TY - JOUR
T1 - HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome
AU - Gbadegesin, Rasheed A
AU - Adeyemo, Adebowale
AU - Webb, Nicholas J A
AU - Greenbaum, Larry A A
AU - Abeyagunawardena, Asiri
AU - Thalgahagoda, Shenal
AU - Kale, Arundhati
AU - Gipson, Debbie
AU - Srivastava, Tarak
AU - Lin, Jen-Jar
AU - Chand, Deepa
AU - Hunley, Tracy E
AU - Brophy, Patrick D
AU - Bagga, Arvind
AU - Sinha, Aditi
AU - Rheault, Michelle N
AU - Ghali, Joanna
AU - Nicholls, Kathy
AU - Abraham, Elizabeth
AU - Janjua, Halima S
AU - Omoloja, Abiodun
AU - Barletta, Gina-Marie
AU - Cai, Yi
AU - Milford, David D
AU - O'Brien, Catherine
AU - Awan, Atif
AU - Belostotsky, Vladimir
AU - Smoyer, William E
AU - Homstad, Alison
AU - Hall, Gentzon
AU - Wu, Guanghong
AU - Nagaraj, Shashi
AU - Wigfall, Delbert
AU - Foreman, John
AU - Winn, Michelle P
PY - 2015/7
Y1 - 2015/7
N2 - Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of
cases of nephrotic syndrome in childhood. However, the etiology and
pathogenesis of SSNS remain obscure. Hypothesizing that coding variation
may underlie SSNS risk, we conducted an exome array association study
of SSNS. We enrolled a discovery set of 363 persons (214 South Asian
children with SSNS and 149 controls) and genotyped them using the
Illumina HumanExome Beadchip. Four common single nucleotide
polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10−6 (Fisher exact test). Two of these SNPs—the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1—were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10−17). In the rare variant gene set–based analysis, the best signal was found in PLCG2 (P=7.825×10−5). In conclusion, this exome array study identified HLA-DQA1 and PLCG2
missense coding variants as candidate loci for SSNS. The finding of a
MHC class II locus underlying SSNS risk suggests a major role for immune
response in the pathogenesis of SSNS.
AB - Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of
cases of nephrotic syndrome in childhood. However, the etiology and
pathogenesis of SSNS remain obscure. Hypothesizing that coding variation
may underlie SSNS risk, we conducted an exome array association study
of SSNS. We enrolled a discovery set of 363 persons (214 South Asian
children with SSNS and 149 controls) and genotyped them using the
Illumina HumanExome Beadchip. Four common single nucleotide
polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10−6 (Fisher exact test). Two of these SNPs—the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1—were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10−17). In the rare variant gene set–based analysis, the best signal was found in PLCG2 (P=7.825×10−5). In conclusion, this exome array study identified HLA-DQA1 and PLCG2
missense coding variants as candidate loci for SSNS. The finding of a
MHC class II locus underlying SSNS risk suggests a major role for immune
response in the pathogenesis of SSNS.
KW - children
KW - genetic renal disease
KW - glomerular disease
KW - nephrotic syndrome
UR - https://corescholar.libraries.wright.edu/pediatrics/508
U2 - 10.1681/ASN.2014030247
DO - 10.1681/ASN.2014030247
M3 - Article
C2 - 25349203
VL - 26
SP - 1701
EP - 1710
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -