some studies have shown that elevated triglyceride ( tg ) levels and low levels of high - density lipoprotein cholesterol ( hdl - c ) accelerate the pathogenesis of type 2 diabetes. recently , several studies have investigated the potential effect of genetic factors associated with risk of type 2 diabetes on plasma lipid levels . analyzed the association of polymorphisms in the glucokinase ( hexokinase 4 ) regulator ( gckr ) gene with type 2 diabetes in a case - control study and with fasting blood glucose and tg levels in the general population . the a allele of snp rs780094 was found to be associated with reduced risk of type 2 diabetes and lower levels of fasting plasma glucose , but higher levels of tg , in a japanese population . in the study reported by chen et al . , the authors found that subjects with minor alleles of snps rs2283228 and rs2237892 in the kqt - like subfamily member 1 ( kcnq1 ) gene , which were associated with type 2 diabetes , had higher levels of tg . this evidence suggests that genetic variants associated with diabetes risk may also be potential genetic determinants of plasma lipid levels . a genome - wide association study ( gwas ) conducted in a french case - control study identified a novel type 2 diabetes susceptibility locus on chromosome 10q23.33 , which is located in a gene cluster including an insulin - degrading enzyme ( ide ) , a kinesin - interacting factor 11 ( kif11 ) , and a hematopoietically expressed homeobox protein ( hhex ) . following this discovery , several studies have confirmed this association in british , finnish , japanese , and chinese populations. recently , we have also found that snps rs7923837 and rs1111875 in the ide - kif11-hhex locus at 10q23.33 were independently associated with risk of type 2 diabetes in a chinese population . however , the relationship between ide - kif11-hhex locus and lipid traits in different populations is not clear . therefore , in an effort to evaluate the influence of the polymorphisms in ide - kif11-hhex locus on plasma lipid concentrations , we performed a fine - mapping study by genotyping seven tagging snps at 10q23.33 in 3,281 han chinese subjects to examine the associations of these variants with plasma levels of total cholesterol ( tc ) , tg , hdl - c and low density lipoprotein cholesterol ( ldl - c ) . the subjects in the current study were selected from a community - based non - communicable diseases screening program comprised of more than 50,000 participants in jiangsu province during 2004 and 2008 . subjects were excluded from the study if they had a history of diabetes , hypertension , coronary heart disease or cancer , or fasting plasma glucose  5.6 mmol / l . after providing informed consent , all subjects were interviewed face - to - face using a standard questionnaire that included demographic characteristics , risk factors and disease history . subjects who smoked 1 cigarette per day for over 1 year were defined as smokers , and those who consumed 3 or more alcohol drinks a week for over 6 months were considered as alcohol drinkers . physical examinations , including measurements of height , weight and blood pressure , as well as laboratory tests to measure tc , tg , hdl - c and fasting plasma glucose concentrations , were performed for each participant . sitting blood pressure body mass index ( bmi ) was calculated as weight ( in kilograms ) divided by the square of height ( in meters ) . fasting blood samples for routine laboratory examinations were obtained in the early morning after an overnight fast . all biochemical parameters were measured enzymatically on an auto - analyzer ( hitachi 7180 biochemistry auto - analyzer , japan ) according to the manufacturer 's instructions . for subjects with tg levels < 4.52 mmol / l , ldl - c levels were estimated indirectly using the friedewald 's formula . the institutional review board of nanjing medical university approved the study . based on our previous study , we used a block - based tagging strategy to select tagging snps using haploview 4.2 software according to the hapmap database[http://www.hapmap.org/ , phaseii nov08 , on ncbi b36 assembly , dbsnpb126 ; population : han chinese population ( chb ) and japanese population ( jpt ) ] . the criteria included snps with minor allele frequency ( maf )  0.10 , hardy - weinberg equilibrium p  0.05 and call rate  95% when using pairwise linkage disequilibrium ( r ) of 0.8 as the threshold for each block . seven tagging snps ( rs7923837 , rs2488075 , rs947591 , rs11187146 , rs5015480 , rs4646957 and rs1111875 ) associated with type 2 diabetes in the ide - kif11-hhex locus at 10q23.33 were included in the current study . genomic dna