Functional Haplotype Frequencies of the Interleukin-1B Promoter in the Korean Population

Abstract Single nucleotide polymorphisms (SNPs) in the promoter region of the IL-1B (interleukin-1) gene have been im-plicated in a variety of diseases that have an in-flammatory component. However, there has been sig-nificant heterogeneity among study results, especially between Caucasian and Asian populations. Recently, it has been reported that SNPs in the IL-1B gene affect transcription, according to haplotype context, and ge-netic association studies may be more informative if functional SNP haplotypes of population are analyzed. Therefore, we estimated the distribution of IL-1B pro-moter haplotypes in 433 Koreans using the three major functional IL-1B promoter SNPs (IL-1B-1464, -511, and -31) and compared the results with those in Caucasians. The difference in IL-1B promoter haplotype frequency between Korean and Caucasian populations was stat-istically significant. The potentially more inflammatory haplotypes had higher frequencies in Koreans when compared with Caucasians. These Korean haplotype da-ta will be useful for future association studies between IL-1B SNPs and disease risk.Keywords: Interleukin-1B; polymorphism; haplotype; Ko-reanSNPs in the promoter region of IL-1B gene have been implicated in a variety of diseases that have an in-flammatory component, including cardiovascular dis-ease, gastric cancer, Alzheimer disease, and periodontal disease (Iacoviello et al., 2005; Camargo et al., 2006; Griffin et al., 2000; Kornman et al., 1997). The IL-1B gene is highly polymorphic, and several SNPs have been frequently associated with several diseases (Iacoviello et al., 2005; Francis et al, 1999; El-Omar et al., 2000). However, there has been significant hetero-geneity among study results, especially between Caucasian and Asian populations (Camargo et al., 2006; Lee et al., 2004; Yang et al., 2004; Zeng et al., 2003; Chang et al., 2005; Ma et al., 2003; Hodge et al., 2001). Recently, Chen et al (Chen et al., 2006) reported that SNPs in the IL-1B gene affect transcription according to haplotype context, and genetic association studies may be more informative if functional SNP haplotypes are analyzed, rather than individual functional SNPs. Further, they showed that the functional haplotypes differ by ethnic population. These findings underlie the relevance of population haplotypes in the design of genetic stud-ies (Chen et al., 2006). In view of these findings, we es-timated the distribution of IL-1B promoter haplotypes in 433 Koreans using three major functional IL-1B pro-moter SNPs (IL-1B-1464, -511, and -31) and compared the results with those in Caucasian and African populations. Although the IL-1B-3737 polymorphism al-so had allele-specific differences in nuclear protein bind-ing, no differences in promoter activity were observed with different alleles of this SNP on a background of the other SNP sets that showed higher promoter activity (Chen et al., 2006). Because it has been suggested that the functional significance of IL-1B-3737 might depend on a broader haplotype, we used the three SNPs for haplotype analysis. Haplotypes were reconstructed by PHASE version 2.1, using previously produced genotype data (Lee et al., 2004). Of the possible eight haplotypes, three common ones accounted for ≥98% of the estimated haplotypes in the Korean population. Table 1 shows the haplotype fre-quency estimation in each population. The potentially more inflammatory IL-1B-511T/-31C haplotype repre-sented 53.5% of the Korean haplotypes, compared with 33.7% of the Caucasian haplotypes. So far, in many previous association studies, the individual SNP ap-proach, most frequently using IL-1B-511 and IL-1B-31, has been adopted. To our knowledge, we reported first that the IL-1B-1464 polymorphism has allele-specific dif-ferences in nuclear protein binding and is associated with a clinical disease (Lee et al., 2004). The biological implication of this polymorphism was supported by in vivo studies by Chen et al. that showed that the IL-1B-1464 polymorphism has substantial allele-specific effects when both IL-1B-511 and IL-1B-31 were alleles T and C, respectively (Chen et al., 2006). The more in-formative haplotype 1 (GTC), containing the IL-1B-1464 polymorphism, which shows the highest transcriptional activity, represents 9.3% and 6.0% of Korean and Caucasian haplotypes, respectively, whereas haplotype