Abstract
Cyclooxygenase-2 (COX-2) is known to be involved in the pathogenesis of migraine, and some polymorphisms are known to affect the expression of COX-2. This retrospective case-control study aimed to explore the associations between the -765 G>C (rs20417), -1759 G>A (rs3218625), and -8473 C>T (rs5275) COX-2 polymorphisms and migraine in Chinese Han individuals. One hundred and ten unrelated Han Chinese patients with migraine and 108 healthy controls were recruited between 03/2014 and 08/2016 at the First Affiliated Hospital of Nanjing Medical University and the First People's Hospital of Lianyungang City. The genotypes of all polymorphisms in controls followed the Hardy-Weinberg equilibrium (P = 0.215, P = 0.884, and P = 0.689). There were differences in the genotype and allele distributions of the COX-2-1759G>A (Gly587Arg) polymorphism between the migraine and control groups (P = 0.038 and P = 0.040, respectively). Compared with the COX-2-1759AG genotype, GG genotype carriers had an increased risk of migraine (odds ratio (OR) = 8.720, 95% confidence interval (CI): 1.072–70.960, P = 0.038). The frequency of the COX-2-1759A allele in patients with migraine was significantly lower than the controls (OR = 0.119, 95%CI: 0.015–0.957, P = 0.040). Adjusted age and sex, a statistical difference was found in the dominant model of COX-2-1759 G>A (OR = 0.118, 95% CI 0.014 to 0.962, P = 0.046). No significant difference was detected regarding the -765G>C and -8473T>C polymorphisms between the two groups. The COX-2 1759A allele might be involved in the development of migraine in Chinese Han individuals, but this will have to be confirmed in large-scale studies.
Introduction
Migraine is a common primary headache disorder of unclear etiology. It is recurrent in nature and classically presents as moderate-to-severe head pain lasting 4–72 hours; it is typically unilateral with a pulsating quality, accompanied by nausea, vomiting, photophobia, and/or phonophobia, and may be preceded by an aura that consists of sensory, motor, or language symptoms [1–3]. The cumulative lifetime incidence is 43% in women and 18% in men [4]. The prevalence is about 11.8% in the world, 15% in the USA, and 9.3% in mainland China [5, 6]. Migraine is classified into two primary subtypes: migraine with aura (MA) and migraine without aura (MO). In MA, the migraine attack follows the typical aura consisting of visual, sensory, and/or speech symptoms [2, 3, 7]. Migraine is associated with a number of other conditions and disorders, including neurological conditions, sleep-related disorders, pregnancy-related and gynecologic conditions, obesity, psychiatric conditions, and cardiovascular conditions [3].
Although the pathophysiology of migraine is still poorly understood, the trigeminal-vascular theory proposed 35 years ago is generally accepted [8], in which prostaglandins, especially PGE2 and PGI2, are considered to play an important role in activating the trigeminal-vascular system (TVS) by involving in the sensitization of peripheral and/or central pain pathways [9, 10]. Cyclooxygenase (COX, also known as prostaglandin-endoperoxide synthase or PTGS) is the key enzyme that catalyzes the formation of prostaglandins from arachidonic acid in response to various stimuli [10]. Two COX isoforms have been identified: COX-1 and COX-2. COX-1 is expressed constitutively with an essentially constant level, but COX-2 is inducible isoform and can be overexpressed in response to pro-inflammatory molecules and can increase prostaglandin production in inflammatory pain [11, 12]. In addition, it was demonstrated, that in rat trigeminal ganglion cells, COX-2 and COX-2-dependent PGE2 could induce the development of pain in migraine [13]. In humans, COX-2 expression is higher in patients with migraines than in controls [14], and selective COX-2 inhibitors are equally effective than non-selective COX inhibitors in the treatment of acute migraine [15, 16]. Collectively, COX-2 is considered to be implicated in the pathogenesis of migraine, and there is no difference in COX-2 levels between MA and MO [17].
The human COX-2 gene is located on chromosome 1q25.2-q25.3 and consists of 10 exons spanning 8.3 kb [18]. Several functional single-nucleotide polymorphisms (SNPs) in COX-2 have been widely investigated, including -765 G>C (rs20417) in the promoter region, -1759 G>A (Gly587Arg, rs3218625) in the coding region, and -8473 C>T (rs5275) in the 3’UTR [19–24]. These three SNPs are related to COX-2 expression level and transcription activity [21–24]. Reportedly, the COX-2-8473 C>T polymorphism has an effect on COX-2 mRNA and protein levels [19], the COX-2-765 G>C polymorphism might modify COX-2 mRNA [20], and the COX-2-1759 G>A polymorphism can influence COX-2 activity [24]. In addition, these SNPs have been demonstrated to be associated with several diseases involving COX-2, including bronchial asthma [23], coronary artery disease [25], cerebral infarction [26], and stroke [27].
