**2. Genetic aspects of tension‐type headache**

experienced TTH. TTH can be brief, episodic or continuous. According to some researchers,

The neurobiological mechanisms of tension‐type headache are concerning. Central sensitiza‐ tion plays a major role in chronic TTH. Whether peripheral mechanisms or central mechanisms are primarily responsible for TTH is an important issue to differentiate it pathophysiologi‐ cally from migraine. The literature suggests that migraine and tension‐type headache may have the similar pathophysiology. Moreover, exact mechanism for both the disorders is still

The prevalence of migraine has been shown to be increasing. The researchers have suggested that the central nervous system (CNS) susceptible to headache has been linked to an impor‐ tant survival or reproductive advantage. Some possible reasons are determined; one of these says that migraine is a defense mechanism; the other one consider it as a result of novel envi‐ ronmental factors; the next one regards migraine as a compromise between genetic harms and benefits. Genetic epidemiological studies are necessary to prove the involvement of genetic factors. Twin studies have been used to assess the respective roles of genetic and environmen‐

We briefly mention here the headache types and characteristics. The first title is TTH. Biological mechanisms of TTH are yet to be explained. This disease usually is associated with depression and anxiety. In addition, the genetic factors are most important for TTH patho‐ genesis. The neurological mechanisms of TTH are not known clearly. Genetic and neurobio‐ logical research studies have increased our understanding of the complex mechanisms that may lead to TTH. There is strong evidence for a genetic predisposition for TTH. Moreover pain pathways in the central nervous system are positively associated with TTH. Research has enhanced our current understanding regarding the means through which psychological factors lead to TTH, suggesting sympathetic hyperactivity as a possible mechanism [9, 10].

The etiology of cluster‐type headache (CH) is still unknown. Until recently, researchers thought that CH was not an inherited disorder; however, several new studies have suggested

TTH could be secondary to the vasoconstriction, rather than dilatation [1–3].

to be elucidated [4–6].

**Figure 1.** Diagram of primary headaches subtypes.

4 Current Perspectives on Less-known Aspects of Headache

tal factors in migraine [7, 8].

While tension‐type headaches (TTH) are the most common primary headache disorder it has not been as thoroughly investigated as migraine headaches. A lifetime prevalence of TTH has been seen in the general population ranging between 30 and 78% in different studies [13]. Nevertheless, 24–37% had TTH several times a month, 10% had it weekly and 2–3% of the population had chronic TTH, usually lasting for the greater part of their lifetime [14] According to the second edition of the International Classification of Headache Disorders, TTH is classified into three subtypes according to headache frequency: infrequent episodic TTH, frequent episodic TTH and chronic TTH [13]. The female‐to‐male ratio of TTH is 5:4 indicating that, unlike migraine, women are affected only slightly more than men [15]. The average age of onset of TTH is higher than in migraine, namely 25 to 30 years in cross‐sec‐ tional epidemiologic studies [16].

Many studies probably provide a valid measure of the major etiologic role that genetic or envi‐ ronmental factors play in TTH. **Table 1** shows the genetic association studies in TTH. In a study of twins from the New Danish Twin Registry, it was found that the concordance rates were significantly higher in MZ than same‐gender DZ twin pairs with no or frequent episodic TTH, while the difference was not significant in chronic TTH due to small number of twin pairs. In monozygotic (MZ) and same‐gender DZ twin pairs, the concordance rates of infrequent epi‐ sodic tension‐type headache was significantly different in women but not in men, although the difference was small in both genders. It was suggested that genetic factors play a role in no and frequent episodic tension‐type headache, while infrequent episodic TTH is caused primarily by environmental factors [17]. However, differently Ulrich et al. suggested that an environmental influence was of major importance for episodic TTH and a genetic factor had minor contribu‐ tion [18] but in chronic tension‐type headache, the genetic factor may be more important.

When the population‐relative risk in first‐ degree relatives compared with normal controls has been calculated in a Danish study, it was shown that first‐degree relatives of 122 pro‐ bands with chronic tension headache had more than three times the risk of chronic tension


**Table 1.** The genetic association studies in TTH.

headache than the general population. An increased family risk can be caused by genetic or environmental factors because probands and spouses share their environment, the risk of chronic tension headache in spouses is used to elucidate the relative role of genetic and environmental factors. As first‐degree relatives had a significantly increased risk of chronic tension headache and spouses had no increased risk, this result supports the importance of genetic factors in chronic tension headache. [19]. For investigation of the mode of inheritance of chronic tension‐type headache complex segregation analysis was performed in 122 Danish families. The complex segregation analysis indicates that chronic tension‐type headache has multifactorial inheritance [20].

