elevated serum uric acid levels are associated with a variety of adverse health outcomes , including gout , hypertension , diabetes mellitus , metabolic syndrome , and cardiovascular diseases .
several genome - wide association studies ( gwass ) have identified genes that may be causally associated with uric acid levels , including the atp - binding cassette , subfamily g , member 2 ( abcg2 ) gene ( mim 603756 ) [ 2 , 3 , 4 , 5 , 6 , 7 ] .
replication studies of abcg2 variants have been performed in western and asian countries [ 8 , 9 ] .
identified a significant association between the rs2725220 single - nucleotide polymorphism ( snp ) on chromosome 4q22 and uric acid levels .
the abcg2 protein is a high - capacity transporter for uric acid excretion in the kidney , liver , and gut [ 10 , 11 ] . in this study
, we analyzed the relationship between uric acid levels and the abcg2 snp rs2725220 using a group of volunteers from the korean metabolic syndrome research initiative study in seoul .
we also analyzed the association of the abcg2 snp with body mass index and waist circumference levels .
subjects for the gwas were recruited from the korean metabolic syndrome research initiative study in seoul city , which was initiated in december 2005 .
a total of 9,128 individuals were recruited in 2006 , and an additional 17,569 individuals were recruited in 2007 [ 12 , 13 , 14 ] .
volunteers from the first round underwent routine health examinations at the health promotion centers in university hospitals between january 2006 and december 2007 . from this
the subject characteristics were described in a previous study . in brief , of the 6,563 individuals whose adiponectin was measured , 1,004 individuals were genotyped .
the 1,004 subjects were all healthy individuals and were not undergoing any treatment for hyperuricemia .
the institutional review board of human research of yonsei university approved the protocols of this study , and written informed consent was obtained from all subjects prior to enrollment .
participants were interviewed using a structured questionnaire to collect a personal history of cigarette smoking ( never smoked , ex - smoker , or current smoker ) and demographic characteristics ( age , gender , etc . ) .
waist circumference was measured midway between the lower rib and iliac crest . for measurements of weight and height ,
body mass indices were calculated as the subject 's weight ( kg ) divided by the square of the subject 's height ( m ) . for clinical chemistry assays ,
serum was separated from peripheral venous blood samples obtained from each participant after a 12-hour fast and stored at -70. biomarkers of metabolic syndrome , including fasting blood glucose , total cholesterol , triglycerides , and high - density lipoprotein cholesterol , and uric acid levels were measured .
quality control of the data was conducted in accordance with the procedures recommended by the korean association of laboratory quality control .
samples from the seoul city cohort were genotyped on the affymetrix genome - wide human snp array 5.0 ( affymetrix inc . ,
santa clara , ca , usa ) at dnalink . for the data obtained from this chip , internal quality control ( qc ) measures
were used : the qc call rate ( dynamic model algorithm ) always exceeded 86% .
ten of the 1,004 individuals were removed due to low genotyping call rates ( < 95% ) .
three individuals were excluded due to failed genotyping of rs2725220 , leaving a total of 991 individuals for the study .
most statistical analyses were performed using plink and sas ( version 9.2 ; sas institute , cary , nc , usa ) .
the abcg2 gene snp rs2725220 was selected using the affymetrix genomewide human snp array 5.0 .
each snp was tested for possible effects on uric acid levels under an additive model .
the multivariate linear regression models used in the study incorporated covariates ( age and sex ) .
odds ratios ( ors ) with 95% confidence intervals ( cis ) were calculated to examine the association of the abcg2 snp with abnormal uric acid levels ( 7 mg / dl for men and 6 mg / dl for women ) .
all statistical tests were two - sided , and the statistical significance was determined as p < 0.05 .
subjects for the gwas were recruited from the korean metabolic syndrome research initiative study in seoul city , which was initiated in december 2005 .
a total of 9,128 individuals were recruited in 2006 , and an additional 17,569 individuals were recruited in 2007 [ 12 , 13 , 14 ] .
