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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.

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