Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.
OBJECTIVE
One hypothesis states that IgA nephropathy (IgAN) is a syndrome with an autoimmune component. Recent studies strongly support the notion of shared genetics between immune-related diseases. This study investigated single-nucleotide polymorphisms (SNPs) reported to be associated with systemic lupus erythematosus (SLE) in a Chinese cohort of patients with IgAN and in controls.


METHODS
This study investigated whether SNP markers that had been reported to be associated with SLE were also associated with IgAN in a Chinese population. The study cohort consisted of 1194 patients with IgAN and 902 controls enrolled in Peking University First Hospital from 1997 to 2008.


RESULTS
Ninety-six SNPs mapping to 60 SLE loci with reported P values <1 × 10(-5) were investigated. CFH (P=8.41 × 10(-6)), HLA-DRA (P=4.91 × 10(-6)), HLA-DRB1 (P=9.46 × 10(-9)), PXK (P=3.62 × 10(-4)), BLK (P=9.32 × 10(-3)), and UBE2L3 (P=4.07 × 10(-3)) were identified as shared genes between IgAN and SLE. All associations reported herein were corroborated by associations at neighboring SNPs. Many of the alleles that are risk alleles for SLE are protective alleles for IgAN. By analyses of two open independent expression quantitative trait loci (eQTL) databases, correlations between genotypes and corresponding gene expression were observed (P<0.05 in multiple populations), suggesting a cis-eQTL effect. From gene-expression databases, differential expressions of these genes were observed in IgAN. Additive interactions between PXK rs6445961 and HLA-DRA rs9501626 (P=1.51 × 10(-2)), as well as multiplicative interactions between CFH rs6677604 and HLA-DRB1 rs9271366 (P=1.77 × 10(-2)), and between HLA-DRA rs9501626 and HLA-DRB1 rs9271366 (P=3.23 × 10(-2)) were observed. Disease risk decreased with accumulation of protective alleles. Network analyses highlighted four pathways: MHC class II antigen presentation, complement regulation, signaling by the B-cell receptor, and ubiquitin/proteasome-dependent degradation.


CONCLUSIONS
From this "systems genetics" perspective, these data provide important clues for future studies on pleiotropy in IgAN and lupus nephritis.
Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China.
Xu-Jie
XJ
Zhou
Fa-Juan
FJ
Cheng
Li
L
Zhu
Ji-Cheng
JC
Lv
Yuan-Yuan
YY
Qi
Ping
P
Hou
Hong
H
Zhang
D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005922:Glomerulonephritis, IGA / Q000208:ethnology / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D006785:Hospitals, University; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D040641:Quantitative Trait Loci; D018570:Risk Assessment; D012307:Risk Factors; D049490:Systems Biology