association of gaba b r1 receptor gene polymorphism with obstructive sleep apnea syndrome

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1 Association of GABA Association of GABA B B R1 R1 Receptor Gene Polymorphism Receptor Gene Polymorphism with Obstructive Sleep Apnea with Obstructive Sleep Apnea Syndrome Syndrome Oğuz Köktürk*, Tansu Ulukavak Çiftçi*, Yıldırım A. Oğuz Köktürk*, Tansu Ulukavak Çiftçi*, Yıldırım A. Beyazıt**, Beyazıt**, Metin Yılmaz**, M.Emin Erdal*** Metin Yılmaz**, M.Emin Erdal*** * Gazi Ü. T. F. Göğüs Hastalıkları A. D., * Gazi Ü. T. F. Göğüs Hastalıkları A. D., ** Gazi Ü. T. F. KBB A.D., ** Gazi Ü. T. F. KBB A.D., ***Mersin Ü. T. F. Tıbbi Biyoloji ve Genetik A.D. ***Mersin Ü. T. F. Tıbbi Biyoloji ve Genetik A.D.

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Association of GABA B R1 Receptor Gene Polymorphism with Obstructive Sleep Apnea Syndrome. Oğuz Köktürk*, Tansu Ulukavak Çiftçi*, Yıldırım A. Beyazıt ** , Metin Yılmaz**, M.Emin Erdal*** * Gazi Ü. T. F. Göğüs Hastalıkları A. D., ** Gazi Ü. T. F. KBB A.D., - PowerPoint PPT Presentation

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Page 1: Association of GABA B R1 Receptor Gene Polymorphism with Obstructive Sleep Apnea Syndrome

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Association of GABAAssociation of GABABBR1 R1 Receptor Gene Polymorphism Receptor Gene Polymorphism with Obstructive Sleep Apnea with Obstructive Sleep Apnea

SyndromeSyndromeOğuz Köktürk*, Tansu Ulukavak Çiftçi*, Yıldırım A. Beyazıt**,Oğuz Köktürk*, Tansu Ulukavak Çiftçi*, Yıldırım A. Beyazıt**,

Metin Yılmaz**, M.Emin Erdal***Metin Yılmaz**, M.Emin Erdal***

* Gazi Ü. T. F. Göğüs Hastalıkları A. D., * Gazi Ü. T. F. Göğüs Hastalıkları A. D., ** Gazi Ü. T. F. KBB A.D.,** Gazi Ü. T. F. KBB A.D.,***Mersin Ü. T. F. Tıbbi Biyoloji ve Genetik A.D.***Mersin Ü. T. F. Tıbbi Biyoloji ve Genetik A.D.

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Introduction and AimIntroduction and Aim

GABA (gamma-amino-butyric acid) is one GABA (gamma-amino-butyric acid) is one of the most common neurotransmitters in of the most common neurotransmitters in the CNS. It might be functionally the CNS. It might be functionally important in cortical disinhibition.important in cortical disinhibition.

The GABA receptors in the brain have The GABA receptors in the brain have been classified into:been classified into:– GABAGABAAAR ve GABAR ve GABABBRR

GABAGABABBRR, inhibits cAMP formation and , inhibits cAMP formation and inositol phosphate turnover. There are 2 inositol phosphate turnover. There are 2 forms: forms: – GABAGABABBR1a ve GABAR1a ve GABABBR1bR1b

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GABAGABABBR1 a and b variants are derived R1 a and b variants are derived from the same gene: Human GABAfrom the same gene: Human GABABBR1 R1 gene (chromosome 6p21.3)gene (chromosome 6p21.3)

The GABAThe GABABBR modulates synaptic R modulates synaptic transmission by presynaptic inhibition of transmission by presynaptic inhibition of neurotransmitter release or by neurotransmitter release or by postsynaptic increase of potassium postsynaptic increase of potassium conductance, which is responsible for conductance, which is responsible for long-lasting inhibitory postsynaptic long-lasting inhibitory postsynaptic potentials.potentials.

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GABAGABABBR mediated neurotransmission R mediated neurotransmission has been implicated in the has been implicated in the pathophysiology of a variety of pathophysiology of a variety of neuropsychiatric disorders including neuropsychiatric disorders including obsessive compulsive disorder, obsessive compulsive disorder, schizophrenia, epilepsy and alcohol schizophrenia, epilepsy and alcohol dependence. GABAdependence. GABABBR1a gene R1a gene polymorphism is not known in OSAS.polymorphism is not known in OSAS.

Recently, three exonic GABARecently, three exonic GABABBR1 gene R1 gene variants were identified.variants were identified.

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We aimed to assess significance We aimed to assess significance of three different GABAof three different GABABBR1 gene R1 gene polymorphisms (polymorphisms (A1a20ValA1a20Val, , Gly489SerGly489Ser and and Phe658PhePhe658Phe) in ) in OSAS.OSAS.

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Materials and MethodsMaterials and Methods

75 patients with OSAS (23 F and 52 M) 75 patients with OSAS (23 F and 52 M) ( (apnea-hypopnea indexapnea-hypopnea index = AHI > 5). = AHI > 5).