Nevertheless, little data is available about the relationship between these SNPs and the risk of migraine [14, 28], especially in Chinese Han individuals. Therefore, the aim of the present study was to investigate the potential role of COX-2-765 G>C, -1759 G>A, and -8473 C>T polymorphisms in migraine susceptibility in a Chinese Han population.
Material and methods
Study design and subjects
This was a retrospective case-control study of 110 unrelated Han Chinese patients with migraine and 108 healthy controls recruited between March 2014 and August 2016 at the First Affiliated Hospital of Nanjing Medical University and the First People's Hospital of Lianyungang City. The study was approved by the ethics committee of the Affiliated Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang. All participants provided written informed consent.
The inclusion criteria were: 1) outpatient at the Neurology department; and 2) diagnosis of migraine determined based on strict neurological examination, computed tomography (CT) or magnetic resonance imaging (MRI), and detailed questionnaire according to the International Classification of Headache Disorders (ICHD-II) criteria [29]. The exclusion criteria were: 1) mental disorders; 2) cardiovascular or cerebrovascular disease, cancer, asthma, anxiety, or depression; or 3) migraine proven to be secondary to another disease.
Non-headache healthy controls were recruited from the physical examination department and were age- (±5 years) and gender-matched with the patients. They were free from any organic diseases or psychiatric disorders and recruited from the same geographic areas. Subjects who received ACE inhibitors were excluded from the study.
DNA extraction and genotyping
A 2-ml peripheral blood sample was collected from each patient in EDTA-containing tubes. Genomic DNA was extracted using the Blood DNA Extraction Kit ((TiangenBiotect [Beijing] Co., Ltd., Beijing, China). DNA samples were stored at -20ºC until analysis.
Each SNP was analyzed using the ligase detection reaction-polymerase chain reaction (LDR-PCR) sequencing method using an ABI 9600 system (Applied Biosystems, Foster City, CA, USA) [30]. The sequences of the primers are shown in Table 1. The PCR cycling parameters were: 1) 94 ºC for 3 min; 2) 35 cycles of 94ºC for 30 s, 55ºC for 30 s, and 72ºC for 90 s; and 3) final extension at 72ºC for 3 min. For each SNP, two discriminating probes and one common probe were designed and synthesized by Shanghai Generay Biotech Co., Ltd. (Shanghai, China). The common probe was phosphorylated at the 5’ end and labeled at the 3’ end with the fluorophore FAM. The probes of LDR are shown in Table 1. LDR was conducted in a total volume of 10 μl containing 3 μl of PCR product, 1 μl of 10× Taq DNA ligase buffer, 0.125 μl of 40 U/μl Taq DNA ligase, 1 μl of 10 pmol probes (0.01 μl each of probe), and 4.875 μl of ddH2O. The ligation reaction was performed with 30 cycles of 94ºC for 30 s and 56ºC for 3 min. Then, 1 μl of the ligation product was mixed with 8 μl of loading dye (marker included) and denatured at 95ºC for 3 min followed by immediate cooling on ice. Ligation samples were analyzed using a 3730XL DNA analyzer (Applied Biosystems, Foster City, CA, USA). In order to validate and confirm the results, 10% of the samples were selected for sequencing to validate the LDR-PCR results [31, 32].
Table 1. Primer sequences and the probes for LDR.
| SNP | Primer sequences | Probes of LDR |
|---|---|---|
| COX-2 -765G>C | Forward: 5'-GCC TTA AGG CAT ACG TTT TGG-3' | TC: TTT TTT TTT TTT TTA TGA GGA GAA TTT ACC TTT CCC C |
| Reverse: 5'-TAC TGT TCT CCG TAC CTT CAC-3' | TG: TTT TTT TTT TTT TTT TTA TGA GGA GAA TTT ACC TTT CCC G | |
| TR: -P-CCT CTC TTT CCA AGA AAC AAG GAG GTT TTT TTT T-FAM- | ||
| COX-2 -8473T>C | Forward: 5'-CAC TGT CGA TGT TTC CAA TGC-3' | TC: TTG AAA TTT TAA AGT ACT TTT GGT C |
| Reverse: 5'-ACA GGT GAT TCT ACC CTA TG-3' | TT: TTT TTG AAA TTT TAA AGT ACT TTT GGT T | |
| TR: -P-ATT TTT CTG TCA TCA AAC AAA AAC AGG T-FAM- | ||
| COX-2 -1759G>A | Forward: 5'-TCA TTC AGT GTT CCA GAT CC-3' | TA: TTT TAT CAA TGC AAG TTC TTC CCG CTC CA |
| Reverse: 5'-CGC AAC AGG AGT ACT GAC TT-3' | TG: TTT TTT TAT CAA TGC AAG TTC TTC CCG CTC CG | |
| TR: -P-GAC TAG ATG ATA TCA ATC CCA CAG TTT TTT TT-FAM- |
Statistical analysis
The continuous data were presented as means ± standard deviation and were analyzed using the Student t-test. The categorical data were presented as numbers and percentages and analyzed using the chi-square test. The distributions of the genotypes and alleles between patients with migraine and healthy controls were compared using the chi-square test. The odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The goodness-of-fit chi-square test was used to evaluate the Hardy-Weinberg equilibrium (HWE) in the control subjects. Statistical analyses were performed using SPSS 18.0 (IBM, Armonk, NY, USA). Two-sided P-values <0.05 were considered statistically significant.
