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Paper text:
although the pathogenesis of menire 's disease remains unknown it is likely to be multifactorial .
a candidate is the gene encoding aquaporin 5 ( aqp5 ) as aquaporins play an important role in maintaining inner ear fluid homeostasis .
furthermore , aqp5 is preferentially localized within the external sulcus cells and the spiral prominence of the cochlea implying a physiological role of aqp5 in auditory function [ 1 , 2 ] . following sequencing of the aqp5 promoter region of 50 healthy white caucasians
we have described a novel , functional , and common single nucleotide ( -1364a / c ) polymorphism .
substitution of c for a at position -1364 was associated with increased binding of transcription factors , as shown for nuclear extracts from hela cells , but reduced transcriptional activation of the aqp5 gene in response to serum and camp .
this latter finding is of special interest since stimulation of the vasopressin v2-receptor by arginine - vasopressin ( adh ) results in increased aqp5 mrna concentrations and increased translocation of aqp5 to the plasma membrane .
this is mediated via an increase in camp concentration and subsequent activation of the protein kinase a pathway .
thus , the c - allele may facilitate the binding of an inhibitory transcription factor .
these results were corroborated by showing that the c - allele was associated with decreased aqp5 mrna transcripts in human right atrial muscle and decreased aqp protein expression in red cell membranes .
furthermore , the c - allele was associated with suppression of the renin - angiotensin - aldosterone system ( raas ) in response to a high salt diet , while the raas suppression in individuals carrying the aa genotype was significantly blunted .
thus , there are good reasons to hypothesize that the aqp5 promoter polymorphism could impact upon key mechanisms of md .
accordingly , we tested the hypothesis that genotypes of the -1364a / c aqp5 promoter polymorphism are associated with an increased risk for md , fmd , or eh .
after approval by the local ethics committee and written informed consent data and blood samples from 102 caucasian patients with menire 's disease ( grade 14 according to aao - hns guidelines ) were included into the study cohort ( 62 females , 40 males ; mean age : 59.1 years 14.3 ( max 96 , min 25 ) , see table 1 ) ) .
the dna of 102 patients , 39 with menire 's disease ( md ) , 54 with familial menire 's disease ( fmd ) , and 9 with endolymphatic hydrops ( eh ) was genotyped for the aqp5 promoter-1364a / c polymorphism
. familial menire 's disease ( fmd ) was assumed when two or more family members were affected by menire 's disease .
endolymphatic hydrops ( eh ) was defined as fluctuating low - tone hearing loss with no signs of vestibular affection .
the group consisted of patients referred to the department for diagnosis and/or therapy of menire 's disease or endolymphatic hydrops by smaller departments or local ent colleagues .
as patients were usually referred to the department when standard conservative treatment was not successful , the groups of patients with grade 2 ( n = 27 ) and grade 3 ( n = 53 ) disease are the largest of our cohorts ( see table 2(b ) ) .
the control cohort consisted of 292 randomly chosen healthy white , caucasian blood donors ( age : 56.7 years  4.1 ) of either gender ( 110 female , 182 male ) who were recruited at the local department for transfusion medicine , university hospital essen .
dna was extracted from whole blood using the qiaamp kit ( qiagen , hilden , germany ) . for genotyping the aqp5
promotor-1364 a / c polymorphism by pyrosequencing , pcr was performed with the forward primer aqp5-se 5-gaaactgcaggatgagagaaat-3 , and the biotinylated reverse primer aqp5-as 5-tctctgttctccacctctcca-3 resulting in a 120  nt fragment .
after denaturation at 94c , 40 cycles of dna amplification were done using taq pcr mastermix ( eppendorf , hamburg , germany ) at 94c for 40  s , 53c for 40  s , and 72c for 40  s. the biotinylated strand was captured on streptavidin sepharose beads and annealed with a sequencing primer aqp5-seq 5-cagagagactaagacagca-3. pyrosequencing was performed using psq hs 96 gold snp reagents and the psq hs 96 ( biotage , uppsala , schweden ) .
all statistical analyses were done using spss 11.0 ( spss , chicago , il , usa ) .
the hardy - weinberg equilibrium was tested by a goodness - of - fit -test .
the -test was applied to compare genotype distributions and allele frequencies between patients and controls .
genotype frequencies were not different between controls ( aa : 69% , ac : 30% , and cc : 1% ) and patients with md aa : 65.7% ( 23 md , 37 fmd , and 8 ed ) ; ac = 23.5% ( 12 md , 11 fmd , and 1 ed ) ; cc = 3.9% ( 1 md , 3 fmd ) ( table 2(a ) ) .
subgroup analysis , however , revealed the cc genotype to be more frequent in patients with fmd than in controls ( p = 0.042 ) .
however , neither the a - allele nor the c - allele was associated with fmd or md .  
