Migraine is a common neurological disease and an important cause of disability worldwide, whose years of life lived with disability is 45.1 million and disability-adjusted life-years is 1.9% (1, 2). It is characterized by a recurrent, unilateral, moderate or severe, pulsating headache. The headache attack may last 4–72 h and be associated with nausea and/or phonophobia/photophobia (2).

Currently, migraine is considered an energy deficit syndrome partially due to mitochondrial dysfunctions (3). Besides, it is a complex neuroinflammatory disorder involving predominant activation of the trigeminovascular system with unclear molecular mechanisms (3, 4). These metabolic factors include behavioral factors, environmental factors, dietary triggers, hormonal changes, and genetic changes (3, 5). Oxidative stress is the imbalance between oxidation and antioxidation, which might be influenced by metabolic factors. Some migraineurs showed lower activity of catalase, non-oxidized thiol concentration, and total antioxidant capacity in serum (6, 7). Meanwhile, migraineurs showed the decreased activity of superoxide dismutase in their platelets and erythrocytes (7, 8).

Serum urate is the end product of exogenous and endogenous purine metabolism in Homo sapiens and other hominoids, which acts as an antioxidant in vivo and is associated with oxidative stress (9). It had been found that serum urate could lead to an increase in oxidative stress levels in a manner independent of xanthine oxidoreductase activity, especially in female (9). The gender-specific relationship of serum urate with oxidative stress might be due to the difference of serum estrogen level (10). Furthermore, serum urate showed lower levels and was posited as a neuroprotective agent in some neurological disorder (9, 11–13). On the contrary, some studies found that serum urate might act as a pro-oxidant, which might promote the oxidation stress (13). In addition, the contradiction of anti-oxidant effects and pro-oxidant effects might be due to the dose effect of serum urate (13). A previous study showed that a lower serum urate level was found in migraine, which was not influenced by the subtypes of migraine (14). However, another study found that serum urate in migraine might be more than control group, which had not shown the results of statistical hypothesis testing (15). Moreover, the reports had never controlled the confounders, which were mainly iron and ferritin, acted as pro-oxidants or anti-oxidants (16). Here, we take the advantage of data from the National Health and Nutrition Examination Survey (NHANES) to clarify the association between serum urate and migraine and explore the dose effect of serum urate in migraine.

According to the nationally representative cross-section study of the United States, there existed no consistent linear relationship between serum urate and migraine according to logistic regression models, without or with stratified by gender or race, except in non-Hispanic White. However, we found an exponential curve relationship between serum urate and migraine, with an infliction point of 7.8 mg/dl. When serum urate was more than 7.8 mg/dl, increased serum urate was correlated with higher migraine occurrence. However, when serum urate was <7.8 mg/dl, there was no consistent relationship between serum urate and migraine without or with confounders adjusted. To the best of our knowledge, our study demonstrates that serum urate is a risk factor for migraine for the first time. Our study provides a target and rationale for serum urate control in migraineurs.

