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

Abstract

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. 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 genes (, ,, , and) was conducted on the basis of Japanese-specific references. We performed genotyping for /- 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. The most significant association was detected in the region and replicated (rs4642516 [minor allele G], combined=7.84×10; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined =1.72×10; OR, 0.29; 95% CI, 0.23 to 0.37). (=1.82×10; OR, 2.62; 95% CI, 1.94 to 3.54) and (=2.09×10; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary alleles associated with childhood SSNS. (=7.01×10; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor. The most significant association with childhood SSNS was detected in the region. Further allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

“…Shown is the LD data for the lead HLA SNPs identified in previous GWAS of SSNS and this analysis, based on European reference data from the 1000 genome dataset. Note that the SNPs rs9273542 and rs2858317, identified in this analysis are in strong LD with rs4642516, identified by Jia et al 23 and with two markers, rs1063348 and rs28366266, identified by Debiec et al. 24 In contrast, the third, most telomeric marker identified by Debiec et al rs9348883 is only in weak LD with the other markers.…”

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report

“…Additionally, HLA-DRB1*04:05-DQB1*04:01, HLA-DRB1*08:02-DQB1*03:02, and HLA-DRB1*09:01-DQB1*03:03 haplotypes are associated with susceptibility to T1DM [ 29 ]. Recently, it has been reported that the HLA-DRB1*08:02, HLA-DQB1*03:02 alleles, and the HLA-DRB1*08:02-DQB1*03:02 haplotype is highly associated with steroid-sensitive nephrotic syndrome in Japanese children [ 30 ]. Although we had speculated that our patient would have HLA-DRB1*08:02-DQB1*03:02, she had HLA-DRB1*09:01/09:01 and DQB1*03:03/03:03.…”

“…Both the patient and her mother had specific HLA haplotypes that are highly associated with T1DM, but only the daughter developed MCNS. HLA-DRB1*09:01-DQB1*03:03-DPB1*02:01 and HLA-A*02:06-C*08:01-B*40:06-DRB1*09:01-DQB1*03:03 haplotypes have been reported to be associated with childhood steroid-sensitive nephrotic syndrome in Japan, so our patient might have either one of the two haplotypes [ 30 ].…”

Aberrant IgM on T cells: biomarker or pathogenic factor in childhood nephrotic syndrome?

“…In addition, recent genetic studies implicate variants in major histocompatibility complex, class II, DQ alpha 1 (HLA-DQA1), other major histocompatibility class II loci, and phospholipase C gamma 2 (PLCG2) as important risk factors for NS and further support the importance of defective B-cell functions in the pathogenesis of the disease. 1,3,4 Corticosteroid is the mainstay of treatment for NS, and the disease is classified as steroid-sensitive nephrotic syndrome (SSNS), frequent relapsing (FR), steroid dependent (SD), and steroid-resistant NS based on response to corticosteroid therapy. The reasons for variability in response to corticosteroid therapy in a disease in which dysregulation of immune cells is central to pathogenesis is largely unknown.…”