was isolated from leucocytes of venous blood by proteinase k digestion and phenol / chloroform extraction . genotyping was performed using the taqman openarray genotyping system ( life technologies , carlsbad , ca , usa ) and the iplex sequenom massarray platform ( sequenom , inc . ) . for quality control , associations between the genotypes and plasma lipid concentrations were determined by multiple linear regression analysis with adjustment for age , sex , smoking status , drinking status and bmi . the hardy - weinberg equilibrium was tested by a goodness - of - fit  test to compare the observed genotype frequencies with the expected ones among the 3,281 subjects . all statistical analyses were performed using statistical analysis system software version 9.1.3 ( sas institute , cary , nc , usa ) . all tests were two - sided and the significance level was set at p < 0.05 . bmi : body mass index ; hdl : high - density lipoprotein cholesterol ; ldl : low density lipoprotein cholesterol . the subjects in the current study were selected from a community - based non - communicable diseases screening program comprised of more than 50,000 participants in jiangsu province during 2004 and 2008 . subjects were excluded from the study if they had a history of diabetes , hypertension , coronary heart disease or cancer , or fasting plasma glucose  5.6 mmol / l . after providing informed consent , all subjects were interviewed face - to - face using a standard questionnaire that included demographic characteristics , risk factors and disease history . subjects who smoked 1 cigarette per day for over 1 year were defined as smokers , and those who consumed 3 or more alcohol drinks a week for over 6 months were considered as alcohol drinkers . physical examinations , including measurements of height , weight and blood pressure , as well as laboratory tests to measure tc , tg , hdl - c and fasting plasma glucose concentrations , were performed for each participant . sitting blood pressure body mass index ( bmi ) was calculated as weight ( in kilograms ) divided by the square of height ( in meters ) . fasting blood samples for routine laboratory examinations were obtained in the early morning after an overnight fast . all biochemical parameters were measured enzymatically on an auto - analyzer ( hitachi 7180 biochemistry auto - analyzer , japan ) according to the manufacturer 's instructions . for subjects with tg levels < 4.52 mmol / l , ldl - c levels were estimated indirectly using the friedewald 's formula . based on our previous study , we used a block - based tagging strategy to select tagging snps using haploview 4.2 software according to the hapmap database[http://www.hapmap.org/ , phaseii nov08 , on ncbi b36 assembly , dbsnpb126 ; population : han chinese population ( chb ) and japanese population ( jpt ) ] . the criteria included snps with minor allele frequency ( maf )  0.10 , hardy - weinberg equilibrium p  0.05 and call rate  95% when using pairwise linkage disequilibrium ( r ) of 0.8 as the threshold for each block . seven tagging snps ( rs7923837 , rs2488075 , rs947591 , rs11187146 , rs5015480 , rs4646957 and rs1111875 ) associated with type 2 diabetes in the ide - kif11-hhex locus at 10q23.33 were included in the current study . genomic dna was isolated from leucocytes of venous blood by proteinase k digestion and phenol / chloroform extraction . genotyping was performed using the taqman openarray genotyping system ( life technologies , carlsbad , ca , usa ) and the iplex sequenom massarray platform ( sequenom , inc . ) . for quality control , associations between the genotypes and plasma lipid concentrations were determined by multiple linear regression analysis with adjustment for age , sex , smoking status , drinking status and bmi . the hardy - weinberg equilibrium was tested by a goodness - of - fit  test to compare the observed genotype frequencies with the expected ones among the 3,281 subjects . all statistical analyses were performed using statistical analysis system software version 9.1.3 ( sas institute , cary , nc , usa ) . all tests were two - sided and the significance level was set at p < 0.05 . bmi : body mass index ; hdl : high - density lipoprotein cholesterol ; ldl : low density lipoprotein cholesterol . the demographic and biochemical characteristics of the 3,281 subjects included in this study are shown in table 1 . the mean age was 56.58 (  9.88 ) years and the mean bmi value was 22.12 (  2.63 ) kg / m . the mean values of tc , hdl - c , ldl - c and tg were 4.40 (  0.80 ) mmol / l , 1.62 (  0.38 ) mmol / l , 2.29 (  0.74 ) mmol / l and 1.09 (  0.45 ) mmol / l , respectively . among these subjects , 827 subjects ( 25.38% ) were smokers and 635 subjects ( 19.51% ) were drinkers . the observed genotype frequencies for the seven snps were all consistent with the hardy - weinberg equilibrium among 3,281 subjects ( p > 0.05 ) ( table 2 ) . we examined the association between each snp and tc , tg , hdl - c or ldl - c levels , respectively , in an additive model using a linear regression model with adjustment for age , sex , smoking , drinking and bmi ( table 2 ) . we found significant associations between rs7923837 and tg ( p = 0.019 ) , between rs2488075 and rs947591 and tc ( p = 0.041 and 0.018 , respectively ) . as shown in table 3 , the g allele of rs7923837 was associated with a lower tg levels ( 0.031 mmol / l average decrease per g allele ) . similarly , the c allele of rs2488075 and the a allele of rs947591 were both associated with lower tc levels ( 0.058 mmol / l average decrease per c allele and 0.063 mmol / l average decrease per a allele , respectively ) . conditional analysis indicated that rs2488075 and rs947591 were not significant after adjustment with each other , as the two snps were in strong linkage equilibrium ( ld ) ( r=0.734 ) . however , no significant associations were observed between the other four snps ( rs11187146 , rs5015480 , rs4646957 and rs1111875 ) and blood lipid concentrations . we then conducted a stratification analysis for rs7923837 , rs2488075 and rs947591 by age , sex , bmi , smoking , and drinking status . as shown in table 4 , the associations between rs7923837 and tg levels were more evident among subjects of the low age group ( p = 0.009 ) , male subjects ( p = 0.003 ) , non - drinkers ( p = 0.019 ) , and subjects with low bmi ( p = 0.003 ) . the associations between rs2488075 , rs947591 and tc levels were more evident among subjects of low age group ( p = 0.021 and 0.013 , respectively ) , female subjects ( p = 0.048 and 0.032 , respectively ) , non - smokers ( p = 0.004 and 0.002 , respectively ) , non - drinkers ( p = 0.007 and 0.003 , respectively ) and subjects with low bmi ( p = 0.038 and 0.037 , respectively ) . to the best of our knowledge , this is the first study to investigate the association between ide - kif11-hhex polymorphisms and plasma lipid concentrations in a chinese population . of the seven tagging snps at the ide - kif11-hhex locus , we found that rs7923837 was associated with plasma concentrations of tg , and rs2488075 and rs947591 were associated with plasma concentrations of tc . hdl - c : high - density lipoprotein cholesterol ; ldl - c : low density lipoprotein cholesterol ; maf : minor allele frequency ; snp : single nucleotide polymorphism . p value derived from the multiple linear regression with adjustment for sex , age , smoking , drinking and bmi assuming an additive genetic model . rs7923837 is located in the 3-flanking region of the hhex gene , which encodes a transcription factor that is involved in wnt signaling and is critical for hepatic and pancreatic development , . in addition , hhex may regulate -cell development and/or function by activating hepatocyte nuclear factor 1. several studies reported that the association between rs7923837 and type 2 diabetes is mediated through decreased -cell secretory capacity or decreased -cell mass. thus , hhex is critical for insulin signaling and islet function . hhex may influence metabolic phenotypes such as tg and tc because insulin is necessary for the regulation of metabolic phenotypes . on chromosome 10q23.33 , genetic variants in hhex have been established as susceptibility loci for type 2 diabetes . in our previous fine - mapping study , we reported that rs7923837 and rs1111875 were independently associated with risk of type 2 diabetes in a chinese population . found that the type 2 diabetes risk - associated g allele of rs7923837 was associated with higher pediatric bmi in european american children . cruz et al . analyzed the association between the hhex rs5015480 and risk of metabolic syndrome ( ms ) in a case - control study from mexico city and found that rs5015480 was significantly associated with ms . taken together , this evidence suggests that genetic variants in the ide - kif11-hhex gene cluster at 10q23.33 may contribute to metabolism - related traits and diseases , including circulating lipid levels and diabetes risk . genetic variants associated with the risk of type 2 diabetes have been found to influence plasma tg levels . the variant rs780094 in gckr was associated with a decreased risk of type 2 diabetes , but with higher tg levels , in a gwas of european population . similarly , in the current study , we found that the risk allele of diabetes was associated with lower tg levels . considering