Usually, serum urate levels higher than 6 mg/dl lead to the deposition of monosodium urate (MSU) crystal in tendons, joints, or other unusual tissues at physiological pH (~7.4) (23). Meanwhile, previous studies have found that inflammation plays an important role in the pathophysiology of migraine, and the levels of serum inflammatory cytokines, such as CRP, IL-1β, IL-6, and TNF-α are higher in migraineurs compared with healthy controls (24). Moreover, NSAIDs and corticosteroids are used for shortening a migraine attack (25, 26). Serum urate has been proposed as a neuroprotective agent in stroke, Parkinson's disease, multiple sclerosis, and Alzheimer's disease, in which the high serum urate levels have been linked to the lower severity of neurological injury (13). However, studies in animal or human had failed to prove the neuroprotective effect of serum urate by regulating the serum urate levels (13). A previous study found that migraineurs had the lower levels of serum urate and ferritin, as compared with healthy controls (14). Meanwhile, there existed no statistically significant differences between the different subtypes of migraine, which compared migraine with/without aura or episodic/chronic migraine (14). Another study, which was aimed at assessing the change of serum urate in migraineurs receiving topiramate, found that the serum urate of migraine pretreatment with topiramate and the well-matched control group were 3.61 ± 0.89 and 3.09 ± 1.86, respectively (15). Besides, topiramate would increase the serum urate level in migraine (15). The normal range of serum urate in humans is 2.5–7.0 mg/dl in men and 1.5–6.0 mg/dl in women (13). Hyperuricemia is defined as a serum urate more than 6.8 mg/dl, which mostly individuals would suffer from gout (13). Furthermore, hyperuricemia is a risk factor for hypercholesterolemia, diabetes, hypertension, cardiovascular and cerebrovascular events, and so on (13). In the present study, the migraine group had lower serum urate before adjusting for confounders. However, the linear relationship was not consistent after adjusting for confounders. Furthermore, an exponential curve relationship, with an infliction point of 7.8 mg/dl, was found in serum urate and the risk of migraine. Our findings demonstrated that serum urate, when more than 7.8 mg/dl, might be a risk factor for migraine. Furthermore, we also suggest that there is a threshold effect on the neuroprotective effect and that the infliction point might be 7.8 mg/dl. Besides, the underlining mechanism might be that MSU crystal formed might trigger inflammation via IL-1b, TNF-a, IL-6, IL-8, and oxidative stress (27–31).

Currently, there are a lot of risk factors for migraine identified by researchers. It had been found that 38 genetic loci, which were enriched in vascular biology, were associated with migraine (4, 32). Meanwhile, another study had found that the genetically mediated hypercalcemia might increase the risk of migraine (32, 33). In addition, migraine with aura was associated with the increasing risk of other comorbidities, such as perioperative stroke, patent foramen ovale, and restless legs syndrome (32). Risk factors associated with the progression from episodic migraine to chronic migraine were summarized in a previous review (34, 35). Besides the fair and non-modifiable risk factors included female gender, low family socioeconomic status, and major life events (34, 35). Furthermore, the moderate and modifiable risk factors were obesity, persistent-frequent nausea associated with migraine, asthma, non-cephalic pain, snoring, and the efficacy of abortive migraine treatments (34, 35). Moreover, strong and modifiable risk factors were the frequency of headache day, depression, and acute medication use/overuse (34, 35). In our analysis, we found that the serum urate levels of more than 7.8 mg/dl might be a risk factor for migraine, which is a modifiable risk factor.

The limitations of this study were as follows: first, the present study could not distinguish the acute attack of migraine, the frequency and intensity of migraine attack, and migraine with/without aura, because of the missing information of NHANES. Second, the present study was a cross-section study, whose follow-up data were absent. Besides, the conclusions needed to be proven according to a prospective longitudinal study in the future, which should control the confounders, such as age, race, gender, intensity and frequency of migraine attack, and drug usage. Finally, the medication usage was analyzed in our analysis, but the dosages of drugs were unknown. Further studies could be conducted to investigate the alteration of serum urate levels in migraineurs with different drugs in real world studies.

In conclusion, there existed an exponential curve relationship between serum urate and migraine, with an infliction point of 7.8 mg/dl. When the serum urate was more than 7.8 mg/dl, increased serum urate was correlated with higher migraine occurrence.

Publicly available datasets were analyzed in this study. This data can be found here: Centers for Disease Control and Prevention (CDC) National Health and Nutrition Examination Survey (NHANES), https://wwwn.cdc.gov/nchs/nhanes/Default.aspx, NHANES 1999-2018.

The studies involving human participants were reviewed and approved by the Prevention National Center for Health Statistics Research (NCHS) and Centers for Disease Control (CDC) Research Ethics Review Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

YX, HX, and YW proposed the idea. PH and YL acquired the data. PH analyzed the data. YX wrote the first draft. HX, YW, and PH revised the draft. All authors have approved the final article.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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