Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus.
OBJECTIVE
We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants affecting susceptibility to SLE.


METHODS
Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate.


RESULTS
Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han [rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal.


CONCLUSIONS
Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.
Institute of Dermatology, Anhui Medical University, Anhui 230032, China.
Yu-Jun
YJ
Sheng
Jin-Ping
JP
Gao
Jian
J
Li
Jian-Wen
JW
Han
Qiang
Q
Xu
Wen-Long
WL
Hu
Ting-Meng
TM
Pan
Yi-Lin
YL
Cheng
Ze-Ying
ZY
Yu
Cheng
C
Ni
Sha
S
Yao
Cai-Feng
CF
He
Yang-Sheng
YS
Liu
Yun
Y
Li
Hong-Mei
HM
Ge
Feng-Li
FL
Xiao
Liang-Dan
LD
Sun
Sen
S
Yang
Xue-Jun
XJ
Zhang
D000328:Adult; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics*; D064546:Protein Kinase C beta; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology
C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D051153:Wnt Proteins; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta