exercise has beneficial effects on human body organs ( kim , 2014 ; kim et al . , 2004 ) .
lifestyle factors , including body mass index ( bmi ) and physical activity ( lee et al . , 2014 ; marshall et al . , 2014 ) , are associated with lower urinary tract symptoms ( luts ) or benign prostate hyperplasia ( bph ) of aged men , and it has been reported that increased physical activities tend to exert a protective role on prostate against the development of bph ( barnard et al . , 2008 ; lee et al . , 2014 ; sea et al . , 2009 ) .
moreover , there are evidences suggest that increased physical activities may elicit apoptosis in cancer cells ( bartlett et al . , 2014 ; ergun et al . , 2013 ;
2008 ) , and such effects have also been shown in prostate cells ( barnard et al . , 2008 ; meyer et al . , 2013
; teixeira et al . , 2012 ; zheng et al . , 2012 ) .
cellular pathways of apoptosis may be affected by the bh3 interacting domain death agonist ( bid ) gene , because which is involved in the control of apoptosis by activation of caspase-8 .
caspase-8 has been intensively studied in the cancer cells ( liu et al . , 2014 ; sharifi et al . ,
2014 ) , as it is related to the cell cycle and apoptosis ( bissoyi et al . , 2014
; wei et al . , 2013 ) which are directly related to modulation of cellular proliferative diseases .
caspase-8 pathway includes bax , a death agonist , and bcl2 , a death antagonist . and bid may heterodimerize with bax or bcl2 , to activate apoptosis ( wang et al . , 1996 ) .
the bid gene polymorphisms may affect the development of immunoglobulin a nephropathy ( park et al .
, 2014 ) , and ossification of the posterior longitudinal ligament ( chon et al . ,
moreover , bid expression is related to cellular reaction to cholesterol oxidation ( jung et al . , 2014 ) ,
insulin resistance ( alkhouri et al . , 2010 ) , effect of fty720 to chronic myelogenous leukemia cells ( kiyota et al . ,
2013 ) , and interestingly , polymorphism of bid may be related to breast cancer ( gaudet et al . , 2009 ) .
among them , cholesterol metabolism and glucose intolerance have been known to be closely associated with bph ( vignozzi et al . , 2013 ) , and
the relation to breast cancer suggests that bid may modulate the sex hormone affected cell proliferation ( gaudet et al . , 2009 ) . however , there was no study reported whether there is association of bid polymorphism and bph development in human
. therefore , in this study , we investigated the relationship between bid single nucleotide polymorphisms ( snps ) and bph in a korean population .
two - hundred and 22 bph patients ( mean age 65.5 + 10.3 yr ) ( table 1 ) were recruited from kyung hee medical center .
the lower urinary tract symptoms ( luts ) of bph patients were scaled using the international prostate symptom score ( ipss ) .
any patients with urinary tract infections , prostate cancer , a neurogenic bladder , uncontrolled diabetes mellitus , and/or cardiovascular diseases were not included in this study . in the analysis of clinical features , bph patients were divided into groups based on the following features : prostate volume ( cutoff at 30 ml ) and ipss ( cutoff at 20 ) .
the controls were 214 aged male ( mean age 61.98.2 yr ) without any of severe diseases mentioned above .
the ethics review committee of medical research institute , kyung hee university school of medicine , seoul , korea has admitted the ethical approval of this study .
we selected 2 snps in bid : rs8190315 ( ser56gly ) , and rs 2072392 ( asp106asp ) .
they were searched from the snp database in ncbi ( http://www.ncbi.nlm.nih.gov/snp ) , and reviewed to select the region in exons and near exons . additionally , the two snps were previously studied polymorphism of bid in the korean population ( chon et al . , 2014 ; park et al . ,
peripheral blood of all patients were sampled in ethylenediaminetetraacetic acid blood tube , stored in 20c freezer before the extraction of genomic dna .
genomic dna was extracted with qiaamp dna extraction kit ( qiagen , valencia , ca , usa ) . in the amplification of dna , polymerase chain reactions ( pcrs ) using the following primers for each snps
was performed : rs8190315 ( sense , 5-acagggtccctcagctctctgg-3 ; antisense , 5-gccta cctgcctctattcttcc-3 , 340 bp ) and rs2072392 ( sense , 5-ggatgagtgcatcacaaaccta-3 ; antisense , 5-agcactggagggaatcaagtag-3 , 367 bp ) .
