DNA Repair Gene Variants in Migraine

Abstract

Aims: Migraine is a common and debilitating episodic disorder characterized by recurrent headache attacks associated with autonomic symptoms. It affects an estimated 12% of the population. The etiology of the underlying neurodegenerative process is widely unknown; however, oxidative stress is a unifying factor in the current theories of migraine pathogenesis. After demonstrating the observation that oxidative DNA damage is detectable in migraine disease, searching the role played by DNA repair systems in migraine diseases could bring us much significant information about the pathogenesis of migraine. We prospectively investigated whether DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, hOGG1 Ser326Cys) account for an increased risk of migraine. The present analyses are based on 135 case subjects with migraine disease and 101 noncase subjects. Genotyping of DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, hOGG1 Ser326Cys) was detected by polymerase chain reaction-restriction fragment length polymorphism. Results: We demonstrated that apurinic endonuclease (APE), X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3), xeroderma pigmentosum D (XPD), and hOGG1 gene variants were associated with an increased risk for development of migraine disease (p<0.05). In contrast, no statistically significant differences were found in genotype distributions of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) and XPG between migraine cases and controls (p>0.05). Conclusions: Our findings have suggested that APE1, XRCC3, XPD, and hOGG1 gene variants could facilitate the development of migraine disease.

Introduction

Migraine is a common and debilitating episodic disorder characterized by recurrent headache attacks associated with autonomic symptoms. It affects an estimated 12% of the population (Stewart et al., 1991). International Criteria for Headache Disorders (ICHDII) has classified migraine into two main categories: migraine with aura (MA) and migraine without aura (MO) (International Headache Society, 2004). In MA, the migraine headaches are preceded by a visual hallucination/illusion known as an aura. Generally, the aura begins in the visual field and expands during a 5- to 20-min period, and is usually followed by headache. Disabling, unilateral throbbing headache typically characterizes attacks of MO. The headache may last 4-72 h, often accompanied by autonomic symptoms like vomiting, nausea, photophobia, and phonophobia (Goadsby et al., 2002). Migraine is a complex neurological disorder caused by a combination of multiple genetic and environmental factors (Mulder et al., 2003). There were several studies to find the genetic factors in the pathophysiology of migraine. Yet, no clear diagnostic marker or objective method to assess the status of the migraineurs has been established. Several studies performed in adult migraineurs suggest that there is an increased vulnerability to oxidative stress, which supports the hypothesis of oxidative stress in migraine (Shimomura et al., 1994; Yilmaz et al., 2007). Shimomura et al. (1994) found lower levels of superoxide dismutase in migraine patients, suggesting that a low superoxide dismutase concentration may have a role in the etiology of migraine. Ciancarelli et al. (2003) has reported a significant increase in urinary nitric oxide (NO) metabolites and lipid peroxidation by-products in migraine. Some studies reported that oxidative stress due to increased NO has been found especially during attacks in patients with migraine (Ciancarelli et al., 2003; Yilmaz et al., 2007). It is suggested that neurogenic inflammation, endothelial dysfunction, and oxidative stress have a role in migraine pathogenesis (Gruber et al., 2009). NO may interact with reactive oxygen substances (ROS), which may induce headache through changes of cerebral blood flow (Ciancarelli et al., 2005). The increase of NO may be caused by interactions with free ROS. Elevated levels of ROS may induce oxidative DNA damage, DNA strand breaks, base modifications, and chromosomal aberrations (Marnett, 2005).