99 healthy volunteers (51 F and 48 M)99 healthy volunteers (51 F and 48 M)

Mental retardation, drug dependence, Mental retardation, drug dependence, alcoholism, somatic or neurological alcoholism, somatic or neurological illnesses were exculeded. illnesses were exculeded.

Venous blood sample was drawn from Venous blood sample was drawn from each individual for genetical analysis.each individual for genetical analysis.

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Using PCR technique, the Ala20Val, Using PCR technique, the Ala20Val, Gly489Ser and Phe658Phe Gly489Ser and Phe658Phe polymorphisms of the GABApolymorphisms of the GABABBR1 R1 gene were analyzed in the DNA gene were analyzed in the DNA obtained from leukocytes of the obtained from leukocytes of the patients and healthy controls.patients and healthy controls.

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ResultsResults

For Ala20Val variants:For Ala20Val variants:– There was no sigificant difference There was no sigificant difference

between the genotypes and allele between the genotypes and allele frequencies of the patients and frequencies of the patients and controls. controls.

– The T/T variant could not be found in The T/T variant could not be found in both groups.both groups.

– Gender specific comparisons did not Gender specific comparisons did not reveal significant difference (F reveal significant difference (F patients – F controls, M patients – M patients – F controls, M patients – M controls, F patients – M patients, F controls, F patients – M patients, F controls – M controls).controls – M controls).

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For Phe658Phe polymorphism:For Phe658Phe polymorphism:– There was no signgficant difference There was no signgficant difference

between the genotypes and allele between the genotypes and allele frequencies of the patients and controls. frequencies of the patients and controls.

– Gender specific comparisons did not reveal Gender specific comparisons did not reveal significant difference (F patients – F significant difference (F patients – F controls, M patients – M controls, F patients controls, M patients – M controls, F patients – M patients, F controls – M controls).– M patients, F controls – M controls).

– However; However; C/C genotype was C/C genotype was overrepresented in M patients than F overrepresented in M patients than F patients while T/C genotype was patients while T/C genotype was overrepresented in F patients than M overrepresented in F patients than M patientspatients (p=0.03). (p=0.03).

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For Phe658Phe polymorphismFor Phe658Phe polymorphism– There was a significant difference There was a significant difference

between the gentoypes of M patients between the gentoypes of M patients versus M controls (p=0.024):versus M controls (p=0.024):

The C/C genotype was The C/C genotype was overrepresented and the T/C overrepresented and the T/C genotype was less frequent in male genotype was less frequent in male patients than male controls.patients than male controls.

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For Gly489Ser polymorphism:For Gly489Ser polymorphism:– All of the patients and controls had All of the patients and controls had

G/G genotype. Therefore further G/G genotype. Therefore further statistical comparisons could not be statistical comparisons could not be made.made.

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Statistical comparisons between Statistical comparisons between the polysomnography findings and the polysomnography findings and genotypes:genotypes:– Ala20Val variants: the arousal index Ala20Val variants: the arousal index

of the M patients with C/C genotype of the M patients with C/C genotype were significantly higher than in the were significantly higher than in the patients with C/T genotype.patients with C/T genotype.

– Phe658Phe variants: The %total sleep Phe658Phe variants: The %total sleep time in stage I of the M patients with time in stage I of the M patients with T/T gentoype were significantly T/T gentoype were significantly higher than in the patients with T/C higher than in the patients with T/C genotype.genotype.

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Statistical comparisons between Statistical comparisons between the polysomnography findings the polysomnography findings and genotypes:and genotypes:– Ala20Val variants: The % total sleep Ala20Val variants: The % total sleep

time in stage II of the F patients with time in stage II of the F patients with C/C gentoype were significantly C/C gentoype were significantly higher than in the patients with C/T higher than in the patients with C/T gentoype.gentoype.

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DiscussionDiscussion

Hypoglossal motoneurons are Hypoglossal motoneurons are cholinergic elements that innervate cholinergic elements that innervate tongue muscles and are thus important tongue muscles and are thus important for functions such as swallowing, for functions such as swallowing, respiration, suckling and vocalization. respiration, suckling and vocalization.

Disorders of hypoglossal motoneurons Disorders of hypoglossal motoneurons appear to be implicated in OSAS.appear to be implicated in OSAS.

GABA is released within the hypoglossal GABA is released within the hypoglossal motor nucleus, with individual motor nucleus, with individual hypoglossal motoneurons containing hypoglossal motoneurons containing receptors for the neurotransmitter.receptors for the neurotransmitter.

