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

Namkung, Jung-Hyun; Lee, Jong-Eun; Kim, Eugene; Kim, Song; Kim, Sook; Shin, Eun-Soon; Cho, Eun-Young; Yang, Jun-Mo.

doi:10.1016/j.jdermsci.2009.12.003

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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

Jung-Hyun Namkung
- Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea
- Bioinformatics Program, Seoul National University, Seoul 151-747, South Korea
- Both authors are co-first authors.
Jong-Eun Lee
- DNA Link Inc., Seoul 120-110, South Korea
- Both authors are co-first authors.
Eugene Kim
- Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea
Song Kim
- Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea
Sook Kim
- DNA Link Inc., Seoul 120-110, South Korea
Eun-Soon Shin
- DNA Link Inc., Seoul 120-110, South Korea
Eun-Young Cho
- DNA Link Inc., Seoul 120-110, South Korea
Jun-Mo. Yang
- Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea
- Corresponding author. Tel.: +82 2 3410 3541; fax: +82 2 3410 3869.

Received 25 August 2009; received in revised form 24 November 2009; accepted 4 December 2009. published online 12 July 2010.
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Abstract

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.

Keywords: Atopic dermatitis, IL-12, IL-12 receptor, Polymorphisms, Gene–gene interaction