Results
Characteristics of the subjects
The mean age of the 110 patients (73 females, 37 males) was 32.7±9.7 years (Table 2). The mean age of the 108 controls (72 females, 36 males) was 33.9±9.1 years. There were no significant differences between the two groups in terms of age and sex (P = 0.349 and P = 0.962, respectively). The migraine cohort included 55 (50.0%) patients with a family history of migraines and 55 (50.0%) without. One (0.9%) patient had hypertension, 14 (12.7%) had a smoking history, and 18 (16.4%) had a drinking history. The course of the disease was 10 (range, 6–16.5) years, the frequency of onset was 2 (range, 1.5–3.5) per month, and the duration of attacks was 24 (range, 12–27) h.
Table 2. Characteristics of the patients.
| Variable | Migraine | Controls | P |
|---|---|---|---|
| n = 110 | n = 108 | ||
| Sex | 0.962 | ||
| Men | 37 (33.6%) | 36 (33.3%) | |
| Women | 73 (66.4%) | 72 (66.7%) | |
| Age | 32.7±9.7 | 33.9±9.2 | |
| Median (IQR) | 30 (25, 40) | 33 (26, 41.5) | 0.368 |
| Aura | 16 (14.5%) | - | |
| Course of disease (years) | 10 (6, 16.5) | - | |
| Frequency of onset (time/month) | 2 (1.5, 3.5) | - | |
| Duration of migraine attacks (h) | 24 (12, 27) | - | |
| Family history | 55 (50%) | ||
| Hypertension | 1 (0.9%) | ||
| Smoking history | 14 (12.7%) | - | |
| Drinking history | 18 (16.4%) |
COX-2 genotypes
The polymorphisms were detected by LDR-PCR analysis (S1 Checklist). For confirmation of the SNPs found by LDR-PCR, 10% of the samples were randomly selected for sequencing, and the consistency rate was 100% (S1 File). The genotype and allele distributions of the COX-2-765G>C, -1759G>A, and -8473T>C polymorphisms are shown in Tables 3 and 4. The genotypes of these three SNPs in controls followed the Hardy-Weinberg equilibrium (P = 0.215, P = 0.884, and P = 0.689, respectively). The frequency of the genotypes and alleles of the COX-2-1759G>A polymorphism were significantly different between the migraine and control groups (P = 0.038 and P = 0.040, respectively). Compared to the COX-2-1759AG genotype carriers, the GG genotype carriers had a higher disease risk (OR = 8.720, 95%CI: 1.072–70.960, P = 0.038) for migraine. The frequency of the COX-2-1759A allele in controls was significantly higher compared with that in the migraine group (OR = 0.119, 95%CI: 0.015–0.957, P = 0.040). The COX-2-1759A allele indicated a decreased risk for the development of migraine compared with that of the 1759G allele. There were no differences in the genotype distribution of COX-2-8473T>C (P = 0.346) and COX-2-765G>C (P = 0.330) polymorphisms between the two groups (Table 3).
Table 3. Genotype distributions of the COX-2-765G>C, -8473T>C, and -1759G>A polymorphisms.