volunteers from the first round underwent routine health examinations at the health promotion centers in university hospitals between january 2006 and december 2007 . from this
the subject characteristics were described in a previous study . in brief , of the 6,563 individuals whose adiponectin was measured , 1,004 individuals were genotyped .
the 1,004 subjects were all healthy individuals and were not undergoing any treatment for hyperuricemia .
the institutional review board of human research of yonsei university approved the protocols of this study , and written informed consent was obtained from all subjects prior to enrollment .
participants were interviewed using a structured questionnaire to collect a personal history of cigarette smoking ( never smoked , ex - smoker , or current smoker ) and demographic characteristics ( age , gender , etc . ) .
waist circumference was measured midway between the lower rib and iliac crest . for measurements of weight and height ,
body mass indices were calculated as the subject 's weight ( kg ) divided by the square of the subject 's height ( m ) . for clinical chemistry assays , serum was separated from peripheral venous blood samples obtained from each participant after a 12-hour fast and stored at -70. biomarkers of metabolic syndrome , including fasting blood glucose , total cholesterol , triglycerides , and high - density lipoprotein cholesterol , and uric acid levels were measured .
quality control of the data was conducted in accordance with the procedures recommended by the korean association of laboratory quality control .
samples from the seoul city cohort were genotyped on the affymetrix genome - wide human snp array 5.0 ( affymetrix inc . , santa clara , ca , usa ) at dnalink . for
the data obtained from this chip , internal quality control ( qc ) measures were used : the qc call rate ( dynamic model algorithm ) always exceeded 86% .
ten of the 1,004 individuals were removed due to low genotyping call rates ( < 95% ) .
three individuals were excluded due to failed genotyping of rs2725220 , leaving a total of 991 individuals for the study .
most statistical analyses were performed using plink and sas ( version 9.2 ; sas institute , cary , nc , usa ) .
the abcg2 gene snp rs2725220 was selected using the affymetrix genomewide human snp array 5.0 .
each snp was tested for possible effects on uric acid levels under an additive model .
the multivariate linear regression models used in the study incorporated covariates ( age and sex ) .
odds ratios ( ors ) with 95% confidence intervals ( cis ) were calculated to examine the association of the abcg2 snp with abnormal uric acid levels ( 7 mg / dl for men and 6 mg / dl for women ) .
all statistical tests were two - sided , and the statistical significance was determined as p < 0.05 .
the majority of individuals in this study was middle - aged ( table 1 ) .
mean levels of uric acid in the dataset were higher in males ( 6.23 mg / dl ) than in females ( 4.21 mg / dl ) .
the percentage of individuals with abnormal uric acid levels ( 7.0 mg / dl ) was 14.7% for the seoul city sample .
the percentage of current smokers in the seoul city dataset was 46.4% among male subjects and 3.9% among female subjects .
table 2 shows the p - values from a linear regression model for uric acid levels in the cohort sample , with age and sex included as covariates in the model .
the rs2725220 snp in the abcg2 gene was found to be associated with mean uric acid levels ( effect per allele 0.25 mg / dl , p < 0.0001 ) , which was significant after bonferroni correction ( p = 0.00025 ) .
the minor allele frequency of rs2725220 was 0.222 , and hardy - weinberg equilibrium was satisfied ( p = 0.7079 ) .
we also analyzed the association of rs2725220 with abnormal uric acid levels ( table 3 ) .
subjects with the gc / cc genotype had a 1.78-fold ( range , 1.22- to 2.62-fold ) higher risk of having abnormal uric acid levels ( 7.0 mg / dl ) than subjects with the gg genotype . when analyzed by gender , the association with abcg2 was stronger in men than in women . in table 4 , we analyzed the association of abcg2 by body mass index ( bmi ) quartile levels and waist circumference quartile levels in male subjects .
the association with abcg2 was much stronger in male subjects with bmi  26.4 ( or , 5.09 ; 95% ci , 2.41 to 10.8 ) than in male subjects with bmi < 26.4 .
