Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: Case-control studies

Tomomitsu Hirota, Hidehisa Saeki, Kaori Tomita, Shota Tanaka, Kouji Ebe, Masafumi Sakashita, Takechiyo Yamada, Shigeharu Fujieda, Akihiko Miyatake, Satoru Doi, Tadao Enomoto, Nobuyuki Hizawa, Tohru Sakamoto, Hironori Masuko, Takashi Sasaki, Tamotsu Ebihara, Masayuki Amagai, Hitokazu Esaki, Satoshi Takeuchi, Masutaka FurueEmiko Noguchi, Naoyuki Kamatani, Yusuke Nakamura, Michiaki Kubo, Mayumi Tamari

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Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1 st population, 916 cases and 1,032 controls; 2 nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10 -6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.

Original languageEnglish
Article numbere26987
JournalPloS one
Volume6
Issue number11
DOIs
Publication statusPublished - 17-11-2011

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Chemokine CCL22
CC Chemokines
atopic dermatitis
chemokines
Atopic Dermatitis
case-control studies
Chemokines
Case-Control Studies
Association reactions
Genes
Alleles
alleles
Single Nucleotide Polymorphism
pathogenesis
Chemokine CCL17
Population
Electrophoretic mobility
Th2 Cells
Functional analysis
genes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hirota, T., Saeki, H., Tomita, K., Tanaka, S., Ebe, K., Sakashita, M., ... Tamari, M. (2011). Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: Case-control studies. PloS one, 6(11), [e26987]. https://doi.org/10.1371/journal.pone.0026987
Hirota, Tomomitsu ; Saeki, Hidehisa ; Tomita, Kaori ; Tanaka, Shota ; Ebe, Kouji ; Sakashita, Masafumi ; Yamada, Takechiyo ; Fujieda, Shigeharu ; Miyatake, Akihiko ; Doi, Satoru ; Enomoto, Tadao ; Hizawa, Nobuyuki ; Sakamoto, Tohru ; Masuko, Hironori ; Sasaki, Takashi ; Ebihara, Tamotsu ; Amagai, Masayuki ; Esaki, Hitokazu ; Takeuchi, Satoshi ; Furue, Masutaka ; Noguchi, Emiko ; Kamatani, Naoyuki ; Nakamura, Yusuke ; Kubo, Michiaki ; Tamari, Mayumi. / Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis : Case-control studies. In: PloS one. 2011 ; Vol. 6, No. 11.
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title = "Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: Case-control studies",
abstract = "Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1 st population, 916 cases and 1,032 controls; 2 nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10 -6; OR, 0.74; 95{\%} CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.",
author = "Tomomitsu Hirota and Hidehisa Saeki and Kaori Tomita and Shota Tanaka and Kouji Ebe and Masafumi Sakashita and Takechiyo Yamada and Shigeharu Fujieda and Akihiko Miyatake and Satoru Doi and Tadao Enomoto and Nobuyuki Hizawa and Tohru Sakamoto and Hironori Masuko and Takashi Sasaki and Tamotsu Ebihara and Masayuki Amagai and Hitokazu Esaki and Satoshi Takeuchi and Masutaka Furue and Emiko Noguchi and Naoyuki Kamatani and Yusuke Nakamura and Michiaki Kubo and Mayumi Tamari",
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Hirota, T, Saeki, H, Tomita, K, Tanaka, S, Ebe, K, Sakashita, M, Yamada, T, Fujieda, S, Miyatake, A, Doi, S, Enomoto, T, Hizawa, N, Sakamoto, T, Masuko, H, Sasaki, T, Ebihara, T, Amagai, M, Esaki, H, Takeuchi, S, Furue, M, Noguchi, E, Kamatani, N, Nakamura, Y, Kubo, M & Tamari, M 2011, 'Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: Case-control studies', PloS one, vol. 6, no. 11, e26987. https://doi.org/10.1371/journal.pone.0026987

Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis : Case-control studies. / Hirota, Tomomitsu; Saeki, Hidehisa; Tomita, Kaori; Tanaka, Shota; Ebe, Kouji; Sakashita, Masafumi; Yamada, Takechiyo; Fujieda, Shigeharu; Miyatake, Akihiko; Doi, Satoru; Enomoto, Tadao; Hizawa, Nobuyuki; Sakamoto, Tohru; Masuko, Hironori; Sasaki, Takashi; Ebihara, Tamotsu; Amagai, Masayuki; Esaki, Hitokazu; Takeuchi, Satoshi; Furue, Masutaka; Noguchi, Emiko; Kamatani, Naoyuki; Nakamura, Yusuke; Kubo, Michiaki; Tamari, Mayumi.

In: PloS one, Vol. 6, No. 11, e26987, 17.11.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis

T2 - Case-control studies

AU - Hirota, Tomomitsu

AU - Saeki, Hidehisa

AU - Tomita, Kaori

AU - Tanaka, Shota

AU - Ebe, Kouji

AU - Sakashita, Masafumi

AU - Yamada, Takechiyo

AU - Fujieda, Shigeharu

AU - Miyatake, Akihiko

AU - Doi, Satoru

AU - Enomoto, Tadao

AU - Hizawa, Nobuyuki

AU - Sakamoto, Tohru

AU - Masuko, Hironori

AU - Sasaki, Takashi

AU - Ebihara, Tamotsu

AU - Amagai, Masayuki

AU - Esaki, Hitokazu

AU - Takeuchi, Satoshi

AU - Furue, Masutaka

AU - Noguchi, Emiko

AU - Kamatani, Naoyuki

AU - Nakamura, Yusuke

AU - Kubo, Michiaki

AU - Tamari, Mayumi

PY - 2011/11/17

Y1 - 2011/11/17

N2 - Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1 st population, 916 cases and 1,032 controls; 2 nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10 -6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.

AB - Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1 st population, 916 cases and 1,032 controls; 2 nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10 -6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.

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