| SNP | Control (n = 108) (%) | Migraine (n = 110) (%) | P | MA1 (n = 16) (%) | P | MO2 (n = 94) (%) | P | F-migraine3 (n = 73) (%) | P | M-migraine4 (n = 37) (%) | P |
|---|---|---|---|---|---|---|---|---|---|---|---|
| COX-2-765G>C | 0.346 | >0.999 | 0.230 | 0.348 | 0.815 | ||||||
| GG | 105 (97.2) | 103 (93.6) | 16 (100.0) | 87 (92.6) | 68 (93.2) | 35 (94.6) | |||||
| CG | 3 (2.8) | 7 (6.4) | 0 | 7 (7.4) | 5 (6.8) | 2 (5.4) | |||||
| CC | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| CC+ CG/GG | 3/105 | 7/103 | 0.346 | 0/16 | >0.999 | 7/87 | 0.230 | 73/0 | 0.348 | 37/0 | 0.815 |
| GG+ CG/CC | 108/0 | 110/0 | - | 16/0 | - | 94/0 | - | 5/68 | - | 2/35 | - |
| COX-2-8473T>C | 0.33 | 0.879 | 0.485 | 0.867 | 0.069 | ||||||
| TT | 76 (70.4) | 74 (67.3) | 11 (68.8) | 63 (67.0) | 53 (72.6) | 21 (56.8) | |||||
| CT | 27 (25.0) | 34 (30.9) | 5 (31.2) | 29 (30.9) | 18 (24.7) | 16 (43.2) | |||||
| CC | 5 (4.6) | 2 (1.8) | 0 | 2 (2.1) | 2 (2.7) | 0 | |||||
| CC+ CT/TT | 32/76 | 36/74 | 0.622 | 5/11 | >0.999 | 31/63 | 0.608 | 20/53 | 0.745 | 16/21 | 0.129 |
| TT+ CT/CC | 103/5 | 108/2 | 0.428 | 16/0 | >0.999 | 33/63 | 0.559 | 71/2 | 0.800 | 37/0 | 0.418 |
| COX-2-1759G>A | 0.038* | 0.562 | 0.071 | 0.138 | 0.198 | ||||||
| GG | 100 (92.6) | 109 (99.1) | 16 (100.0) | 93 (98.9) | 72 (98.6) | 37 (100) | |||||
| AG | 8 (7.4) | 1 (0.9) | 0 | 1 (1.1) | 1 (1.4) | 0 | |||||
| AA | 0 | 0 | 0 | 0 | 0 | 0 | |||||
| AA+ AG/GG | 8/100 | 1/109 | 0.038* | 0/16 | 0.562 | 1/93 | 0.066 | 73/0 | - | 37/0 | - |
| GG+ AG/AA | 108/0 | 110/0 | - | 16/0 | - | 94/0 | - | 1/72 | 0.138 | 0/37 | 0.198 |
1MA: migraine with aura.
2MO: migraine without aura.
3F-Migraine: female migraine cases.
4M-Migraine: male migraine cases.
*Significant difference in genotype distribution comparing migraine cases with controls: OR = 8.720, 95%CI = 1.072–70.960.
Table 4. Allele frequencies of the COX-2-765G>C, -8473T>C, and -1759G>A polymorphisms.
| SNP | Control (n = 108) (%) | Migraine (n = 110) (%) | P | MA1 (n = 16) (%) | P | MO2 (n = 94) (%) | P | F-Migraine3 (n = 73) (%) | P | M-Migraine4 (n = 37) (%) | P |
|---|---|---|---|---|---|---|---|---|---|---|---|
| COX-2-765G>C | |||||||||||
| G | 213 (98.6) | 213 (96.8) | 0.352 | 32 (100.0) | >0.999 | 181 (96.3) | 0.236 | 141 (96.6) | 0.353 | 72 (97.3) | 0.817 |
| C | 3 (1.4) | 7 (3.2) | 0 | 7 (3.7) | 5 (3.4) | 2 (2.7) | |||||
| COX-2-8473T>C | |||||||||||
| T | 179 (82.9) | 182 (82.7) | 0.968 | 27 (84.4) | 0.832 | 155 (82.5) | 0.911 | 124 (84.9) | 0.602 | 58 (78.4) | 0.388 |
| C | 37 (17.1) | 38 (17.3) | 5 (15.6) | 33 (17.5) | 22 (15.1) | 16 (21.6) | |||||
| COX-2-1759G>A | |||||||||||
| G | 208 (96.3) | 219 (99.6) | 0.040# | 32 (100.0) | 0.568 | 187 (99.5) | 0.069 | 145 (99.3) | 0.143 | 74 (100) | 0.205 |
| A | 8 (3.7) | 1 (0.4) | 0 | 1 (0.5) | 1 (0.7) | 0 |
1MA: migraine with aura.
2MO: migraine without aura.
3F-Migraine: female migraine cases.
4M-Migraine: male migraine cases.
#Migraine cases compared with controls by allele: OR = 0.119, 95%CI = 0.015–0.957.
Subgroup analyses
Subgroup analyses were performed regarding MA vs. MO and regarding migraine in females vs. males. The three polymorphisms were not associated with the type of migraine or gender (all P>0.05) (Tables 3 and 4).
