Headache Medicine 2021, 12(4):278-282 p-ISSN 2178-7468, e-ISSN 2763-6178

278

ASAA

DOI: 10.48208/HeadacheMed.2021.45

Headache Medicine

Review

Evaluation of the genetic variant -889 C>T of Il-1α in migraine -

partial analysis

Maria Paula Bertoletti Juliani , Amanda Brant Rocha , Giovana Ortiz Zendrini , Valéria Aparecida Bello ,

Regina Célia Poli-Frederico , Aline Vitali da Silva

Universidade Católica do Paraná, Paraná, Brazil

Abstract

Introduction

The pathophysiology of migraine integrates inammatory and genetic aspects, with

interleukin-1α being a component of this picture. This pro-inammatory cytokine, respon-

sible for inducing pyrogenic, hematological, and metabolic phenomena, is produced by

macrophages and monocytes. Genetic variants, which can be found in the regulatory

region of the gene for this substance, have clinical implications in different systems.

Objective

To evaluate the frequency of the -889C>T genetic variant of IL-1α and its association with

clinical variables related to migraine.

Methods

Prospective case-control study composed of migraine patients and healthy controls aged

between 18 and 60 years of age. Project approved by the Research Ethics Committee

of PUCPR (No. 3,029,972). Demographic, clinical data on migraine classication and

characteristics were collected using a structured form and validated questionnaires on

anxiety (STAIY2), depression (BDI) and migraine-related disability (MIDAS). Genetic

evaluation was performed with blood or saliva samples that were subjected to polymerase

chain reaction (PCR), followed by electrophoresis in 1.5% agarose gel. Categorical data

were analyzed by chi-square test or Fisher's exact test and continuous data by t-test or

Mann-Whitney test.

Results

A total of 156 participants, 73 migraineurs and 83 controls, were evaluated. The

-889C>T variant of IL-1α was not associated with increased susceptibility to migraine

when evaluated in allelic, codominant, dominant, or recessive models. The C allele, the

lowest producer of the cytokine, was associated with a higher frequency of osmophobia

in patients with migraine (65.5% vs. 48.2%; p=0.038).

Conclusion

No association was identied between the -889C>T variant of IL-1α and susceptibility to

migraine. Its effect on osmophobia should be further investigated. However, the present

work is a partial analysis whose main limitation is the small sample size.

Maria Paula Bertoletti Juliani

mariapaula_bertoletti@hotmail.com

Edited by:

Marcelo Moraes Valença

Keywords:

Migraine

Interleukin 1

Genetic polymorphism

Pathophysiology

Received: February 16, 2022

Accepted: February 21, 2022

279

ASAA

Juliani MPB, Rocha AB, Zendrini GO, Bello VA, Poli-Frederico RC, Silva AV

Evaluation Of The Genetic Variant - 889 C > T Of Il-1α In Migraine - Partial Analysis

Introduction

he main characteristic of migraine is headache, and it

belongs to the group of primary headaches because it

causes physiological changes in the nervous system, which

determine the pain.

In this context, it can be understood

as an inammatory disease resulting from the interaction of

genetic, environmental, hormonal, and metabolic factors.

This disease can present up to four phases: prodrome,

aura, pain, and postdrome.

1,2

Thus, the crises are a sum of

these phenomena and can last ve to six days.

It is rated

as the third most disabling disease in the world 1, affecting

10-20% of the world's population, as well as 15.8% of

Brazilians.

3,4

It is noteworthy that it affects females three

times more often than males, with a rst peak of incidence

at 18-29 years of age and a second one at 40-49, with

a reduction in prevalence concomitant with menopause.

5,6

The pathophysiology of migraine is not yet fully understood,

but it is known that cytokines play a key role in pain.

Substances such as interleukin 1 (IL-1), interleukin 10 (IL-

10), interleukin 4 (IL-4), interleukin 13 (IL-13), interleukin 2

(IL-2), and tumor necrosis factor-α (TNF- α) may be relevant

to the condition.

Therefore, as the pathophysiology of the disease

involves a neurogenic inammation, pro-inammatory

genes, such as interleukin 1 alpha, may interfere in the

manifestations of migraine.

This interleukin is produced

by macrophages, monocytes, broblasts, and endothelial

cells in physiological situations and in situations of cellular

injury due to infection and inammation.

