Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive nephrotic syndrome in the Japanese population

Xiaoyuan Jia, Tomoko Horinouchi, Yuki Hitomi, Akemi Shono, Seik Soon Khor, Yosuke Omae, Kaname Kojima, Yosuke Kawai, Masao Nagasaki, Yoshitsugu Kaku, Takayuki Okamoto, Yoko Ohwada, Kazuhide Ohta, Yusuke Okuda, Rika Fujimaru, Ken Hatae, Naonori Kumagai, Emi Sawanobori, Hitoshi Nakazato, Yasufumi OhtsukaKoichi Nakanishi, Yuko Shima, Ryojiro Tanaka, Akira Ashida, Koichi Kamei, Kenji Ishikura, Kandai Nozu, Katsushi Tokunaga, Kazumoto Iijima

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12 Citations (Scopus)

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 Pallelic=7.84310223; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72310225; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.8231029; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09310212; 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=7.01310211; 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.

Original languageEnglish
Pages (from-to)2189-2199
Number of pages11
JournalJournal of the American Society of Nephrology
Volume29
Issue number8
DOIs
Publication statusPublished - 08-2018

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Jia, X., Horinouchi, T., Hitomi, Y., Shono, A., Khor, S. S., Omae, Y., Kojima, K., Kawai, Y., Nagasaki, M., Kaku, Y., Okamoto, T., Ohwada, Y., Ohta, K., Okuda, Y., Fujimaru, R., Hatae, K., Kumagai, N., Sawanobori, E., Nakazato, H., ... Iijima, K. (2018). Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive nephrotic syndrome in the Japanese population. Journal of the American Society of Nephrology, 29(8), 2189-2199. https://doi.org/10.1681/ASN.2017080859