allergies , metabolic disorders ( diabetes mellitus , impairment of cholesterol metabolism ) , hypertension , and depression were significantly more frequent in the group of patients with md than in patients with fmd . however , there was no significant association between these disorders and specific genotypes of the aqp5 promoter polymorphism in these patients . additionally , severity of md was not associated with the aqp5 promoter-1364a / c polymorphism , as depicted in table 2(b ) .
however , this calculation has to be interpreted carefully as the different grades are only a  snapshot  in the course of disease in patients presenting for diagnosis or therapy .
the present investigation suggests for the first time that genotypes of the -1364a / c aqp5 promoter polymorphism are neither associated with the incidence nor the severity of md , fmd , or eh .
although the cc genotype was more frequent in patients with fmd than in controls ( p = 0.042 ) , we believe that this association is fortuitous because neither the a - allele nor the c - allele was associated with fmd or md .  
comorbidities such as allergies , metabolic disorders , hypertension , and depression were more frequent in patients with md than in those with fmd .
with regard to the relatively small number of patients in each group these results have to be interpreted carefully . however , it is well known that depression and allergies might act as cofactors or so - called  triggers  evoking menire attacks [ 8 , 9 ] .   the preferential presence of aqp5 within the external sulcus cells and the spiral prominence of the cochlea implies a physiological role of aqp5 in auditory cell function and inner ear water homeostasis [ 1 , 2 ] and the -1364a / c aquaporin 5 gene promoter polymorphism impacts upon aqp5 expression in different cohorts
. nevertheless , the -1364a / c aquaporin 5 gene promoter polymorphism was not associated with the incidence of md , fmd , or eh .
we speculate , therefore , that aqp5 expression in the apical turns of the cochlea only may play a limited role in inner ear fluid homeostasis in patients with menire 's disease .  
this speculation is supported by observations of klar et al . who defined a new candidate region for an increased risk for fmd on chromosome 12 .
although this region on chromosome 12p12 is close to the aqp 2 , 5 , and 6 loci , there was no overlapping or linkage disequilibrium between these loci .
reported normal hearing in aqp5 knockout mice and suggested redundant or alternative mechanisms for regulation of water homeostasis in the inner ear .  
however , according to the findings of hirt and coworkers , there should be further attention paid to the special differential localization and role of aqp5 and aqp 4 in the outer sulcus cells , as it suggests a possible water shunt in the perilymph  endolymph barrier which could have an impact on dysfunctional water regulation such as endolymphatic hydrops or sensorinureal hearing loss .   limitations of this report should be mentioned .
the study population was relatively small and it was hardly possible to build matched pairs as far as comorbidities and age are concerned .
different selection criteria of blood donors and an unrecognized selection bias , inherent to many genetic association studies , can not be excluded , too .
however , the low incidence of md , fmd , and eh in the general population suggests an interaction of extrinsic ( e.g. , allergies , inflammation , metabolic and endocrinological disorders , trauma , and migraine ) , genetic , and developmental intrinsic factors .
this investigation represents a further step towards identifying candidate genes which could impact on the onset or severity of md and eh .
however , in this survey on caucasians neither comorbidities nor the aqp5 polymorphism was associated with the incidence or severity of md , fmd , or eh .
objective . 
 aquaporin 5 plays an important role in maintaining inner ear water and fluid homeostasis . 
 since the aquaporin ( aqp ) 5 promoter-1364a / c polymorphism is associated with altered aqp5 expression and this could impact upon key mechanisms of menire 's disease , we tested the hypothesis that genotypes of the aqp5 promoter-1364a / c polymorphism are associated with the incidences of menire 's disease ( md ) , familial menire 's disease ( fmd ) , or endolymphatic hydrops ( eh ) . 
 methods . with approval of the local ethics committee , 
 dna of 102 patients ( 39 with md , 54 with fmd , and 9 with eh ) and of 292-matched caucasian controls was isolated from blood samples and genotyped for the aqp 5 promoter-1364a / c polymorphism . 
 the 2-test was applied to compare genotype distributions and allele frequencies between patients and controls . 
 results . 
 overall , genotype frequencies were not different between controls ( aa 69% , ac 30% , cc 1% ) and patients with md aa : 65.7% ( 23 md , 37 fmd , and 8 eh ) ; ac : 23.5% ( 12 md , 11 fmd , and 1 eh ) ; cc : 3.9% ( 1 md , 3 fmd , and 0 eh ) . however , subgroup analysis revealed the cc genotype to be more frequent in patients with fmd ( 5.9% ) than in healthy controls ( 1% ) ( p = 0.042 ) . 
 conclusions . 
 overall , genotypes of the -1364a / c aqp5 gene polymorphism are not associated with a significant increased risk for menire 's disease .