Because TTH treatment features medication with inhibitors for selective reuptake of serotonin and monoamine oxidase inhibitors, The polymorphic patterns of MAOA and MAOB, both in TTH patients and the healthy population were addressed in our previous study. MAO gene polymorphisms were examined in a group of 120 TTH patients and in another 168 unrelated healthy volunteers (control group). MAOA promoter and MAOB intron 13 polymorphisms were genotyped using PCR‐based methods. But an overall comparison between genotype and allele frequencies of the patients and the control group did not reveal any statistically significant difference between the patients and the control group [21].

The catechol‐O‐methyltransferase (COMT) is an enzyme involved in the metabolic degra‐ dation of dopamine, norepinephrin and epinephrine [22]. It is accepted that COMT gene is one of the several potential headache genetic determinants. Several studies indicate that the genetic polymorphism due to a G→A substitution at codon 158 of the COMT gene, which leads to the formation of a heat‐stable, high‐activity COMT variant (Val/Val) and heat‐labile, low‐activity variants (Val/Met or Met/Met) [23]. Zubieta et al. demonstrated that a measure of pain sensitivity paralleled the COMT activity of the genotypes and individuals with Val/Val genotype have reduced pain sensitivity compared with those with the Met/Met genotype [24]. And also, Fernández‐de‐las‐Peñas C et al. investigate the relationship between Val158Met polymorphisms, headache and pressure hypersensitivity in children with chronic tension‐ type headache (CTTH). But it was reported that the Val158Met COMT polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype [25]. Nitric oxide has an impor‐ tant role in the pathophysiology of tension‐type headache. It is suggested nitric oxide synthe‐ tase inhibitors are helpful in the management of chronic tension‐type headache by reducing the central sensitization [26]. Besides nitric oxide synthetase, nitric oxide production is also dependent on apolipoprotein E (APOE) polymorphism and this production is gene specific [27]. And it was investigated that APOE polymorphism may be associated with migraine as well as tension‐type headache. And the results of the study showed that APOE epsilon2 gene increases the risk of migraine, while APOE epsilon4 gene is protective against migraine and tension‐type headache [28].

As other neurotransmitters, serotonin have a role in pain mechanisms, selective serotonin re‐uptake inhibitors (SSRIs) reduce the symptomatic/analgesic medication use for acute head‐ ache attacks of tension‐type headache [29]. Serotonin is taken up from the synaptic space regularly with a 5‐hydroxytryptamine transporter (5‐HTT) [30, 31]. Two polymorphic sites in 5‐HTT gene was studied in various studies: different numbers of variable‐number‐tandem‐ repeat (VNTR) region of 16‐17 base‐pair (bp) in the second intron of 5‐HTT gene leads several alleles such as STin 2.7, STin 2.9, STin 2.10, STin 2.11, STin 2.12 and a 44‐base pair inser‐ tion/deletion in the 5'‐‐flanking promoter region (5‐HTT gene‐linked polymorphic region‐5‐ HTTLPR) creating a short (S) and a long (L) allele [32]. The possible role of 5‐HTTLPR and VNTR polymorphisms was evaluated individually and in combination in risk of CTTH. Moreover, the relationship between the clinical response of the drugs or analgesic overuse and the serotonin transporter (5‐HTT) gene polymorphisms was investigated [33, 34]. Park et al. reported that S/S genotype frequency was significantly higher in patients with CTH (76%) than in those with controls (59%; *P* =.02). The authors suggested that 5‐HTTLPR might be one of the genetically contributing factors [35].

headache than the general population. An increased family risk can be caused by genetic or environmental factors because probands and spouses share their environment, the risk of chronic tension headache in spouses is used to elucidate the relative role of genetic and environmental factors. As first‐degree relatives had a significantly increased risk of chronic tension headache and spouses had no increased risk, this result supports the importance of genetic factors in chronic tension headache. [19]. For investigation of the mode of inheritance of chronic tension‐type headache complex segregation analysis was performed in 122 Danish families. The complex segregation analysis indicates that chronic tension‐type headache has

**Gene Genetic variants Results Reference**

Val158Met may be involved in the

C677T and A1298C Association [38]