Multivariable analyses
Table 5 presents the multivariable analyses. After adjustment for age and sex, the COX-2-1759A was associated with migraine (OR = 0.118, 95% CI 0.014 to 0.962, P = 0.046).
Table 5. Univariable and multivariable analyses.
| Variables | Univariable | Multivariable* | ||||
|---|---|---|---|---|---|---|
| OR | OR 95% CI | P-value | OR | OR 95% CI | P-value | |
| COX-2-765G>C | ||||||
| Dominant model (CG+CC vs. GG) | 2.379 | (0.599, 9.451) | 0.218 | 2.387 | (0.599, 9.516) | 0.217 |
| COX-2-8473T>C | ||||||
| TT | 1 | |||||
| CT | 1.293 | (0.711, 2.352) | 0.399 | 1.274 | (0.696, 2.334) | 0.432 |
| CC | 0.411 | (0.077, 2.184) | 0.297 | 0.408 | (0.076, 2.184) | 0.295 |
| Dominant model (CT+CC vs. TT) | 1.155 | (0.651, 2.051) | 0.622 | 1.14 | (0.638, 2.037) | 0.659 |
| Recessive model (CT+TT vs. CC) | 2.621 | (0.497, 13.813) | 0.256 | 2.633 | (0.497, 13.946) | 0.255 |
| COX-2-1759G>A | ||||||
| Dominant model (AG+AA vs. GG) | 0.115 | (0.014, 0.933) | 0.043 | 0.118 | (0.014, 0.962) | 0.046 |
*: Adjusted age and sex.
Discussion
COX-2 is known to be involved in the pathogenesis of migraine [13–16], and some polymorphisms are known to affect the expression of COX-2 [14, 20, 24, 28]. Therefore, this study aimed to explore the associations between the -765 G>C (rs20417), -1759 G>A (rs3218625), and -8473 C>T (rs5275) COX-2 polymorphisms and migraine in Chinese Han individuals. The COX-2 1759A allele might be involved in the development of migraine in Chinese Han individuals. This is the first study, to our knowledge, to reveal the effect of 1759G>A polymorphism on migraine. The COX-2 -765G>C and -8473T>C polymorphisms did not have a significant impact on migraines. Nevertheless, large-scale studies are necessary to confirm the results.
The SNP 1759G>A is located at codon 587 of exon 10. This variant leads to a substitution from glycine to arginine in the COX-2 protein, and, in vitro, the 1759A allele has a significantly higher enzymatic activity towards arachidonic acid than the 1759G allele [24]. Therefore, individuals carrying the 1759A allele might have higher activity of this enzyme and higher production of prostaglandins, which are related to migraine [11, 12]. On the other hand, in the present study, the 1759AG heterozygotes were overrepresented in controls compared with patients with migraine, suggesting that the 1759A allele might play a protective role in migraine and that the 1759AG genotype is associated with a reduced risk of migraine. These conflicting results with those of the previous functional study might be partly explained by the fact that the enzymatic activities of COX-2-587Gly and COX-2-587Arg were measured in vitro and that the sample size was small (n = 18) in the functional study.
On the other hand, the functional effects of the COX-2-765G>C and -8473T>C SNPs have been investigated. The -765G>C polymorphism is in the promoter region of COX-2 and seems to have a functional impact on transcription [22]. The COX-2-8473T>C polymorphism was reported to be related to alterations at the COX-2 mRNA and protein levels as sequences within the 3’UTR are important for mRNA stability and translational efficiency [19, 33]. Previous studies suggested that the -765C allele had a lower promoter activity and significantly reduced COX-2 expression compared with the -765G allele [34], and the individuals with 8473 CC genotype showed significantly higher plasma COX-2-dependent PGE2 levels [35]. Dasdemir et al. [28] reported that the COX-2-765C allele was related to a decreased risk of migraine in individuals from Turkey. In Iranians, the COX-2-765CC, -765CG, -1195GG, and -1195AG genotypes were associated with an increased risk of migraine [36]. On the other hand, a recent in colorectal cancer indicated that the COX-2-765G>C and -8473T>C polymorphisms did not alter the PTGS-2 mRNA levels and COX-2 activity [37]. In the present case-control study, there were no associations between migraine and the COX-2-765G>C and -8473T>C polymorphisms in Chinese Han individuals. These conflicting results may suggest that the effect of the COX-2 polymorphisms on mRNA levels and disease risks could be influenced by the ethnic background or the environment. Further investigations are needed to confirm these results.