Demonstrating the observation that oxidative DNA damage is detectable in the brain of individuals affected by one of several neurodegenerative diseases, it is important to understand the possible role played by DNA repair systems in healthy aging of the brain and neurodegeneration (Coppede and Migliore, 2010). In addition, there is a current interest in the understanding of the role played by polymorphisms of DNA repair genes in the risk to develop neurodegenerative pathologies, as well as in the onset and the progression of disease symptoms. There are several studies about whether the DNA repair system has an effect on neurodegenerative disease (Mantha et al., 2013). Gencer et al. (2012) showed that apurinic endonuclease 1 (APE1), X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), and X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3) genetic variants might be molecular markers for Parkinson's disease by their role on oxidative stress. Despite this, Parildar-Karpuzoğlu et al. (2008) found that hOGG1, APE1, and XRCC1 genes are unrelated to Alzheimer's disease, which is one of the types of neurodegenerative diseases. However, Gencer et al. (2012) suggested that APE1, XRCC1, and XRCC3 genes have a statistically significant role in Parkinson's disease. Parildar-Karpuzoğlu et al. (2008) suggested that the single-nucleotide polymorphism in 8-oxoguanine DNA-glycosylase 1 (hOGG1), APE1, and XRCC1 genes do not play a role in Alzheimer's disease. According to these conflicting results, we aimed to investigate the role of DNA repair genes, for the first time, on migraine as a neurodegenerative disorder.

We prospectively investigated whether DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, hOGG1 Ser326Cys) account for an increased risk of migraine.

Materials and Methods

Population collection and phenotype

One hundred thirty-five unrelated patients with migraine (88 without aura, 47 with aura), from the neurology outpatient clinic, at clinic of Neurology, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey, were sequentially enrolled in this study. Migraineurs were diagnosed as having either MA or MO, according to the 2004 International Headache Society diagnostic criteria. Potential control subjects were selected from the healthy volunteer registry maintained by the Haydarpasa Numune Education and Research Hospital. Control subjects were healthy volunteers without a history of migraine matched with case subjects on the basis of age and sex. A diagnostic interview was performed in cases and controls, based on the operational criteria of the International Headache Society, using the same structured questionnaire. Assessment was done on a form that required patient information regarding demographic and personal details of the patients and informants, complaints of the patients, history of present illness, details of medical or surgical interventions, past history, family history, personal history, premorbid personality, details of physical examination, mental status examination, and diagnostic formulation. The study protocol included history, direct clinical and neurological examination.

The subjects with a known history of cerebrovascular disease, intracranial hemorrhage, intracranial mass, seizure disorder, organic central nervous system disease, headache as a result of traumatic head or neck injury, alcohol or substance abuse, uncontrolled hypertension, known pregnancy, paradoxical embolism, or decompression illness were excluded. Specific exclusion criteria for control subjects were any history of migraine as defined by the case-inclusion criteria above, chronic daily headache, tension headache occurring more than once per month, prior cerebrovascular disease, history of intracranial hemorrhage, intracranial mass, seizure disorder, organic central nervous system disease, headache as a result of traumatic head or neck injury, alcohol or substance abuse, uncontrolled hypertension, or known pregnancy.

The study population comprised 135 migraineurs (M/F 6/129; age 36.50±9.81 years; MA/MO 47/88). The patients who were affected with complicated migraine were excluded from the study. All provided informed consent to the research procedures, including molecular genetic analyses. Controls were from the same ethnic and geographical origin as the cases. To minimize the effect of ethnic differences in gene frequencies, the study participants were of Turkish population living in the western region of Turkey. The Medical Ethics Committee of Haydarpasa Numune Education and Research Hospital approved the study.

For the statistical analysis, three experimental groups were considered: all migraineurs together and MA and MO separately. Healthy control individuals (90 females and 11 males aged 39.02±9.75 years) of Turkish origin matching for age and sex of the migraineurs served as control for all three experimental groups.

Polymorphism analysis

Genomic DNA was extracted from isolated lymphocytes by a standard nonorganic procedure (Miller et al., 1988). The extracted DNA was used for characterization of the following polymorphic DNA repair genes. Polymerase chain reaction (PCR), followed by restriction fragment length polymorphism, was used for genotyping (Sturgis et al., 1999; Hu et al., 2001; Le Marchand et al., 2002; Mort et al., 2003; Yeh et al., 2005). Initially, PCR was performed to determine the polymorphic regions using suitable primers. PCR products of XRCC3 Thr241Met, APE Asp148Glu, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XPG Asp1104His, and XPD Lys751Gln were further subjected to digestion with Hsp92II, FspBI, Fnu4HI, PvuII, Hsp92II, and PstI restriction enzymes, respectively. The PCR products were visualized by electrophoresis through a 3% agarose gel. The relative size of the PCR products was determined by comparison of the migration of a 50-1000 bp DNA molecular weight ladder. A permanent visual image was obtained using a UV illuminator. Two independent researchers read all genotypes. In case of any conflicts, the genotypes were repeated.