direct sequencing was done with abi prism 3730xl analyzer ( pe applied biosystems , foster city , ca , usa ) and analyzed with seqmanii software ( dnastar , madison , wi , usa ) . in the analysis of genotypes and allele frequencies , snpstats ( http://bioinfo.iconcologia.net/index.php?module=snpstats ) and spss 20.0 ( spss inc . ,
chicago , il , usa ) were used to obtain odds ratios ( ors ) , 95% confidence intervals ( cis ) , and p - values of multiple logistic regression models .
each component of the model was : codominant1 ( major allele homozygotes vs heterozygotes ) , codominant2 ( major allele homozygotes vs minor allele homozygotes ) , dominant ( major allele homozygotes vs heterozygotes+minor allele homozygotes ) , recessive ( major allele homozygotes+heterozygotes vs minor allele homozygotes ) , and log - additive ( major allele homozygotes vs heterozygotes vs minor allele homozygotes ) ( kim et al . , 2013 ) .
the linkage disequilibrium ( ld ) block and haplotypes between pairs of snps were tested with haploview 4.2 software ( daly lab , cambridge , ma , usa ) . significant level of p - value was regarded at < 0.05 .
two - hundred and 22 bph patients ( mean age 65.5 + 10.3 yr ) ( table 1 ) were recruited from kyung hee medical center .
the lower urinary tract symptoms ( luts ) of bph patients were scaled using the international prostate symptom score ( ipss ) .
any patients with urinary tract infections , prostate cancer , a neurogenic bladder , uncontrolled diabetes mellitus , and/or cardiovascular diseases were not included in this study . in the analysis of clinical features , bph patients were divided into groups based on the following features : prostate volume ( cutoff at 30 ml ) and ipss ( cutoff at 20 ) .
the controls were 214 aged male ( mean age 61.98.2 yr ) without any of severe diseases mentioned above .
the ethics review committee of medical research institute , kyung hee university school of medicine , seoul , korea has admitted the ethical approval of this study .
we selected 2 snps in bid : rs8190315 ( ser56gly ) , and rs 2072392 ( asp106asp ) .
they were searched from the snp database in ncbi ( http://www.ncbi.nlm.nih.gov/snp ) , and reviewed to select the region in exons and near exons . additionally , the two snps were previously studied polymorphism of bid in the korean population ( chon et al . , 2014 ; park et al . , 2014 )
peripheral blood of all patients were sampled in ethylenediaminetetraacetic acid blood tube , stored in 20c freezer before the extraction of genomic dna .
genomic dna was extracted with qiaamp dna extraction kit ( qiagen , valencia , ca , usa ) . in the amplification of dna , polymerase chain reactions ( pcrs ) using the following primers for each snps
was performed : rs8190315 ( sense , 5-acagggtccctcagctctctgg-3 ; antisense , 5-gccta cctgcctctattcttcc-3 , 340 bp ) and rs2072392 ( sense , 5-ggatgagtgcatcacaaaccta-3 ; antisense , 5-agcactggagggaatcaagtag-3 , 367 bp ) .
direct sequencing was done with abi prism 3730xl analyzer ( pe applied biosystems , foster city , ca , usa ) and analyzed with seqmanii software ( dnastar , madison , wi , usa ) .
in the analysis of genotypes and allele frequencies , snpstats ( http://bioinfo.iconcologia.net/index.php?module=snpstats ) and spss 20.0 ( spss inc . , chicago , il , usa ) were used to obtain odds ratios ( ors ) , 95% confidence intervals ( cis ) , and p - values of multiple logistic regression models .
each component of the model was : codominant1 ( major allele homozygotes vs heterozygotes ) , codominant2 ( major allele homozygotes vs minor allele homozygotes ) , dominant ( major allele homozygotes vs heterozygotes+minor allele homozygotes ) , recessive ( major allele homozygotes+heterozygotes vs minor allele homozygotes ) , and log - additive ( major allele homozygotes vs heterozygotes vs minor allele homozygotes ) ( kim et al . , 2013 ) .
the linkage disequilibrium ( ld ) block and haplotypes between pairs of snps were tested with haploview 4.2 software ( daly lab , cambridge , ma , usa ) . significant level of p - value was regarded at < 0.05 .
the frequencies of genotype and allele of two bid snps in control and patients with bph were displayed in the table 2 , however , there was no significant association between the snps and bph development .
the hardy - weinberg equilibrium p - value of the snps were > 0.05 ( data not shown ) .
the genotypes and allele distributions of bid snps in the groups divided based on prostate volume are shown in table 3 .
