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

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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 ( IF 13.6 ) Pub Date : 2018-08-01 , DOI: 10.1681/asn.2017080859
Xiaoyuan Jia ₁ , Tomoko Horinouchi ₂ , Yuki Hitomi ₁ , Akemi Shono ₂ , Seik-Soon Khor ₁ , Yosuke Omae ₁ , Kaname Kojima _{3,

4,

5} , Yosuke Kawai _{1,

3} , Masao Nagasaki _{3,

4,

5} , Yoshitsugu Kaku ₆ , Takayuki Okamoto ₇ , Yoko Ohwada ₈ , Kazuhide Ohta ₉ , Yusuke Okuda ₁₀ , Rika Fujimaru ₁₁ , Ken Hatae ₁₂ , Naonori Kumagai ₁₃ , Emi Sawanobori ₁₄ , Hitoshi Nakazato ₁₅ , Yasufumi Ohtsuka ₁₆ , Koichi Nakanishi ₁₇ , Yuko Shima ₁₇ , Ryojiro Tanaka ₁₈ , Akira Ashida ₁₉ , Koichi Kamei ₂₀ , Kenji Ishikura ₂₀ , Kandai Nozu ₂ , Katsushi Tokunaga ₁ , Kazumoto Iijima ₂ ,

Affiliation

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan;
Department of Integrative Genomics, Tohoku Medical Megabank Organization,
Graduate School of Medicine, and
Graduate School of Information Sciences, Tohoku University, Sendai, Japan;
Department of Nephrology, Fukuoka Children’s Hospital, Fukuoka, Japan;
Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan;
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan;
Department of Pediatrics, Kanazawa Medical Center, Kanazawa, Japan;
Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan;
Department of Pediatrics, Osaka City General Hospital, Osaka, Japan;
Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan;
Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan;
Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan;
Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan;
Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan;
Department of Pediatrics, Wakayama Medical University, Wakayama, Japan;
Department of Nephrology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan;
Department of Pediatrics, Osaka Medical College, Osaka, Japan; and
Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan

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.

中文翻译：

HLA-DR / DQ基因座与儿童类固醇敏感性肾病综合征在日本人口中的强关联

背景肾病综合征是儿童慢性肾小球疾病的最常见原因。这些患者大多数会发展为类固醇敏感性肾病综合征（SSNS），但主要导致儿童期SSNS易感的基因座尚不清楚。

方法我们在日本人群中进行了全基因组关联研究（GWAS）。在发现阶段，使用Affymetrix Japonica Array对224名儿童期SSNS患者和419名成人健康对照组进行了基因分型。根据日语参考文献，对6个HLA基因（HLA-A，-C，-B，-DRB1，-DQB1和-DPB1）进行插补。我们对HLA-DRB1 / DQB1进行了基因分型在Luminex平台上使用序列特异性寡核苷酸探测方法。使用2049个健康日本人的分阶段参考小组进行了全基因组估算。在一个独立的日本样本集中（包括216位患者和719位健康对照）进行复制。我们使用DigiTag2分析对候选单核苷酸多态性进行基因分型。

结果在HLA-DR / DQ区中检测到了最显着的关联，并进行了复制（rs4642516 [次要等位基因G]，合并的P_等位基因= 7.84×10 ^-23；比值比[OR]，0.33； 95％的置信区间[95％ CI]，0.26至0.41； rs3134996 [次要等位基因A]，合并的P_等位基因= 1.72×10 ^-25； OR，0.29； 95％CI，0.23至0.37）。HLA-DRB1 * 08：02（Pc = 1.82×10 ^-9 ; OR，2.62; 95％CI，1.94至3.54）和HLA-DQB1 * 06：04（Pc = 2.09×10 ^-12 ; OR，0.10; 95 ％CI（0.05到0.21）被认为是原发性HLA与儿童SSNS相关的等位基因。HLA-DRB1 * 08：02-DQB1 * 03：02（Pc = 7.01×10 ^-11 ; OR，3.60; 95％CI，2.46至5.29）被确定为最重要的遗传易感性因子。