Statistical analyses

Statistical analyses were performed using the SPSS software package (revision 11.5; SPSS, Inc., Chicago, IL). Data are expressed as mean±SD. Differences in the distribution of DNA repair gene polymorphism genotypes or alleles between cases and controls were tested using the Chi-square (χ²) statistic, respectively. Relative risk at 95% confidence intervals (95% CIs) was calculated as the odds ratio (OR). Linkage disequilibrium among DNA repair gene polymorphisms was assessed using D⁰ and r² values obtained through the Haploview program (www.broad.mit.edu/mpg/haploview/documentation.php). A multivariate logistic regression model was performed to investigate the possible effects of genotypes and alleles after adjustment for age. Values p<0.05 were considered statistically significant.

Results

Controls and patients were adjusted for age and sex. We classified our patients according to migraine subtypes (Table 1). Table 2 shows the distributions of genotypes of APE1, XRCC1, XRCC3, xeroderma pigmentosum D (XPD), XPG, and hOGG1 genes among cases and controls. The distributions of the genotypes of the study groups were in the Hardy-Weinberg equilibrium. We did not find any significant differences for XRCC1 and XPG genotype frequencies between patients with migraine disease and controls.

Table 1.

Characteristics of Patients with Migraine and Control Group

Parameters	Controls (n=101)	Migraine with aura (n=47)	Migraine without aura (n=88)	Total patients (n=135)
Mean age, years±SD	39.02±9.75	37.27±9.71	36.33±10.07	36.50±9.81
Sex (F/M)	90/11	44/3	85/3	129/6

Table 2.

Distribution of APE1, XRCC1, XRCC3, XPD, XPG, and hOGG1 Genotype Frequencies in Patients with Migraine and Control Groups

	Control (n=101)		Migraine with aura (n=47)		Migraine without aura (n=88)		All Patients (n=135)
Polymorphism	n	%	n	%	n	%	n	%	p^a-c-Value
APE rs3136820
TT	45	44.6	24	51.1	38	43.2	62	45.9
GG	20	19.8	3	6.4	10	11.4	13	9.6
TG	36	35.6	20	42.6	40	45.5	60	44.4	0.11, 0.19, 0.017
T	126	62.3	68	72.3	116	65.9	184	69.6
G	76	37.6	26	27.6	60	34.3	80	30.3	0.09, 0.47, 0.09
XRCC1 rs25487
GG	82	81.2	40	85.1	79	89.8	119	88.1
AA	0	0	0	0	0	0	0	0
GA	19	18.8	7	14.9	9	10.2	16	11.9	0.56, 0.09, 0.137
G	183	90.5	87	92.5	167	94.8	254	94.07
A	19	9.4	7	7.4	9	5.1	16	5.92	0.57, 0.11, 0.15
XRCC3 rs861539
CC	27	26.7	17	36.2	36	40.9	53	39.3
TT	11	10.9	7	14.9	18	20.5	25	18.5
CT	63	62.4	23	48.9	34	38.6	57	42.2	0.30, 0.004, 0.008
C	117	57.9	57	60.6	106	60.2	163	60.3
T	85	42.0	37	39.3	70	39.7	107	39.6	0.65, 0.64, 0.59
hOGG1 rs1052133
CC	70	69.3	28	59.6	51	58.0	79	58.5
GG	7	6.9	0	0	4	4.5	4	3.0
CG	24	23.8	19	40.4	33	37.5	52	38.5	0.034, 0.114, 0.031
C	164	81.1	75	79.7	135	76.7	210	77.7
G	38	18.8	19	20.1	41	23.2	60	22.2	0.77, 0.28, 0.36
XPG rs17655
GG	59	58.4	25	53.2	50	56.8	75	55.6
CC	10	9.9	2	4.3	8	9.1	10	7.4
GC	32	31.7	20	42.6	30	34.1	50	37.0	0.28, 0.93, 0.611
G	150	74.2	70	74.4	130	73.8	200	74.0
C	52	25.7	24	25.5	46	26.1	70	25.9	0.96, 0.93, 0.96
XPD rs1052559
AA	40	39.6	11	23.4	19	21.6	30	22.2
CC	11	10.9	11	23.4	26	29.5	37	27.4
AC	50	49.5	25	53.2	43	48.9	68	50.4	0.052, 0.001, 0.001
A	130	64.3	47	50	81	46.0	128	47.4
C	72	35.6	47	50	95	53.9	142	52.5	0.01, 0.000, 0.000

