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

Abstract

<b>Background</b> 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.<b>Methods</b> 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 <i>HLA</i> genes (<i>HLA-A</i>, <i>-C, -B</i>, <i>-DRB1</i>, <i>-DQB1</i>, and <i>-DPB1</i>) was conducted on the basis of Japanese-specific references. We performed genotyping for <i>HLA-DRB1</i>/-<i>DQB1</i> 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.<b>Results</b> The most significant association was detected in the <i>HLA-DR/DQ</i> region and replicated (rs4642516 [minor allele G], combined <i>P</i>_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 <i>P</i>_allelic=1.72×10^-25; OR, 0.29; 95% CI, 0.23 to 0.37). <i>HLA-DRB1*08:02</i> (<i>Pc</i>=1.82×10^-9; OR, 2.62; 95% CI, 1.94 to 3.54) and <i>HLA-DQB1*06:04</i> (<i>Pc</i>=2.09×10^-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary <i>HLA</i> alleles associated with childhood SSNS. <i>HLA-DRB1*08:02-DQB1*03:02</i> (<i>Pc</i>=7.01×10^-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.<b>Conclusions</b> The most significant association with childhood SSNS was detected in the <i>HLA-DR/DQ</i> region. Further <i>HLA</i> allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.