Eun-Soon Shin

Gene–gene interaction between IL-13 and IL-13Rα1 is associated with total IgE in Korean children with atopic asthma

AbstractInterleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Rα and IL-13Rα1. We investigated the effects of IL-13 and IL-13Rα1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Rα1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A−1512C and C−1112T) and IL-13Rα1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of −1512C, −1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene-gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Rα1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Rα1 polymorphisms may interact to enhance IgE production.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma†

Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand‐foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib‐induced HFSR and genetic polymorphisms in Korean patients with HCC.

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans.

Essential hypertension (EH) is considered a typical polygenic disease, so the evaluation of gene–gene interactions rather than the determination of single gene effects is crucial to understanding any genetic influences. The G-protein β3-subunit (GNB3) 825T allele, associated with enhanced G-protein signalling, is a strong candidate for interactions with polymorphisms, such as insertion/deletion (I/D) polymorphism of angiotensin I-converting enzyme (ACE) gene. We investigated whether there is an association between GNB3 C825T and ACE I/D polymorphisms for the development of EH. We carried out a case–control study of 688 hypertensive and 924 normotensive subjects recruited from South Korea. The GNB3 C825T and ACE I/D genotypes were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods, respectively. The distributions of alleles and genotypes for the GNB3 C825T and ACE I/D polymorphisms were not found to be significantly associated with hypertensive status in either males or females. Logistic regression analysis indicated that the GNB3 825T allele carriers were positively associated with EH in males (odds ratio (OR) for TT/CT, 1.459; 95% confidence interval (CI), 1.048–2.033, P=0.0255). In analysis of gene–gene interaction, we found that there was a significant interaction between the GNB3 825T and ACE D alleles (P<0.05). OR for EH was significantly higher in 825T allele carriers with ACE D allele (OR, 1.490; 95% CI, 1.117–1.987, P=0.0067). A significant interaction between the GNB3 825T and the ACE D alleles may contribute to the predisposing effect for the development of EH in Koreans.

An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population

BACKGROUND The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals. OBJECTIVE To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis. METHOD We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (-4091G/A) SNP located in the IL-9 gene promoter region. RESULT The rs31563 (-4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene-gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development. CONCLUSION Significant evidence exists to suggest that the rs31563 SNP (-4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene-gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies.

Association of single nucleotide polymorphisms in the IL-12 (IL-12A and B) and IL-12 receptor (IL-12Rβ1 and β2) genes and gene-gene interactions with atopic dermatitis in Koreans.

BACKGROUND The acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12. OBJECTIVE We evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene-gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported. METHOD We genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case-control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene-gene interactions. RESULT The rs582504 (IVS-798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12+1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe. CONCLUSION This study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD.

Single nucleotide polymorphisms and the haplotype in the DEFB1 gene are associated with atopic dermatitis in a Korean population

BACKGROUND Atopic dermatitis (AD) patients have been recognized to have an increased susceptibility to cutaneous colonization and infection by bacteria, fungi and viruses. OBJECTIVE We wanted to evaluate the associations of single nucleotide polymorphism (SNP) and the haplotype in the defensin (DEFA) and defensin (DEFB) genes, and so we performed genotyping for the SNPs in these genes in both AD patients and normal controls. METHOD We genotyped 27 SNPs from the DEFA 4, 5 and 6 genes and the DEFB1 gene for 1089 case-control samples (631 AD patients and 458 normal controls). We analyzed the SNPs and haplotypes in each gene. RESULT We identified that two SNPs and the haplotype CT in the DEFB1 gene are associated with AD in Koreans. The rs5743399 (-2266T/C) SNP is associated with AD, and especially with the high IgE, extrinsic type, and the rs5743409 (-1241T/G) SNP is associated with AD. On the haplotype analysis of these two SNPs, the haplotype CT is associated with AD, and especially with the allergic, extrinsic type of AD. However, we could not find any significant associations between the SNPs in the three DEFA genes and AD. CONCLUSION We found that the rs5743399 SNP, the rs5743409 SNP and the CT haplotype in the DEFB1 gene were significantly associated with the susceptibility to AD. We also found that rs5743399 polymorphism and the haplotype CT in this gene showed a strong association with the allergic, extrinsic type of AD. These results suggest that the DEFB1 gene has a main effect on the skin inflammation and/or skin responsiveness to any kind of allergic reaction.

