Strong Association of the HLA-DR/DQ Locus with Childhood... : Journal of the American Society of Nephrology (original) (raw)

Clinical Epidemiology

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Jia, Xiaoyuan1; Horinouchi, Tomoko2; Hitomi, Yuki1; Shono, Akemi2; Khor, Seik-Soon1; Omae, Yosuke1; Kojima, Kaname3,4,5; Kawai, Yosuke1,3; Nagasaki, Masao3,4,5; Kaku, Yoshitsugu6; Okamoto, Takayuki7; Ohwada, Yoko8; Ohta, Kazuhide9; Okuda, Yusuke10; Fujimaru, Rika11; Hatae, Ken12; Kumagai, Naonori13; Sawanobori, Emi14; Nakazato, Hitoshi15; Ohtsuka, Yasufumi16; Nakanishi, Koichi17; Shima, Yuko17; Tanaka, Ryojiro18; Ashida, Akira19; Kamei, Koichi20; Ishikura, Kenji20; Nozu, Kandai2; Tokunaga, Katsushi1; Iijima, Kazumoto2; for the Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan

Collaborators

Okamoto, Takayuki; Aoyagi, Hayato; Ueno, Tomohiko; Nakanishi, Masanori; Toita, Nariaki; Uetake, Kimiaki; Kobayashi, Norio; Fujita, Shoji; Tsuruga, Kazushi; Kumagai, Naonori; Kudo, Hiroki; Tanaka, Eriko; Okada, Mari; Ishikuyra, Kenji; Kamei, Koichi; Ogura, Masao; Sato, Mai; Kano, Yuji; Miura, Kenichiro; Motoyoshi, Yaeko; Sawanobori, Emi; Kobayashi, Anna; Kojika, Manabu; Ohwada, Yoko; Hamada, Riku; Hataya, Hiroshi; Goto, Miwa; Ohta, Kazuhide; Tamamura, Soichi; Mori, Yukiko; Iijima, Kazumoto; Nozu, Kandai; Kaito, Hiroshi; Yamamura, Tomohiko; Minamikawa, Shogo; Nakanishi, Keita; Fujimura, Junya; Nagano, China; Sakakibara, Nana; Tanaka, Ryojiro; Kanda, Kyoko; Nakagawa, Taku; Shibano, Takayuki; Maekawa, Kohei; Hattori, Masuji; Hashimura, Yuya; Ishimori, Shingo; Fujimaru, Rika; Ueda, Hiroaki; Ashida, Akira; Matsumura, Hideki; Sawai, Toshihiro; Sakai, Tomoyuki; Okuda, Yusuke; Shima, Yuko; Itoh, Shigeru; Nagatani, Koji; Kaku, Yoshikazu; Nishimura, Manao; Hatae, Ken; Hinokiyama, Maiko; Kuroki, Rie; Ohtsuka, Yasufumi; Nishimura, Shinji; Nakazato, Hitoshi; Tamura, Hiroshi; Nakanishi, Koichi

1Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;

2Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan;

3Department of Integrative Genomics, Tohoku Medical Megabank Organization,

4Graduate School of Medicine, and

5Graduate School of Information Sciences, Tohoku University, Sendai, Japan;

6Department of Nephrology, Fukuoka Children’s Hospital, Fukuoka, Japan;

7Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan;

8Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan;

9Department of Pediatrics, Kanazawa Medical Center, Kanazawa, Japan;

10Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan;

11Department of Pediatrics, Osaka City General Hospital, Osaka, Japan;

12Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan;

13Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan;

14Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan;

15Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan;

16Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan;

17Department of Pediatrics, Wakayama Medical University, Wakayama, Japan;

18Department of Nephrology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan;

19Department of Pediatrics, Osaka Medical College, Osaka, Japan; and

20Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan

X.J. and T.H. contributed equally to this work.

Present address: Dr. Koichi Nakanishi, Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Correspondence: Prof. Kazumoto Iijima, Department of Pediatrics, Kobe University Graduate School of Medicine, 5-1 Kusunoki-cho 7 chome, Chuo-ku, Kobe 650-0017, Japan, or Dr. Katsushi Tokunaga, Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: [email protected] or [email protected]

Abstract

Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.

Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.

Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined _P_allelic=7.84×10−23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined _P_allelic=1.72×10−25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (_Pc_=1.82×10−9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (_Pc_=2.09×10−12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (_Pc_=7.01×10−11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.

Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.