Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study

Chikashi Terao; Koichiro Ohmura; Ryo Yamada; Takahisa Kawaguchi; Masakazu Shimizu; Yasuharu Tabara; Meiko Takahashi; Kazuya Setoh; Takeo Nakayama; Shinji Kosugi; Akihiro Sekine; Fumihiko Matsuda; Tsuneyo Mimori

doi:10.1002/art.38867

Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study

Chikashi Terao
, Koichiro Ohmura
, Ryo Yamada
, Takahisa Kawaguchi
, Masakazu Shimizu
, Yasuharu Tabara
, Meiko Takahashi
, Kazuya Setoh
, Takeo Nakayama
, Shinji Kosugi
, Akihiro Sekine
, Fumihiko Matsuda
, Tsuneyo Mimori

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

Objective While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes.

Methods A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed.

Results Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB10405, was significantly associated with ANA positivity (P = 1.3 × 10^-11). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns (P = 7.5 × 10^-12 and P = 2.2 × 10^-11, respectively) but decreasing effects on the frequency of the nucleolar pattern (P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity.

Conclusion SNP rs2395185 linked with HLA-DRB10405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus.

Original language	English
Pages (from-to)	3395-3403
Number of pages	9
Journal	Arthritis and Rheumatology
Volume	66
Issue number	12
DOIs	https://doi.org/10.1002/art.38867
Publication status	Published - 01-12-2014
Externally published	Yes

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Rheumatology
Immunology

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10.1002/art.38867

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Terao, C., Ohmura, K., Yamada, R., Kawaguchi, T., Shimizu, M., Tabara, Y., Takahashi, M., Setoh, K., Nakayama, T., Kosugi, S., Sekine, A., Matsuda, F., & Mimori, T. (2014). Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study. Arthritis and Rheumatology, 66(12), 3395-3403. https://doi.org/10.1002/art.38867

@article{99ff025489444ea8a7538140bb8fa856,

title = "Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study",

abstract = "Objective While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes.Methods A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed.Results Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB10405, was significantly associated with ANA positivity (P = 1.3 {\texttimes} 10-11). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns (P = 7.5 {\texttimes} 10-12 and P = 2.2 {\texttimes} 10-11, respectively) but decreasing effects on the frequency of the nucleolar pattern (P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity.Conclusion SNP rs2395185 linked with HLA-DRB10405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus.",

author = "Chikashi Terao and Koichiro Ohmura and Ryo Yamada and Takahisa Kawaguchi and Masakazu Shimizu and Yasuharu Tabara and Meiko Takahashi and Kazuya Setoh and Takeo Nakayama and Shinji Kosugi and Akihiro Sekine and Fumihiko Matsuda and Tsuneyo Mimori",

note = "Publisher Copyright: {\textcopyright} 2014 by the American College of Rheumatology.",

year = "2014",

month = dec,

day = "1",

doi = "10.1002/art.38867",

language = "English",

volume = "66",

pages = "3395--3403",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "12",

}

Terao, C, Ohmura, K, Yamada, R, Kawaguchi, T, Shimizu, M, Tabara, Y, Takahashi, M, Setoh, K, Nakayama, T, Kosugi, S, Sekine, A, Matsuda, F & Mimori, T 2014, 'Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study', Arthritis and Rheumatology, vol. 66, no. 12, pp. 3395-3403. https://doi.org/10.1002/art.38867

TY - JOUR

T1 - Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns

T2 - The nagahama study

AU - Terao, Chikashi

AU - Ohmura, Koichiro

AU - Yamada, Ryo

AU - Kawaguchi, Takahisa

AU - Shimizu, Masakazu

AU - Tabara, Yasuharu

AU - Takahashi, Meiko

AU - Setoh, Kazuya

AU - Nakayama, Takeo

AU - Kosugi, Shinji

AU - Sekine, Akihiro

AU - Matsuda, Fumihiko

AU - Mimori, Tsuneyo

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Objective While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes.Methods A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed.Results Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB10405, was significantly associated with ANA positivity (P = 1.3 × 10-11). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns (P = 7.5 × 10-12 and P = 2.2 × 10-11, respectively) but decreasing effects on the frequency of the nucleolar pattern (P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity.Conclusion SNP rs2395185 linked with HLA-DRB10405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus.

AB - Objective While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes.Methods A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed.Results Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB10405, was significantly associated with ANA positivity (P = 1.3 × 10-11). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns (P = 7.5 × 10-12 and P = 2.2 × 10-11, respectively) but decreasing effects on the frequency of the nucleolar pattern (P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity.Conclusion SNP rs2395185 linked with HLA-DRB10405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus.

UR - https://www.scopus.com/pages/publications/84912001310

UR - https://www.scopus.com/pages/publications/84912001310#tab=citedBy

U2 - 10.1002/art.38867

DO - 10.1002/art.38867

M3 - Article

C2 - 25186300

AN - SCOPUS:84912001310

SN - 2326-5191

VL - 66

SP - 3395

EP - 3403

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 12

ER -

Association between antinuclear antibodies and the hla class ii locus and heterogeneous characteristics of staining patterns: The nagahama study

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