Association of HLA-DR/DQ alleles and haplotypes with nephrotic syndrome

Nephrology (Carlton). 2016 Sep;21(9):745-52. doi: 10.1111/nep.12669.

Abstract

Background: Nephrotic syndrome (NS) is a debilitating renal problem in children resulting from an interaction between environmental and genetic factors including human leukocyte antigen genes (HLA). The aim of this work was to study the probable link between HLA alleles/haplotypes and NS in south India.

Methods: HLA DRB1*/DQB1* alleles were genotyped in 183 NS (76 steroid sensitive-SSNS; 107 steroid resistant-SRNS) and paediatric healthy controls (PHCs; n = 91) using polymerase chain reaction-sequence specific primers (PCR-SSP). HLA-A/-B genotyping was performed for patients (n = 70) positive for DRB1*07-DQB1*02 haplotype to identify four locus extended haplotype.

Results: The following alleles and haplotypes were strongly associated with NS (P < 0.05 as significant): DRB1*07 (SSNS, P < 7.98 × 10(-6) ; SRNS, P < 0.008), DQB1*02 (SSNS, P < 3.99 × 10(-6) ; SRNS, P < 0.002), DRB1*07-DQB1*02 (SSNS, P < 1.32 × 10(-4) ; SRNS, P < 0.010), DRB1*07-DQB1*0301,0304 (DQ7) (SSNS, P < 0.001) and DRB1*03-DQB1*02 (SRNS, P < 0.048). Protective associations were observed for alleles DRB1*10 (SRNS, P < 0.013), DQB1*05 (SSNS, P < 4.34 × 10(-6) ; SRNS, P < 0.01), DQB1*06 (SSNS, P < 0.003), and haplotypes DRB1*10-DQB1*06 (SSNS, P < 0.046; SRNS, P < 0.032) and DRB1*15-DQB1*05 (SSNS, P < 0.018). HLA-A/-B typing of 70 NS cases with two locus haplotype DRB1*07-DQB1*02 (70/183; 38.25%) revealed the presence of an extended haplotype 'A*03-B*07-DRB1*07-DQB1*02' (n = 35; 50%).

Conclusion: Our study revealed strong susceptible association of DRB1*07 with SRNS and DQB1*02 with SSNS. A gender predominant protective association was observed for DRB1*10 with SRNS females; DQB1*05 with SSNS and SRNS males. Further, the study documented the presence of an extended haplotype and pleiotropic action of DRB1*/DQB1* alleles in immune-mediated aetiology of NS in south India.

Keywords: Extended haplotype; focal segmental glomerulosclerosis; human leukocyte antigen; nephrotic syndrome; south Indian children; steroid resistant nephrotic syndrome.

MeSH terms

  • Biopsy
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Glomerulosclerosis, Focal Segmental / diagnosis
  • Glomerulosclerosis, Focal Segmental / drug therapy
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / immunology
  • Glucocorticoids / therapeutic use
  • HLA-DQ beta-Chains / genetics*
  • HLA-DQ beta-Chains / immunology
  • HLA-DRB1 Chains / genetics*
  • HLA-DRB1 Chains / immunology
  • Haplotypes*
  • Humans
  • India
  • Male
  • Nephrosis, Lipoid / diagnosis
  • Nephrosis, Lipoid / drug therapy
  • Nephrosis, Lipoid / genetics*
  • Nephrosis, Lipoid / immunology
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / diagnosis
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / immunology
  • Phenotype
  • Polymerase Chain Reaction
  • Prednisolone / therapeutic use
  • Remission Induction
  • Risk Factors
  • Sex Factors
  • Treatment Outcome

Substances

  • Genetic Markers
  • Glucocorticoids
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DRB1 Chains
  • HLA-DRB1*07 antigen
  • Prednisolone

Supplementary concepts

  • Nephrotic syndrome, idiopathic, steroid-resistant