the association with abcg2 was also a little bit stronger in male subjects with waist circumference ( wc )  91 ( or , 2.10 ; 95% ci , 1.08 to 4.10 ) than in male subjects with wc < 91 .
in a cohort study of 991 subjects , an abcg2 gene snp was associated with increased uric acid , consistent with previous studies .
several gwass have reported that abcg2 exerts a major influence on uric acid levels [ 2 , 3 , 6 , 7 ] .
conducted a genomewide study in which an snp in the abcg2 gene , rs2231142 , displayed strong evidence of an association with uric acid levels ( p < 10 ) .
another gwas also reported that rs2231142 showed a strong association with uric acid levels ( p = 5.1  10 ) .
more recently , a gwas in european - american obesity cases and controls reported significant genome - wide association of two snps with uric acid levels : rs2622605 and rs1481017 .
another recent gwas also reported a strong association between rs2231142 and uric acid levels ( p = 3.34.1  10 ) . in the present study , rs2725220 was found to have a strong association with uric acid levels . in agreement with these findings
, a recent study reported that rs2725220 was strongly associated with uric acid levels ( effect per allele -0.135 mg / dl , p = 4.2  10 ) .
several recent studies reported that the association between serum uric acid and the allelic effects of snps in abcg2 was sex - specific [ 8 , 9 ] . in a recent study of 4 us populations ,
the association between rs2231142 and serum uric acid was significantly stronger in men and postmenopausal women compared to their premenopausal counterparts . in the present study , the association of the abcg2 gene snp with uric acid was stronger in men than in women .
a modification of the effect of the associations between abcg2 snps and serum uric acid concentrations by interactions with obesity has been reported [ 3 , 9 ] . in a recent study of 4 us populations ,
the association between rs2231142 and serum uric acid was stronger in normal - weight subjects than in obese subjects .
in the present study , we also examined the association of the abcg2 snp with uric acid levels according to bmi level and waist circumference .
the association was stronger in subjects with a high bmi and high wc levels than in subjects with a low bmi and low wc levels .
the abcg2 gene encodes a membrane transporter belonging to the atp - binding cassette superfamily of membrane transporters , a group involved in the trafficking of biological molecules across cell membranes .
. allikmets et al .   mapped the abcg2 gene to human chromosome 4q22 using radiation hybrid analysis .
we estimated the identity by state over all snps , and only four individuals were shown to be biological relatives .
genetic studies in asian populations may not identify the same set of genes as those in european populations .
nevertheless , the seoul city cohort study in korean populations indicates that the abcg2 gene on chromosome 4 is associated with serum uric acid levels , as is the case in several other populations .
 elevated serum uric acid levels are associated with a variety of adverse health outcomes , including gout , hypertension , diabetes mellitus , metabolic syndrome , and cardiovascular diseases . 
 several genome - wide association studies on uric acid levels have implicated the atp - binding cassette , subfamily g , member 2 ( abcg2 ) gene as being possibly causal . 
 we investigated an association between the single - nucleotide polymorphism ( snp ) rs2725220 in the abcg2 gene and uric acid levels in the korean population . 
 a total of 991 subjects in seoul city were used for a replication study with abcg2 snp rs2725220 . 
 the rs2725220 snp in the abcg2 gene was associated with mean uric acid levels ( effect per allele 0.25 mg / dl , p < 0.0001 ) . 
 subjects with the gc / cc genotype had a 1.78-fold ( range , 1.22- to 2.62-fold ) higher risk of having abnormal uric acid levels ( 7.0 mg / dl ) than subjects with the gg genotype . when analyzed by gender , the association with abcg2 was stronger in men than in women . 
 the association with abcg2 was much stronger in male subjects with body mass index ( bmi )  26.4 ( odds ratio , 5.09 ; 95% confidence interval , 2.41 to 10.8 ) than in male subjects with bmi < 26.4 . 
 this study clearly demonstrates that genetic variations in abcg2 influence uric acid levels in korean adults . 