclusion, but they were certainly helpful for future research.

As mentioned above, several observational studies had reported that obesity contributed to the development of allergic rhinitis.11–13 But, the results of the present study at the genetic level did not support these findings. Considering that the pathogenesis of this allergic disease was complex, it certainly included multiple genetic and environmental factors. So, it was still possible that obesity may have an impact on the risk of developing allergic rhinitis through phenotypic-level mechanisms.

IL-6 was a classical inflammatory factor that can be secreted by several types of cells. In the peripheral circulation, approximately 1/3 of this factor was derived from adipose tissue and therefore IL-6 was also considered as an adipokine with inflammatory regulatory functions. Two previous observational studies found that there were rs1800795 (G/C at −174) and rs1800796 (G/A at −597) polymorphisms in IL-6 and that rs1800795 was associated with allergic rhinitis risk.26,27 Of them, the study from China reported that individuals expressing the C allele of rs1800795 were at higher risk of developing this allergic disease, whereas the other study from Middle Asia concluded that individuals expressing the G allele were more susceptible to allergic rhinitis.26,27 These contradictory results may be explained by the different study populations. Meanwhile, the present study included a European population and reported that peripheral IL-6 levels may nominally reduce the risk of this allergic disease, which did not consider genetic polymorphisms due to insufficient data. So, both the present MR study and the two observational studies mentioned above suggested that IL-6 had the potential to affect the development of allergic rhinitis, and the mechanism might be influenced by race and genetic polymorphism.

FABP were fatty acid carriers in a wide range of cells (including adipocytes) and played an important role in the physiological use of fatty acids in these cells. A previous animal study using mice explained the role of this proteins in allergic lung inflammation.28 Briefly, knockdown of FABP in the lungs can cause severe allergic lung inflammation, and up-regulation of this proteins suppressed allergy-associated immune cell activity. In addition, a high-fat diet may result in down-regulation of FABP expression in the lungs. The present study investigated the correlation between peripheral A-FABP levels and allergic rhinitis, and the obtained results appeared to be partially consistent with this animal study.

The main advantage of this study is the MR design. Compared to observational studies, this study allowed causal inferences to be made at the genetic level between the exposures and the outcome, avoiding many confounding factors and the appearance of causal inversions. So, the results obtained from this study were more reliable. Meanwhile, there were still some limitations in this study. For example, IL-6 was polymorphic, and it was likely that this polymorphism had a significant impact on allergic rhinitis. Also, closely related to this issue was the speculation that the effect of IL-6 on allergic rhinitis may be ethnospecific. In addition, the number of instrumental variables for several exposures (i.e., adipokines) might be somewhat inadequate due to the lack of sufficient summary data. All of these questions remained to be explored in future studies.

The present study provided some interesting, but not sufficient, evidence to suggest that IL-6 and A-FABP might play a protective role in the development of allergic rhinitis at the genetic level. However, it was important to emphasize that this was not a final conclusion, and the above findings should be validated by more research. In addition, the study did not find a genetic association of obesity or peripheral lipid levels with this allergic disease. These studies helped us to objectively validate previous observational studies and deepen our understanding of the risk factors and pathogenesis of allergic rhinitis.

Not applicable.

The authors declare no conflicts of interest.