the allele frequencies of rs8190315 were associated with increased volume of prostate in bph patients { odd ratio ( or)=1.90 , 95% confidence interval ( ci)=1.073.41 , p=0.03 } , showing about 1.8-fold increase of minor allele in the bph group ( 16.5% ) compared to controls ( 9.4% ) .
the genotypes of rs8190315 were also associated with increased prostate volume in dominant model ( or=1.94 , 95% ci=1.013.74 , p=0.42 ) . and
the genotype of rs2072392 were associated with increased prostate volume in dominant model ( or=1.94 , 95% ci=1.013.74 , p=0.42 ) , however , the allele frequencies of rs2072392 were not associated with prostate volume in bph patients .
the genotypes and allele distributions of bid snps in the groups divided based on ipss are shown in table 4 , however , there was no significant association between the snps and ipss of the bph patients .
in our study result , bid snps were not associated with development of bph , however , prostate volume of bph patients were associated with bid snps .
rs8190315 was associated with the risk of breast cancer in european woman ( gaudet et al . , 2009 ) , meanwhile , rs8190315 and rs2072392 were associated with the proteinuria levels of igan patients ( park et al . , 2014 ) , and risk of developing opll in korean population ( chon et al . , 2014 ) .
maf of rs8190315 were 0.018 in european , 0.062 in sub - saharan african , 0.128 in han chinese , and 0.106 in japanese ; maf of rs2072392 were 0.008 in european , 0.075 in sub - saharan african , 0.122 in han chinese , and 0.125 in japanese .
there are more than five - fold to ten - fold differences between mafs of rs8190315 and rs2072392 in european and asian populations , and it may contributed to the diversion of results
. results of this study accord to previous studies performed in korean population , that the both of rs8190315 and rs2072392 may affect the volume of enlarged prostate in bph patients .
previous reports suggest that , hyperplasia of the prostate may be affected by modulation of stress by cholesterol oxidation ( vignozzi et al . ,
2013 ) , because oxidized low - density lipoprotein ( ldl ) may cause decreased apoptosis in progressing bph lesions ( gonzalez - chavarria et al . , 2014 ; lin et al . ,
( pace et al . , 2010 ) is on the contrary that oxidized ldl was not correlated with bph .
additionally , regarding the role of bid , variation in bid may have contributed to alteration in apoptosis pathways ( asmarinah et al . , 2014 ) .
although there was no reported direct relationship between bph and bid , however , bph and prostate cancer have similarity that testosterone drives cellular hyperplasia in both diseases ( negri et al . , 2005 ) , and activation of bid was associated with apoptosis of androgen - stimulated prostatic cells ( deeb et al . , 2003 ; goldberg et al . , 2013 ;
our study results may partially accord with those previous studies . in summary , we suggest that rs8190315 and rs2072392 of bid may contribute to the disease severity of bph .
regarding the role of bid in modulating apoptotic signal in metabolic syndrome or dyslipidemia , this study result may intensify the role of physical activity in preventing bph .
our study has some limitations , such as only small population of korean was analyzed .
 exercise has beneficial effect on cancer apoptosis and benign prostatic hyperplasia ( bph ) . 
 the bh3 interacting domain death agonist ( bid ) gene expression is associated with apoptosis or cell proliferation . in this study , we investigated the association between bid single nucleotide polymorphisms ( snps ) and the development , prostate volume , and international prostate symptom score ( ipss ) of bph . in 222 bph males and 214 controls , 
 two snps in bid [ rs8190315 ( ser56gly ) , and rs2072392 ( asp106asp ) ] were genotyped and analyzed using multiple logistic regression models . in the result , 
 the genotype and allele frequencies of rs8190315 and rs2072392 were not associated with bph development or ipss , however , the allele frequencies [ odd ratio ( or)= 1.90 , 95% confidence interval ( ci)= 1.073.41 , p= 0.03 ] and genotype frequencies ( in dominant model , or= 1.94 , 95% ci= 1.013.74 , p= 0.42 ) of rs8190315 , and the genotype frequencies of rs2072392 ( in dominant model , or= 1.94 , 95% ci= 1.013.74 , p= 0.42 ) were associated with increased prostate volume . 
 we propose that rs8190315 and rs2072392 of bid may contribute to the disease severity of bph . 
INTRODUCTION
MATERIALS AND METHODS
Study subjects
SNP selection and genotyping
Statistical analysis
RESULTS
DISCUSSION