9,10

Specically in

the brain they are produced pathologically by astrocytes,

oligodendrocytes, microglia and neurons.

IL-1 induces

endogenous pyrogenic phenomena and inuences the

hematological, metabolic, and central nervous systems.

One of the genetic variants found in the IL-1 ALPHA gene

is the - 889 C > T, which consists of the exchange of a

cytosine for a thymine in the regulatory region of the DNA.

In the case of migraine, only one study has addressed

this issue and concluded that patients homozygous for

the T allele (T/T) have a greater chance of early onset

of headache than patients with CC and CT genotype

migraine.

Furthermore, this same study found a higher

prevalence of aura in patients homozygous for the T allele

(TT) than other genotypes.

Hence, the present study aims to analyze the association

of clinical aspects of migraine and the IL-1alpha -889 C>T

gene polymorphism (rs1800587) and to verify a possible

association of genetic variants and disease activity.

Methods

Ethical Considerations

The present study was carried out after approval by the

Research Ethics Committee (CEP) of PUCPR, according

to report 3.029.972, by means of Informed Consent

Form (ICF) signed by the participants, after a detailed

explanation of its development, being in accordance with

resolution 466/2012 of the National Health Council.

Study Population

The universe of this study was made up of a convenience

sample with 156 participants - 73 patients and 83 controls,

and the participants were seen at the PUCPR Headache

Academic Outpatient Clinic - Londrina Campus, Paraná,

Brazil.

Inclusion Criteria

Patients and controls between the ages of 18 and 60

years of age, of both.

Exclusion Criteria

Individuals with severe and uncontrolled neurological,

psychiatric, and inammatory diseases were excluded.

Study design

This is a retrospective longitudinal case-control study

investigating the possible association between clinical

aspects of migraine, sociodemographic variables, and

genetic polymorphism of IL1-α and TNF-α in individuals

seen at the Academic Outpatient Clinic of PUCPR Londrina

Campus, Brazil.

Instruments used

The diagnosis of migraine was made according to the

International Classication of Headache, published

in 2018. The interview was structured and based on the

form developed electronically by the Headache Research

Group of the PUCPR Londrina Campus, through the

Google Forms tool®. Composed by the following topics:

demographic data, diagnostic criteria, and temporality of

280

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Juliani MPB, Rocha AB, Zendrini GO, Bello VA, Poli-Frederico RC, Silva AV

Evaluation Of The Genetic Variant - 889 C > T Of Il-1α In Migraine - Partial Analysis

migraine; associated clinical characteristics; crisis triggers,

medications used, lifestyle habits, performance of aerobic

physical activity, sleep time, and comorbidities. The

following scales were applied MIDAS (

Migraine Disability

Assessment

)

HIT-6 (

Headache Impact Test-6

)

and form

Y-STAI (

State-Trait Anxiety Inventory

Genotyping

To obtain DNA, extraction was performed from peripheral

blood leukocytes by venipuncture in tubes containing

EDTA (0.6%) and DNA extraction- kit Pure Link Genomic

DNA (Invitrogen, Carlsbad, EUA) was used, following the

guidelines provided by the manufacturer. The extracted

DNAs were stored in a freezer at -80º C. The quality and

quantity of DNA was measured by means of absorbance

analysis in a spectrophotometer (NanoDrop 2000 – Thermo

Scientic) at 260 nm and 280 nm. Next, DNA was diluted

in ultrapure water Milli-Q® to a nal concentration of 100

ng/uL. Genotyping of genetic variants of the cytokine

IL-1α

-889 C>T (rs1800587) was performed by PCR with allele-

specic sequence primers (PCR-SSP) described by Bunce.

Results

Table 1 presents the main characteristics of the population

analyzed in this study. The mean age of patients with

migraine was 31 years old. There was a prevalence of

migraine in females of 82.2% of patients (p=0.036), as

well as a higher prevalence in Caucasians than other

ethnicities. It was found that majority of the patients did

not have associated comorbidities such as diabetes and

hypertension.