C677T No association [39]

No association [21]

[25]

phenotypic expression

No association [119]

Association [33]

No Association [42]

polymorphism of a variable number of tandem repeats

Tumor necrosis factor (TNF) TNFA 308G > A and TNFB 252G > A No association [40]

Apolipoprotein E (APOE) Association [28]

the variable number of tandem repeats (VNTR) and 5'‐flanking promoter region (5‐HTTLPR)

Serotonin transporter gene 5‐HTTLPR) Association [34] Serotonin transporter gene 5‐HTTLPR Association [35] Serotonin transporter gene 5HTR2c‐Cys23Ser No association [36]

GST M1 and T1 null polymorphism

GSTP1 Ile105Val

ESR1 PvuII (rs2234693), ESR1 325 C→G (rs1801132)] and [(rs1042838)

Monoamine oxidase (MAO) rs1799836 G/A promoter

6 Current Perspectives on Less-known Aspects of Headache

Catechol‐O‐methyltransferase

Serotonin (5‐hydroxytryptamine,

Glutathione S‐transferase (GST)

Methylenetetrahydrofolate reductase gene (MTHFR)

Methylenetetrahydrofolate reductase gene (MTHFR)

**Table 1.** The genetic association studies in TTH.

Estrogen receptor (ESR1) progesterone receptor (PROGINS)

5HT) transporter gene

M1, T1, P1

(COMT)

(VNTR)

Because TTH treatment features medication with inhibitors for selective reuptake of serotonin and monoamine oxidase inhibitors, The polymorphic patterns of MAOA and MAOB, both in TTH patients and the healthy population were addressed in our previous study. MAO gene polymorphisms were examined in a group of 120 TTH patients and in another 168 unrelated healthy volunteers (control group). MAOA promoter and MAOB intron 13 polymorphisms were genotyped using PCR‐based methods. But an overall comparison between genotype and allele frequencies of the patients and the control group did not reveal any statistically

significant difference between the patients and the control group [21].

multifactorial inheritance [20].

But differently in another study any statistically significant results based on the 5‐HTTLPR gene alleles and CTTH risk were not found. Only, when it was investigated the combined effect of the two polymorphic loci of the 5‐HTT gene, genotypes S/S‐12/10 and L/S‐12/10 dis‐ played statistically significant frequency in the CTTH group than in the control group. Aylin et al. reported that the presence of homozygous L and STin12 alleles may play a protective role against CTTH [33]. Also in a different study showed that the S/S genotype frequency was significantly higher in CTTH patients with analgesic overuse. And it was suggested that serotonergic activity may be involved in the development of analgesic overuse in CTTH and that 5‐HTTLPR might be one of the genetically contributing factors [34]. But no significant differences were noticed between the 5‐HTTLPR and VNTR haplotype groups and success in treatment. 5HT2c‐receptor (5HTR2c) is another subtypes of 5HT2 families. The relationship between 5HTR2c Cys23Ser polymorphism and TTH was also investigated. However, there were no differences found among TTH and control groups [36].

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. So vasodilation of cerebral blood vessels may result in headache, or high levels of homocysteine may cause temporary thrombosis of cere‐ bral blood vessels, allowing less oxygen into the brain thus possibly causing headache. Frosst et al. reported an association between the homozygous C677T mutation in the 5,10‐methy‐ lenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels [37]. In a case‐ control study, the prevalence of two common MTHFR polymorphisms, C677T and A1298C, in tension‐type headache patients and healthy controls was compared. And it was suggested that patients with C1298C and C677C/C1298C genotypes may predispose to tension‐type headache [38]. On the contrary, the study of Kowa et al. could not reach the same results. It was reported that MTHFR gene polymorphisms was not a genetic risk factor for TTH in their study [39].

Also it was investigated the relationship between TTH and tumor necrosis factor (TNF) gene polymorphisms (TNFA 308G > A and TNFB 252G > A) [40] and also estrogen receptor [ESR1 PvuII (rs2234693), ESR1 325 C→G (rs1801132)] and progesterone receptor [PROGINS (rs1042838)] polymorphisms [41]. But no risk was observed when TTH patients were com‐ pared with HC. Similarly, in a study that evaluates the relationship between GSTM1, T1 and P1 gene polymorphism and TTH, no difference was found between two groups in the geno‐ type and allele distribution [42].