It has been shown that the COX-2-765G>C polymorphism is a protective factor against ischemic stroke in Italians [34], but the association between COX-2-765G>C and ischemic stroke and leukoaraiosis could not be replicated in Chinese [27, 38] and Koreans [39]. As for COX-2-8473T>C, Maguire et al. [40] demonstrated a significant effect of the COX-2-8473T>C polymorphisms on ischemic stroke functional outcome in Australians, while no association between the COX-2-8473T>C polymorphisms and intracerebral hemorrhage was observed in Koreans [41]. Similarly, a previous study reported that COX-2-765G>C was associated with migraine in Turkish individuals [28]. Taken together, those results from different countries suggest genetic and phenotypic heterogeneity among the diverse ethnic populations.
A number of limitations of the present study should be considered. First, the sample size may not be large enough to allow a definitive conclusion. Second, migraine is a complex and multifactorial disorder [42, 43], and the migraine phenotype is probably influenced by many genetic variants and environmental factors, which means that each genetic variant only confers a small to moderate change in the risk of migraine [44]. Third, selection bias may occur because the patients with migraines and the controls in this study were from one province in China. Nevertheless, the genotypes of the three SNPs in controls followed the Hardy-Weinberg equilibrium. Fourth, this is the first time 1749G>A is investigated in Chinese Han individuals, lacking evidence from other ethnic populations. Fifth, the pressure at spiritual and physical levels can affect the occurrence of migraines, but they were not assessed in this study. Sixth, age was taken into account, but not in terms of pressures from spiritual and physical levels in both groups. Seventh, there were too few factors related to migraine in the multivariate analysis. Finally, in view of the case-control study only investigated in the Chinese Han population, it needs caution when considering other ethnic populations.
In conclusion, the COX-2-1759A allele might be involved in migraine development in Chinese Han individuals. Further functional investigations and independent cohorts are needed to clarify the effect of the COX-2 gene polymorphisms on migraine susceptibility, but this will have to be confirmed in large-scale studies and across multiple ethnicities and populations.
Supporting information
(DOC)
(DOCX)
Data Availability
All relevant data are within the paper and its Supporting Information files.
Funding Statement
This work was supported by the National Natural Science Foundation of China (No. NSFC81070896) / the Haiyan Project of Lianyungang/ the Youth talent program of Lianyungang 1st Peoples’s Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References
- 1.Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. The Lancet Neurology. 2006;5(2):148–57. 10.1016/S1474-4422(06)70348-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Charles A. Migraine. The New England journal of medicine. 2017;377(6):553–61. 10.1056/NEJMcp1605502 . [DOI] [PubMed] [Google Scholar]
- 3.MacGregor EA. Migraine. Annals of internal medicine. 2017;166(7):ITC49–ITC64. 10.7326/AITC201704040 . [DOI] [PubMed] [Google Scholar]
- 4.Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. The Lancet Neurology. 2017;16(1):76–87. 10.1016/S1474-4422(16)30293-9 . [DOI] [PubMed] [Google Scholar]
- 5.Yu S, Liu R, Zhao G, Yang X, Qiao X, Feng J, et al. The prevalence and burden of primary headaches in China: a population-based door-to-door survey. Headache. 2012;52(4):582–91. 10.1111/j.1526-4610.2011.02061.x . [DOI] [PubMed] [Google Scholar]
- 6.Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants. Journal of the neurological sciences. 2017;372:307–15. 10.1016/j.jns.2016.11.071 . [DOI] [PubMed] [Google Scholar]
- 7.Headache Classification Subcommittee of the International Headache S. The International Classification of Headache Disorders: 2nd edition. Cephalalgia: an international journal of headache. 2004;24 Suppl 1:9–160. 10.1111/j.1468-2982.2003.00824.x . [DOI] [PubMed] [Google Scholar]
- 8.Moskowitz MA. The neurobiology of vascular head pain. Annals of neurology. 1984;16(2):157–68. 10.1002/ana.410160202 . [DOI] [PubMed] [Google Scholar]
- 9.Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. Origin of pain in migraine: evidence for peripheral sensitisation. The Lancet Neurology. 2009;8(7):679–90. 10.1016/S1474-4422(09)70090-0 . [DOI] [PubMed] [Google Scholar]