Association of polymorphisms in genes encoding IL‐4, IL‐13 and their receptors with atopic dermatitis in a Korean population

Abstract:  Th2‐dominated immune responses are believed to contribute to the pathogenesis of atopic dermatitis (AD). IL‐4 and IL‐13 are typical pleiotropic Th2 cytokines that play a central role in IgE‐dependent inflammatory reactions. Single‐nucleotide polymorphisms (SNPs) in IL‐4 and IL‐13 have been reported in patients with allergic disease from numerous countries. Gene–gene interactions among genes have been identified in patients with asthma, although negative results have been reported. To investigate the associations of SNPs in these genes and the interactions between these genes in AD, we genotyped 23 SNPs of the IL‐4, IL‐13, IL‐4R, IL‐13Rα1 and IL‐13Rα2 genes for 1089 case‐control samples (631 AD patients and 458 controls) and analysed the SNPs and haplotypes in these genes. We also searched for gene–gene interactions among these five genes. Our data identified an association between rs3091307 and rs20541 in the IL‐13 gene and between rs2265753 and rs2254672 in the IL‐13Rα1 gene and the AD phenotype. In particular, three of the four SNPs were especially predictive of the allergic type of AD (ADe), and the haplotype TCGG in the IL‐13Rα1 gene showed significant association with AD, especially ADe. Furthermore, the combination of rs3091307 GG/ rs2265753 GG (IL‐13/IL‐13Rα1) conveyed a significantly higher risk for developing ADe. However, we did not identify any SNPs in the IL‐4, IL‐4R and IL‐13Rα2 genes that were associated with AD. As IL‐13Rα1 is most likely expressed in Th17 cells rather than in Th2 cells, these data suggest diversity in the classification of Th cells that needs to be verified in future studies.

Human leukocyte antigen alleles and haplotypes associated with chronicity of hepatitis B virus infection in Koreans.

CONTEXT Chronic hepatitis B infection is the leading cause of cirrhosis and hepatocellular carcinoma. Human leukocyte antigen may be involved in the chronicity of hepatitis B virus (HBV) infection. OBJECTIVE To analyze the association between HBV chronicity and human leukocyte antigen alleles and haplotypes of 636 organ donors and recipients. DESIGN Subjects were categorized into 2 groups according to their clinical and serologic profiles, specifically, an HBV natural convalescent group and an HBV chronic carrier (CC) group. RESULTS Hepatitis B chronicity was positively associated with A33 (P = .004, odds ratio [OR] = 1.59) and DR7 (P < .001, OR = 2.58), and negatively associated with HLA-DR13 (P < .001, OR = 0.40). Coexpression of A33 and DR7 was significantly higher in the CC group (OR = 3.63), compared with that of either allele alone (OR = 1.76 in A33; OR = 2.53 in DR7). The statistically significant haplotypes were B44-DR7 (P < .001, OR = 5.44), A33-DR7 (P < .001, OR = 4.47), and A33-B44-DR7 (P < .001, OR = 7.31) in the CC group. CONCLUSIONS Our results indicate that alleles of A33, DR7, and haplotypes containing DR7 are associated with HBV chronicity among Koreans. Moreover, the 2 antigens had an additive effect on chronicity. These findings support the theory that human leukocyte antigen class I-restricted cytotoxic T cells and human leukocyte antigen class II-restricted helper T cells play an important role in HBV chronicity.

Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival

BACKGROUND & AIMS We aimed at determining whether single nucleotide polymorphisms (SNPs) of DNA repair genes influence the development and clinical outcomes of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS We evaluated 14 SNPs of eight DNA repair genes in 708 patients with HCC and 388 HBsAg positive controls without HCC. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of HCC patients according to the genotype. RESULTS The SNP of XRCC4 rs1805377 was significantly associated with decreased risk of HCC development (OR, 0.592; p=0.028) and improved overall survival of patients with HCC (median survival time (MST) of 48, 72, and 89 months for the AA, AG, and GG genotypes, respectively; p=0.044). In addition, SNP of OGG1 rs1053133 was significantly associated with postoperative recurrence (OR, 0.604; p=0.049), tumor differentiation (OR, 0.571; p=0.041), and improved survival of resected HCC (MST of 55 and 108 months for the GG and GC/CC genotypes, p=0.001). The multivariate analysis showed that OGG1 rs1052133, XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 had a significant effect on survival. Moreover, a strong dose-dependent association was observed between the number of putative high-risk genotypes of OGG1, XRCC1, ERCC5, and XRCC4 with the overall survival. The MST of HCC with ≥2 putative high-risk genotypes was significantly prolonged compared to those with ≥3 high-risk genotypes (76 vs. 46 months, respectively, p=0.002). CONCLUSIONS Polymorphisms of DNA repair genes play a potential role in the development, progression, and survival of Korean HCC patients with chronic HBV infection.

Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B

Our goal was to determine whether single‐nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)‐associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen‐positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase‐associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10−5). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose‐dependent association between the number of putatively high‐risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high‐risk genotypes versus those with three or more high‐risk genotypes (85 versus 44 months, log‐rank P = 4.483 × 10−5), and this was demonstrated in the replication cohort (52 versus 37 months, log‐rank P = 0.026). Conclusion: These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections. (Hepatology 2014;59:1912–1920)