Nicotinamide-N-Methyltransferase gene rs694539 variant and migraine risk
Sazci et al. The Journal of Headache and Pain
Nicotinamide-N-Methyltransferase gene rs694539 variant and migraine risk
Ali Sazci 0
Gensay Sazci 0
Bilgen Sazci 0
Emel Ergul 0
Halil Atilla Idrisoglu 1
0 Department of Medical Biology and Genetics, Faculty of Medicine, University of Kocaeli , Kocaeli 41380 , Turkey
1 Department of Neurology, Istanbul Faculty of Medicine, University of Istanbul , Istanbul, Capa 34290 , Turkey
Background: Migraine is a common neurovascular disorder affecting 10 to 20 % of the world population usually subdivided into migraine with auro (MA) and migraine without auro (MO). Homocysteine is involved in the pathophysiology of a number of neurological disorders. Elevated levels of homocysteine in the plasma is produced by the MTHFR gene rs 1801133 and rs 1801131 variants as well as the NNMT gene rs 694539 variant. Methods: With the polymerase chain reaction-restriction fragment length polymorphism method developed recently in our laboratory, we were able to show an association between the NNMT gene rs694539 variant and migraine for the first time. Results: Here we report the association of the Nicotinamide-N-methyltransferase gene (NNMT) rs694539 variant with migraine in a case-control study of 433 patients with migraine and 229 healthy controls (χ2 = 6.076, P = 0. 048). After stratification, we were able only to show an association between the NNMT gene rs694539 variant and female patients with migraine on the genotype and allelic levels. However there was no association in male patients with migraine (χ2 = 1.054, P = 0.590). Conclusions: Consequently our results clearly indicate that the NNMT gene rs694539 variant is a genetic risk factor for migraine.
NNMT gene; Association; rs694539; One carbon metabolism; Gender association; Turkey
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Background
Migraine is a common and chronic neurovascular disorder
affecting approximately 10–20 % of the world population.
Clinically, It is sub-classified into migraine with aura (MA)
and migraine without aura (MO) accompanied by severe
recurrent headache attacks and associated symptoms such
as nausea, vomiting, photo- and phonophobia [1].
Homocysteine, a sulfur-containing amino acid derived
from the metabolism of methionine, has been implicated
in the pathophysiology of a variety of neurological
disorders such as migraine [1], essential tremor [2], stroke
[3], epilepsy [4]), schizophrenia [5, 6] and bipolar
disorders [7, 8]. 5,10-Methylenetetrahydrofolate reductase
(MTHFR), a key enzyme in the metabolism of folate
catalyzes the reduction of 5,10-methylenetetrahydrofolate
to 5-methyltetrahydrofolate, the predominant form of
folate and carbon donor for the remethylation of
homocysteine to metionine. Variants of the MTHFR
C677T (rs1801133) and A1298C (rs1801131) gene,
associated with significantly elevated plasma homocysteine
levels, were shown to be associated with migraine [9–21].
A meta-analysis has revealed that the MTHFR C677T
(rs1801133) variant is a genetic risk factor for migraine
[22]. Another enzyme implicated in one-carbon
metabolism is nicotinamide-N-methyltransferase (NNMT). Human
NNMT (EC 2.1.1.1), a cytoplasmic enzyme belonging to
Phase II conjugating enzymes, is reported to be expressed
in brain and other nervous tissues [23]. This gene is
16.703 bp in lenght on chromosome 11q23.1, having three
exons and two introns. NNMT catalyzes the transfer of
methyl group from S-adenosyl-L-methionine (SAM) to
nicotinamide (NA), thus creating 1-methylnicotinamide
(1MNA) and S-adenosylhomocysteine (SAH) which is later
hydrolyzed to homocysteine [24]. Homocysteine is one of
the key components of one-carbon metabolism. The
rs694539 NNMT variant, localized at the 114133419 bp
(G > A transition) is found to be significanly associated with
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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elevated plasma homocysteine levels [25]. Elevated plasma
homocysteine levels were shown to be associated with an
increased risk of migraine in patients with the MTHFR
C677T and A1298C polymorphisms [1, 11].
Recently, we showed that the MTHFR C677T and
A1298C variants were associated with migraine [1]. We
also wanted to reveal whether the rs694539 variant of
NNMT gene is associated with migraine. To do so we
analyzed the allele and genotype frequencies of the NNMT
gene rs694539 variant in 433 patients with migraine and
229 healthy controls.
Methods
Subjects
The subjects were 433 [351 (81 %) female; 82 (19 %)
male] patients with migraine and 229 [184 (80 %)
female; 45 (20 %) male] healthy controls recruited from
the Istanbul University neurological clinic. The mean
age of migraine was 36.96 (...truncated)