- 10.Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandins in migraine: update. Current opinion in neurology. 2013;26(3):269–75. 10.1097/WCO.0b013e328360864b . [DOI] [PubMed] [Google Scholar]
- 11.Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. Journal of neuropathology and experimental neurology. 2004;63(9):901–10. 10.1093/jnen/63.9.901 . [DOI] [PubMed] [Google Scholar]
- 12.Tassorelli C, Greco R, Armentero MT, Blandini F, Sandrini G, Nappi G. A role for brain cyclooxygenase-2 and prostaglandin-E2 in migraine: effects of nitroglycerin. International review of neurobiology. 2007;82:373–82. 10.1016/S0074-7742(07)82020-4 . [DOI] [PubMed] [Google Scholar]
- 13.Neeb L, Hellen P, Boehnke C, Hoffmann J, Schuh-Hofer S, Dirnagl U, et al. IL-1beta stimulates COX-2 dependent PGE(2) synthesis and CGRP release in rat trigeminal ganglia cells. PloS one. 2011;6(3):e17360 10.1371/journal.pone.0017360 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hershey AD, Tang Y, Powers SW, Kabbouche MA, Gilbert DL, Glauser TA, et al. Genomic abnormalities in patients with migraine and chronic migraine: preliminary blood gene expression suggests platelet abnormalities. Headache. 2004;44(10):994–1004. 10.1111/j.1526-4610.2004.04193.x . [DOI] [PubMed] [Google Scholar]
- 15.Wentz AL, Jimenez TB, Dixon RM, Aurora SK, Gold M, Investigators CXAS. A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine. European journal of neurology. 2008;15(4):420–7. 10.1111/j.1468-1331.2008.02093.x . [DOI] [PubMed] [Google Scholar]
- 16.Misra UK, Jose M, Kalita J. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial. Postgraduate medical journal. 2004;80(950):720–3. 10.1136/pgmj.2003.012393 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Li C, Zhu Q, He Q, Wang J, Wang F, Zhang H. Plasma Levels of Cyclooxygenase-2 (COX-2) and Visfatin During Different Stages and Different Subtypes of Migraine Headaches. Medical science monitor: international medical journal of experimental and clinical research. 2017;23:24–8. 10.12659/msm.899269 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Piranda DN, Festa-Vasconcellos JS, Amaral LM, Bergmann A, Vianna-Jorge R. Polymorphisms in regulatory regions of cyclooxygenase-2 gene and breast cancer risk in Brazilians: a case-control study. BMC cancer. 2010;10:613 10.1186/1471-2407-10-613 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Young LE, Dixon DA. Posttranscriptional Regulation of Cyclooxygenase 2 Expression in Colorectal Cancer. Current colorectal cancer reports. 2010;6(2):60–7. 10.1007/s11888-010-0044-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Di Marco S, Hel Z, Lachance C, Furneaux H, Radzioch D. Polymorphism in the 3'-untranslated region of TNFalpha mRNA impairs binding of the post-transcriptional regulatory protein HuR to TNFalpha mRNA. Nucleic acids research. 2001;29(4):863–71. 10.1093/nar/29.4.863 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Moore AE, Young LE, Dixon DA. A common single-nucleotide polymorphism in cyclooxygenase-2 disrupts microRNA-mediated regulation. Oncogene. 2012;31(12):1592–8. 10.1038/onc.2011.349 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, et al. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arteriosclerosis, thrombosis, and vascular biology. 2002;22(10):1631–6. 10.1161/01.atv.0000030340.80207.c5 . [DOI] [PubMed] [Google Scholar]
- 23.Szczeklik W, Sanak M, Szczeklik A. Functional effects and gender association of COX-2 gene polymorphism G-765C in bronchial asthma. The Journal of allergy and clinical immunology. 2004;114(2):248–53. 10.1016/j.jaci.2004.05.030 . [DOI] [PubMed] [Google Scholar]
- 24.Zhao D, Zhang X, Guo Y, Tan W, Lin D. Cyclooxygenase-2 Gly587Arg variant is associated with differential enzymatic activity and risk of esophageal squamous-cell carcinoma. Molecular carcinogenesis. 2009;48(10):934–41. 10.1002/mc.20543 . [DOI] [PubMed] [Google Scholar]
- 25.Wang H, Fu Y, Liu D, Zhang M, Zhang G, Wu W, et al. The COX-2 rs20417 polymorphism and risk of coronary artery disease: evidence from 17,621 subjects. Heart, lung & circulation. 2014;23(6):572–7. 10.1016/j.hlc.2014.01.002 . [DOI] [PubMed] [Google Scholar]
- 26.Yi XY, Zhou Q, Lin J, Chi LF, Chi WZ. Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population. Genetics and molecular research: GMR. 2013;12(2):1660–9. 10.4238/2013.May.14.6 . [DOI] [PubMed] [Google Scholar]