that the subjects included in this study were from a healthy population , the lipid level - related variant might interpret the variation of lipid levels of baseline . the relationships between the same variant and diabetes risk and lipid levels implies that low lipid baseline levels in some subjects are , in part , genetically determined , causing them to be more susceptible to type 2 diabetes . this was also supported by the results from the stratification analysis , which showed that the associations between genetic variants at 10q23.33 and lipid levels were more evident among young subjects , non - smokers , non - drinkers and subjects with low bmi . however , the underlying mechanism remains unclear , and further studies are needed to elucidate the roles of genetic variants at 10q23.33 in circulating lipid levels . c / c , c / r and r / r represent homozygotes for the common allele , and heterozygotes and homozygotes for the rare allele , respectively . p value for the multiple linear regression with adjustment for sex , age , smoking , drinking and bmi assuming an additive genetic model p value for the multiple linear regression with adjustment for sex , age , smoking , drinking and bmi assuming an additive genetic model ( the stratified factor in each stratum was excluded ) . the study by hao et al . suggested that plasma cholesterol plays a direct role in pancreatic islet dysfunction and may be a key factor underlying the progression of type 2 diabetes . genetic variants that are associated with the risk of type 2 diabetes have also been found to influence plasma tc levels . revealed a significant association between rs10885409 in tcf7l2 with type 2 diabetes and tc levels in asian indians . chen et al . found rs2237895 in kcnq1 , which was thought to be a candidate gene of diabetes that influenced plasma tc levels in the han chinese population . they argued that this variant might result in an increased expression of kcnq1 and a subsequent increase in insulin secretion , which could stimulate lipid synthesis . in this study , we also found that rs2488075 and rs947591 were associated with plasma tc levels . rs2488075 and rs947591 are located downstream of hhex , which may affect metabolic phenotypes . however , the mechanism that allows the cc genotype in rs2488075 and the aa genotype in rs947591 to contribute to lower levels of tc is still unknown first , the number of subjects in our study was moderate , thus the statistical power was limited . second , the associations were not strong statistically ; none of them passed multiple correction . third , bias and reverse causation can not be completely excluded in this observational epidemiological study . a mendelian randomization approach that uses the random inheritance of genetic variants from parents to offspring may be of benefit in further studies . thus , larger , well - designed epidemiological studies with ethnically diverse populations are warranted to confirm our findings . in summary , the results in the current study indicate that genetic variants in the ide - kif11-hhex gene cluster at 10q23.33 are associated with plasma lipid levels in the chinese population . these findings highlight the important correlation between lipid levels and diabetes development at the genetic level .
plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes . 
 the ide - kif11-hhex gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes . 
 we hypothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations . 
 seven tagging single nucleotide polymorphisms ( snps : rs7923837 , rs2488075 , rs947591 , rs11187146 , rs5015480 , rs4646957 and rs1111875 ) at 10q23.33 were genotyped in 3,281 subjects from a han chinese population , using the taqman openarray and sequenom massarray platforms . 
 multiple linear regression analyses showed that snp rs7923837 in the 3-flanking region of hhex was significantly associated with triglyceride levels ( p = 0.019 , 0.031 
 mmol / l average decrease per minor g allele ) and that rs2488075 and rs947591 in the downstream region of hhex were significantly associated with total cholesterol levels ( p = 0.041 , 0.058 
 mmol / l average decrease per minor c allele and p = 0.018 , 0.063 
 mmol / l average decrease per minor a allele , respectively ) . 
 however , the other four snps ( rs11187146 , rs5015480 , rs4646957 and rs1111875 ) were not significantly associated with any plasma lipid concentrations in this chinese population . 
 our data suggest that genetic variants in the ide - kif11-hhex gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the han chinese population . 
 further studies are required to confirm these findings in other populations .