Interleukin 10 (IL10) is a powerful Th-2 cell cytokine produced by lymphoid cells that exerts its functions by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL1, TNFA, TGFB, IL6, IL8 and IL12). Genetic association analysis of a well-characterized HBV cohort revealed that one of IL10 haplotypes, IL10-ht2, was strongly associated with hepatocellular carcinoma (HCC) occurrence in gene dose-dependent manner. The frequency of susceptible IL10-ht2 was much higher in HCC patients and significantly increased in order of susceptibility to HBV progression from chronic hepatitis to liver cirrhosis and HCC among hepatitis B patients. In addition, survival analysis clearly showed that the onset age of HCC was also accelerated among chronic hepatitis B patients who were carrying IL10-ht2. Increased IL10 production mediated by IL10-ht2 suggests that up-regulated IL10 accelerates progression of chronic HBV infection, especially to HCC development.

The GWAS and the subsequent validation study identified new variants associated with the risk of CHB. These findings may advance the understanding of genetic susceptibility to CHB.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-␣, -␥, and -␦, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-␦ serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-␦, including ؊1,500 bp of the 5 flanking region. Nine polymorphisms were identified in PPAR-␦: four in the intron, one in the 5 untranslated region (UTR), and four in the 3 UTR. Among identified polymorphisms, five common sites, including c.؊13454G>T, c.؊87T>C, c.2022؉12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n ‫؍‬ 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-␦ polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-␦ from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases. Diabetes 53: 847-851, 2004 T he peroxisome proliferator-activated receptor (PPAR) superfamily includes receptors that mediate the size and number of peroxisomes produced by cells in response to a diverse group of chemicals of both biologic and nonbiologic origin (1). PPARs have been implicated in many normal and diseaserelated processes, including lipid metabolism, inflammation, embryo implantation, diabetes, and cancer (2). To date, three isotypes have been identified: PPAR-␣, -␥, and -␦ (also known as PPAR-␤ and NUC-1). PPARs bind to sequence-specific DNA response elements as a heterodimer with the retinoic acid receptor (3). Unlike the PPAR-␣ and -␥ receptors, little is known about the physiological role of the PPAR-␦ isoform. PPAR-␦ (MIM# 600409) was mapped to 6p21.2-p21.1 with 11 exons spanning 35 Kbp (4) and is expressed ubiquitously. It has been known as a potential downstream target of the adenomatous polyposis coli/␤-catenin/T-cell factor-4 tumor suppressor pathway (5), as well as shown to be experimentally activated by arachidonic and oleic acids and the peroxisome proliferator activator WY14643 (6). It has also been implicated in keratinocyte differentiation and wound healing and in mediating VLDL signaling of the macrophage (7-10). Recently, it was demonstrated that activation of PPAR-␦ promotes fatty acid oxidation and utilization in adipocytes and skeletal muscle cells, suggesting that PPAR-␦ serves as a widespread regulator of fat burning (11). Despite potential important roles in m...

Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3' regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case-control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD (p = 5.11 × 10(-7); OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge (p = 2.82 × 10(-7)). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.

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