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Under GABA derivatives, various Under GABA derivatives, various patients had a tendency towards an patients had a tendency towards an increase in total sleep duration and increase in total sleep duration and reduction in the number of reduction in the number of spontaneous wake-ups during night*spontaneous wake-ups during night*

In another study, GABA was shown to In another study, GABA was shown to induce a marked sedation and induce a marked sedation and potentiated nitrazepam**potentiated nitrazepam****Vlasov NA. Effect of gamma-aminobutyric acid derivatives Vlasov NA. Effect of gamma-aminobutyric acid derivatives on sleep disorders in neuroses. Biull Eksp Biol Med 1978; 85: on sleep disorders in neuroses. Biull Eksp Biol Med 1978; 85: 174-7 .174-7 .****Wambebe C. Influence of some GABAergic agents on Wambebe C. Influence of some GABAergic agents on nitrazepam-induced sleep in the domestic fowl (Gallus nitrazepam-induced sleep in the domestic fowl (Gallus domesticus). Jpn J Pharmacol 1983; 33: 1111-8.domesticus). Jpn J Pharmacol 1983; 33: 1111-8.

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The GABAThe GABABBR1 polymorphism may affect R1 polymorphism may affect EEG recording and be is one of the EEG recording and be is one of the important mediators invoved in sleep.important mediators invoved in sleep.

Reciprocal interactions occur between Reciprocal interactions occur between serotonin and GABAserotonin and GABABBR in CNS and R in CNS and serotonergic mechanisms appear to be serotonergic mechanisms appear to be associated with the occurrence of OSAS, associated with the occurrence of OSAS, especeially in M patients*especeially in M patients***YYıılmaz M, Bayazit YA, Ciftci TU, Erdal ME, Urhan M, lmaz M, Bayazit YA, Ciftci TU, Erdal ME, Urhan M, Kokturk O, Kemaloglu YK, Inal E. Association of serotonin Kokturk O, Kemaloglu YK, Inal E. Association of serotonin transporter gene polymorphism with obstructive sleep transporter gene polymorphism with obstructive sleep apnea syndrome. Laryngoscope 2005; 115: 832-6.apnea syndrome. Laryngoscope 2005; 115: 832-6.

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For Ala20Val variants:For Ala20Val variants:– There was no sigificant difference between There was no sigificant difference between

the genotypes and allele frequencies of the the genotypes and allele frequencies of the patients and controls. patients and controls.

– The T/T variant could not be found in both The T/T variant could not be found in both groups.groups.

– Gender specific comparisons did not reveal Gender specific comparisons did not reveal significant difference (F patients – F significant difference (F patients – F controls, M patients – M controls, F patients controls, M patients – M controls, F patients – M patients, F controls – M controls).– M patients, F controls – M controls).

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Ala20Val gene poymorphism is not Ala20Val gene poymorphism is not associated with the occurence of OSAS.associated with the occurence of OSAS.

These genetic variations may alter sleep These genetic variations may alter sleep efficiency. Some patients with OSAS are efficiency. Some patients with OSAS are aware of their symptoms like arousals at aware of their symptoms like arousals at night, decreased sleep efficiency and night, decreased sleep efficiency and day time sleepiness whereas some day time sleepiness whereas some others do not complain these symptoms others do not complain these symptoms despite abnormal polysomnography despite abnormal polysomnography results.results.

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For Gly489Ser polymorphism:For Gly489Ser polymorphism:– All of the patients and controls had All of the patients and controls had

G/G genotype, which may be G/G genotype, which may be representative for the population in representative for the population in this country. Since almost all this country. Since almost all population had the same genotype, population had the same genotype, it is plausible to say that the this it is plausible to say that the this polymorphism is not associated with polymorphism is not associated with occurrence of OSAS in this country.occurrence of OSAS in this country.

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For Phe658Phe polymorphism:For Phe658Phe polymorphism:– There was no significant difference There was no significant difference

between the genotypes and allele between the genotypes and allele frequencies of the patients and controls. frequencies of the patients and controls.

– Gender specific comparisons did not reveal Gender specific comparisons did not reveal significant difference (F patients – F significant difference (F patients – F controls, M patients – M controls, F patients controls, M patients – M controls, F patients – M patients, F controls – M controls).– M patients, F controls – M controls).

– However; However; C/C genotype was C/C genotype was overrepresented in M patients than F overrepresented in M patients than F patients while T/C genotype was patients while T/C genotype was overrepresented in F patients than M overrepresented in F patients than M patientspatients (p=0.03). (p=0.03).

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The Phe658Phe polymorphism is The Phe658Phe polymorphism is associated with occurrence of associated with occurrence of OSAS. OSAS.

Especially males with the C/C Especially males with the C/C genotype are highly likely to have genotype are highly likely to have OSAS.OSAS.

This gene polymorphism seems be This gene polymorphism seems be related to regulation of sleep in related to regulation of sleep in male OSAS patients.male OSAS patients.

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ConclusionConclusion

The Ala20Val polymorphism of GABAThe Ala20Val polymorphism of GABABBR1 R1 gene may be associated with gene may be associated with symptomatology in OSAS. symptomatology in OSAS.

The C/C variant of the Phe658Phe The C/C variant of the Phe658Phe polymorphism GABApolymorphism GABABBR1 gene seems R1 gene seems associated with occurrence and associated with occurrence and symptomatology of OSAS, especially in symptomatology of OSAS, especially in male patients. male patients.

Gly489Ser polymorphism does not seem Gly489Ser polymorphism does not seem to be involved in OSAS, especially in this to be involved in OSAS, especially in this country. country.