p-Value for migraine with aura versus control.

p-Value for migraine without aura versus control.

p-Value for all patients versus control.

APE1, apurinic endonuclease 1; XPD, xeroderma pigmentosum D; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; XRCC3, X-ray repair complementing defective repair in Chinese hamster cells 3.

There were statistically significant differences in APE Asp148Glu, XRCC3 Thr241Met, XPD Lys751Gln, and HOGG1 Ser326Cys genotypes between the controls and patients.

APE Asp148Glu genotypes were significantly different in patients compared with controls (p=0.048). Frequencies of T+ genotype in patients were higher than the controls (90.4% and 80.2%, respectively). It seems that APE T+ genotype increases the risk of migraine (p=0.026, OR: 2.31, 95% CI: 1.09-4.91).

There were statistically significant differences in XRCC3 Thr241Met (p=0.015), XPD Lys751Gln (p=0.002), and hOGG1 Ser326Cys (p=0.036) genotypes between the controls and patients.

We have detected that frequencies of XPD C+ genotype in patients were higher than the controls (77.8% and 60.4%, respectively, p=0.004). Moreover, the XPD CC genotype in patients was significantly higher than the controls (p=0.002, χ²: 9.27, OR: 3.08, 95% CI: 1.48-6.41).

In haplotype analysis, we have seen that when APE T: XPD C was high in the patient group, APE G:XPD A was significantly high in the control group (Table 3).

Table 3.

The Frequencies of Haplotypes of DNA Repair Genes in All Migraine Patients and Controls

	Frequency
Number of haplotype	Overall	All patients	Control	Chi-square	p-Value
All patients
APE:XPD
TA	0.347	0.312	0.394	3.451	0.0632
TC	0.310	0.370	0.230	10.587	0.0011
GA	0.200	0.162	0.250	5.501	0.019
GC	0.144	0.156	0.127	0.819	0.3655
Migraine with aura
APE:XPD
TA	0.374	0.336	0.391	0.845	0.3581
TC	0.282	0.387	0.232	7.634	0.0057
GA	0.224	0.164	0.252	2.86	0.0908
GC	0.120	0.113	0.124	0.081	0.7755

We also looked at the frequencies of APE1, XRCC1, XRCC3, XPD, XPG, and hOGG1 genotype distributions in MA and MO patients and controls, separately (Table 2). In MA, APE T+ genotype in patients was significantly higher than the controls (93.6% and 80.2%, respectively, p=0.027, OR: 3.62, 95% CI: 1.019-12.86), and XPD C+ genotype in patients was nearly significantly higher than the controls (76.6% and 60.4%, respectively, p=0.054, OR: 2.14, 95% CI: 0.98-4.70). In addition, the XPD CC genotype in patients was significantly higher than the controls (p=0.046, χ²: 3.96, OR: 2.5, 95% CI: 0.99-6.27). In haplotype analysis, we have seen that APE T: XPD C was higher in MA patients.

In MO, XPD C+ genotype in patients was significantly higher than the controls (78.4% and 60.4%, respectively, p=0.008, χ²: 7.1, OR: 2.38, 95% CI: 1.24-4.54), and XPD CC genotype in patients was significantly higher than the controls (p=0.001, χ²: 10.36, OR: 3.43, 95% CI: 1.58-7.45). We did not do haplotype analysis in the MO group.