- 27.Chen GZ, Shan XY, Cheng GP, Tao HM. Cyclooxygenase-2 genetic polymorphism and stroke subtypes in Chinese. Journal of molecular neuroscience: MN. 2013;51(2):467–73. 10.1007/s12031-013-0078-5 . [DOI] [PubMed] [Google Scholar]
- 28.Dasdemir S, Cetinkaya Y, Gencer M, Ozkok E, Aydin M, Cakmakoglu B. Cox-2 gene variants in migraine. Gene. 2013;518(2):292–5. 10.1016/j.gene.2012.12.110 . [DOI] [PubMed] [Google Scholar]
- 29.Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia: an international journal of headache. 2018;38(1):1–211. 10.1177/0333102417738202 . [DOI] [PubMed] [Google Scholar]
- 30.Niu W, Zhang Y, Ji K, Gu M, Gao P, Zhu D. Confirmation of top polymorphisms in hypertension genome wide association study among Han Chinese. Clinica chimica acta; international journal of clinical chemistry. 2010;411(19–20):1491–5. 10.1016/j.cca.2010.06.004 . [DOI] [PubMed] [Google Scholar]
- 31.Zhang Z, Wang BJ, Guan HY, Pang H, Xuan JF. A LDR-PCR approach for multiplex polymorphisms genotyping of severely degraded DNA with fragment sizes <100 bp. J Forensic Sci. 2009;54(6):1304–9. Epub 2009/10/07. 10.1111/j.1556-4029.2009.01166.x . [DOI] [PubMed] [Google Scholar]
- 32.Xhang L, Liu X, Wang BJ, Xu Q, Zhu J, Zhang F, et al. Association of SORL1 Polymorphisms with the Risk of Amnestic Mild Cognitive Impairment in the Han Chinese Population. J Geriatr Med Gerontol. 2015;1:005. [Google Scholar]
- 33.Cok SJ, Morrison AR. The 3'-untranslated region of murine cyclooxygenase-2 contains multiple regulatory elements that alter message stability and translational efficiency. The Journal of biological chemistry. 2001;276(25):23179–85. 10.1074/jbc.M008461200 . [DOI] [PubMed] [Google Scholar]
- 34.Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, et al. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. Jama. 2004;291(18):2221–8. 10.1001/jama.291.18.2221 . [DOI] [PubMed] [Google Scholar]
- 35.Fawzy MS, Aly NM, Shalaby SM, El-Sawy WH, Abdul-Maksoud RS. Cyclooxygenase-2 169C>G and 8473T>C gene polymorphisms and prostaglandin E2 level in breast cancer: a case-control study. Gene. 2013;527(2):601–5. 10.1016/j.gene.2013.06.007 . [DOI] [PubMed] [Google Scholar]
- 36.Mozaffari E, Doosti A, Arshi A, Faghani M. Association of COX-2 Promoter Polymorphisms -765G/C and -1195A/G with Migraine. Iranian journal of public health. 2016;45(12):1625–35. [PMC free article] [PubMed] [Google Scholar]
- 37.Vogel LK, Saebo M, Hoyer H, Kopp TI, Vogel U, Godiksen S, et al. Intestinal PTGS2 mRNA levels, PTGS2 gene polymorphisms, and colorectal carcinogenesis. PloS one. 2014;9(8):e105254 10.1371/journal.pone.0105254 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Shan XY, Chen GZ, Cheng GP, Tao HM. Cyclooxygenase 2 genetic polymorphism may increase the risk of developing leukoaraiosis in Chinese. Journal of molecular neuroscience: MN. 2013;51(2):461–6. 10.1007/s12031-013-0066-9 . [DOI] [PubMed] [Google Scholar]
- 39.Lee C, Kong M. An interactive association of common sequence variants in the neuropeptide Y gene with susceptibility to ischemic stroke. Stroke. 2007;38(10):2663–9. 10.1161/STROKEAHA.107.482075 . [DOI] [PubMed] [Google Scholar]
- 40.Maguire J, Thakkinstian A, Levi C, Lincz L, Bisset L, Sturm J, et al. Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome: a novel finding. Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association. 2011;20(2):134–44. 10.1016/j.jstrokecerebrovasdis.2009.10.011 . [DOI] [PubMed] [Google Scholar]
- 41.Kim DH, Ahn WY, Kim DK, Choe BK, Kim SK, Jo DJ, et al. A Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population. Prostaglandins, leukotrienes, and essential fatty acids. 2011;85(3–4):115–20. 10.1016/j.plefa.2011.07.004 . [DOI] [PubMed] [Google Scholar]
- 42.MacKenzie A, Quinn J. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(26):15251–5. 10.1073/pnas.96.26.15251 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Gardner KL. Genetics of migraine: an update. Headache. 2006;46 Suppl 1:S19–24. 10.1111/j.1526-4610.2006.00486.x . [DOI] [PubMed] [Google Scholar]
- 44.Schurks M. Genetics of migraine in the age of genome-wide association studies. The journal of headache and pain. 2012;13(1):1–9. 10.1007/s10194-011-0399-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
(DOC)
(DOCX)
Data Availability Statement
All relevant data are within the paper and its Supporting Information files.