Table 1. General characteristics of participants with migraine and controls

Migraine Control

n % n %

Age

31 26

Sex

Male 13 17.8 27 32.5 0.036

Female 60 82.2 56 67. 5

Ethnicity

Caucasian 61 83.6 58 81.7 0.767

Non caucasian 12 16.4 13 18.3

Hypertension

Yes 5 6.8 7 8.4 0.711

No 68 93.2 76 91.6

Diabetes

Yes 2 2.7 5 6 0.323

No 71 97.3 78 94.0

Body mass index (average in kg/m²)

24.6 24.0

Another relevant nding is that the -889C>T variant of

IL-1α

was not associated with increased susceptibility

to migraine when evaluated in allelic, codominant,

dominant or recessive models (Table 2). However, the

C allele, a lower cytokine producer, was associated

with higher frequency of osmophobia in patients with

migraine (65.5%

. 48.2%; p=0.038). This same allele

is associated with higher presence of aura in patients.

However, it is observed that there was no association with

the classication (episodic or chronic) and other symptoms

associated with migraine (Table 3).

Table 2. Assessment of genetic susceptibility to migraine of the -889 C>T

variant

Control Migraine

n % n %

Allylic Model

C 97 58.4 90 61.6 0.564

T 69 41.6 56 38.4

Codominant Model

CC 22 26.5 24 32.9 0.674

CT 53 63.9 42 57. 5

TT 8 9. 6 7 9.6

Dominant Model

CC 22 26.5 24 32.9 0.384

CC + CT 61 73.5 49 67. 1

Recessive Model

CC + CT 75 90.4 66 90.4 0.992

TT 8 9. 6 7 9.6

Table 3. Evaluation of comparative clinical characteristics in T and C alleles

C T

Count % Count %

Type of

migraine

Episodic 46 52.3 34 60.7

Chronic 42 47. 7 22 39.3

Migraine with

aura

Yes 38 42.20 20 35.70

No 52 57. 8 0 36 64.30

Phonophobia

Yes 78 86.70 46 82.10

No 12 13.30 10 17.90

Photophobia

Yes 82 91.10 50 89.30

No 8 8.90 6 10.70

Osmophobia

Yes 59 65.60 27 48.20

No 31 34.40 29 51.80

Allodynia

Yes 43 47. 8 0 19 33.90

No 47 52.20 37 66.10

Prodrome

Yes 69 76. 70 41 73.20

No 21 23.30 15 26.80

Postdrome

Yes 75 87.20 43 76.80

No 11 12.80 13 23.20

MIDAS_dico

Mild or no disability 28 33.30 18 33.30

Moderate to severe

disability

56 66.70 36 66.70

HIT6_dico

Moderate to no impact 13 15.30 13 23.60

Substantial to severe

impact

72 84.70 42 76.40

281

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Juliani MPB, Rocha AB, Zendrini GO, Bello VA, Poli-Frederico RC, Silva AV

Evaluation Of The Genetic Variant - 889 C > T Of Il-1α In Migraine - Partial Analysis

Discussion

In agreement with the epidemiological data presented in

the literature, the results found in the present study indicate

that patients in the migraine group are mostly female and

Caucasian.

In addition, individuals aged 15-49 years are

the most affected, as evidenced by the average age of the

patients analyzed, i.e. 31 years.

Studies show that women with migraine are 15% more likely

than women without migraine to develop hypertension.

However, the correlation of comorbidities with migraine

in the present analysis was divergent from the evidence in

the literature.

The scarcity of studies in the literature that denitively

correlate the genotype of such polymorphisms and migraine

incidence is equivalent to this study, since there was no

relevant change in susceptibility in any genetic model.

However, the association of the C allele with osmophobia

and aura reinforces the need for further research.

Finally, it is believed that, since this is a partial analysis,

with a reduced sample size, there are losses. Thus, it is

necessary to continue the analysis.

Contribution authors: All authors had the same contribution.

Funding: No

Conflict of interests: The authors report no conict of interest.

Maria Paula Bertoletti Juliani

https://orcid.org/0000-0002-7168-1232

Amanda Brant Rocha

https://orcid.org/0000-0002-5196-7727

Giovana Ortiz Zendrini

https://orcid.org/0000-0003-4508-575X

Valéria Aparecida Bello

https://orcid.org/0000-0001-7919-6218

Regina Célia Poli-Frederico

https://orcid.org/0000-0003-4631-4606

Aline Vitali da Silva

https://orcid.org/0000-0001-7797-9227

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