Discussion

The present study is the first study about the relationship between DNA repair genes and migraine in the literature. We have studied the effect of genetic polymorphisms in the DNA repair genes and the development of migraine disease. In our study, we demonstrated that APE1, XRCC3, XPD, and hOGG1 gene variants were associated with an increased risk for development of migraine. When ROS production exceeds the capacity of detoxification, they can cause oxidative DNA damage and DNA damage accumulation can lead to genetic instability, which is a hallmark of cancer, aging, and several age-related disorders (Olinski et al., 2007; Wilson and McNeill, 2007). After demonstrating the observation that oxidative DNA damage is detectable in migraine disease (Gruber et al., 2009), searching the role played by DNA repair systems in migraine diseases could bring us a great deal of significant information about the pathogenesis of migraine. Genetic variations in DNA repair genes can modulate DNA repair capacity and, consequently, alter migraine risk.

At present, it is hard to explain by which mechanisms the genotypes of DNA repair enzymes result in oxidative stress. Nevertheless, we can make some plausible interpretations depending on the previous study findings. Genetic variants may affect directly the function of base excision repair (BER) or APE1, which might affect each other, or the other BER regulatory proteins, leading to oxidative stress. BER is the major pathway responsible for removing oxidative DNA damage and restoring the integrity of the genome (Rao, 2007). APE1 is thought to be one of the rate-limiting steps in the BER pathway under a variety of conditions. Our study indicated that there were statistically significant differences in APE Asp148Glu genotypes between the controls and patients. Functional studies about this polymorphism reported that the Glu allele may have altered endonuclease and DNA-binding activity and reduced ability to communicate with other BER proteins (Hadi et al., 2000).

Although it is not known how the genetic variations cause diseases, there are some explanations related to genetic variants responsible for modulation of DNA repair capacity, leading to diseases. A recent study reported that the APE1 T1349G polymorphism might contribute to genetic susceptibility to cancer (Ito et al., 2004; Li et al., 2007; Pardini et al., 2008). To our knowledge, there are no published reports regarding the association between APE1 polymorphisms and the risk of migraine. We found an association between this polymorphism and the risk of developing migraine, indicating that this polymorphism may play a role in migraine etiopathogenesis.

The XRCC3 gene codes a protein involved in homologous recombinational repair of double-strand DNA and is required for genomic stability (Cui et al., 1999; Griffin et al., 2000). The XRCC3 gene has a sequence variation in exon 7 (C18067T), which results in an amino acid substitution at codon 241 (Thr241Met) that may affect the enzyme's function and/or its interaction with other proteins involved in DNA damage and repair (Matullo et al., 2001). We showed a positive relationship between migraine and XRCC3Thr241Met polymorphism in our study.

There were statistically significant differences in XPD Lys751Gln and hOGG1 Ser326Cys genotypes between the controls and patients in our study. hOGG1 is an important component of the BER process and known to be involved in the repair of oxidative damage in neurons (Coppede et al., 2006). In addition, nucleotide excision repair (NER) is a fundamental repair pathway, which is able to remove a variety of bulky DNA lesions. XPD (ERCC2) encodes an ATP-dependent 5′-3′ helicase that participates in the opening of the damaged DNA after the damage recognition step in NER (Costa et al., 2003).

Previous studies have shown that females develop migraine more than males as in our results (Borsook et al., 2014). Facchinetti et al. (2000) have suggested that not only sex- and brain-related changes are highly important in the disease process but also hormones in women have an effective role on migraine. These conditions make women more susceptible to migraine than men (Alstadhaug, 2009).

In conclusion, our findings have suggested that APE1, XRCC3, XPD, and hOGG1 gene variants could facilitate the development of migraine disease. Further studies with larger sample groups are necessary to clarify the role of DNA repair genes and the development of migraine disease.

Footnotes

Acknowledgment

The Research Fund of Istanbul University supported this work. Project no. 18681.

Author Disclosure Statement

The authors have no conflicts of interest.

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