| Objective.This study aimed to investigate the association between single nucleotide polymorphisms?SNP?in PLA2R1?TMEM39A?APRIL?SPATA8?PDGFRA?POLB and systemic lupus erthematosus?SLE??lupus nephritis?LN??neuropsychiatric lupus?CNS-SLE?in a north China han population and to clarify the genetic pathogenesis of SLE.Methods.SNPs rs3792192?PLA2R1??rs4664308?PLA2R1??rs6438528?TMEM39A??rs2282175?TMEM39A??rs79931821?TMEM39A??rs3803800?APRIL??rs8023715?SPATA8??rs1364989?PDGFRA?and rs12678588?POLB?were genotyped in a cohort of 1247 SLE patients and 1174 healthy controls,using the Sequenom MassArray system method,using immune double diffusion method and indirect immunofluorescence to test anti-SSA?anti-SSB?anti-Sm,anti-RNP and anti-dsDNA antibodies,using enzyme-linked imunosorbent method to determine the level of serum complement C3 and C4,at the same time,SLE patients were classified into different clinical subtypes according to the serological indexes and the common manifestations in SLE?lupus nephritis and neuropsychological lupus?for the relevance analysis of the selected SNPS loci with SLE subtypes.All the results were analyzed by using PLINK1.07 and Haploview4.0 software.Results.1.Gene and genotype frequency analysis:The allele frequencies of rs3792189 and rs3792192 were significantly different between the SLE patients and controls(for rs4664308,P=0.02,odds ratio[OR]:1.16,95%confidence interval[CI]:1.02-1.31;for rs3792192,P=7.9×10-3,OR:1.18,95%CI:1.05-1.34).The frequencies of genotypes of rs3792189 and rs3792192 were significantly different between the SLE patients and controls?for rs3792189,P=0.04;for rs3792192,P=0.02?,and the haplotype?AA?formed by rs3792189 and rs3792192 was associated with SLE?P=0.02?.The differences in the frequencies ofthe SNPs?rs3828323 at PLA2R1?rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs3803800 at APRIL?rs8023715at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB?alleles and the genotypes were statistically insignificant between SLE patients and controls?all,P>0.05?.2.Analysis under three genetic models:The genotypes of rs4664308?PLA2R1?were statistically significant between SLE patients and controls using additive and dominant models?P=0.02,P=0.04?;The genotypes of rs3792192?PLA2R1?was statistically significant different between SLE patients and controls only whenusing dominant model(P=6.5×10-3);The genotypes of rs3792189?PLA2R1?was statistically significant between SLE patients and controls only whenusingrecessive model?P=0.02?;Moreover,no statistically significant difference were detected in the SNPs?rs3828323 at PLA2R1?rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs3803800 at APRIL?rs8023715 at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB?using different genetic models?additive,dominant,and recessive;all,P>0.05?.3.Analysis between the hypotypes of SLE with controls:There were statistically significant difference between LN and controls in the rs4664308?PLA2R1??P=0.04,OR1.16,95%CI 1.00-1.35?and also between SLE without LN and controls in the rs3792192?PLA2R1??P=0.01,OR1.22,95%CI 1.04-1.42?.There were no statistically significant difference between LN?SLE without LN and controls in the rs3828323?PLA2R1?and rs3792189?PLA2R1?.Moreover,no associations were detected in the SNPs?rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs8023715 at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB?between the hypotypes of SLE and controls?all,P>0.05?.There were statistically significant difference between anti-RNP antibody positive?anti-Sm antibody positive patients with controls in the rs8023715 at SPATA8?P=0.01,OR3.64,95%CI 1.28-10.4;P=0.01,OR3.30,95%CI 1.27-8.58?and also between anti-SSA negative?anti-SSB negative?anti-RNP negative?anti-dsDNAnegative patients with controls in the rs3803800 at APRIL?P=0.01,OR0.61,95%CI 0.41-0.89;P=0.02,OR0.73,95%CI 0.56-0.96;P=0.04,OR0.3,95%CI 0.54-0.99;P=0.04,OR0.71,95%CI 0.51-0.98?.4.Haplotype analysis:Rs3792189?PLA2R1?and rs3792192?PLA2R1?located in the same haplotype area?r2=1?and formed three haplotypes:CG?AA and AG.There were statisticallysignificantdifferencebetweenSLEandcontrolsintheAA haplotype?P=0.019?.5.Clinical analysis in neuropsychiatric lupus:The frequency of cerebrospinal fluid?CSF?abnormality?73.8%,among them,especially the increased CSF pressure?69%?and protein quantitative?34.5%??was significant higher than that of brain CT or MRI scan?31%?.Laboratory tests were remarkable for anti-SSA?58.3%??anti-RNP?53.6%?and anti-rRNP?38.1%?antibody positive patients with controls.Conclusion.1.The allele frequencies of rs4664308?PLA2R1?and rs3792192?PLA2R1?were related to SLE;The frequencies of genotypes of rs3792189 and rs3792192 at PLA2R1were related to SLE;Theallele frequencies and genotypes of the SNPs?rs3828323 at PLA2R1?rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs3803800 at APRIL?rs8023715 at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB?were unrelated to SLE.2.The genotypes of rs4664308?PLA2R1?were related to SLE in additive and dominant models;The genotypes of rs3792192?PLA2R1?was related to SLE only in dominant model;The genotypes of rs3792189?PLA2R1?was related to SLE only in recessive model;Moreover,no associations were detected in the SNPs?rs3828323 at PLA2R1?rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs3803800 at APRIL?rs8023715 at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB?in three genetic models?additive,dominant,and recessive;all,P>0.05?.3.Rs4664308?PLA2R1?was related to LN;Rs3828323?PLA2R1?and rs3792189?PLA2R1?were unrelated to LN;Rs6438528 at TMEM39A?rs2282175 at TMEM39A?rs79931821 at TMEM39A?rs8023715 at SPATA8?rs1364989 at PDGFRA and rs12678588 at POLB were unrelated to the hypotypes of SLE?LN?neuropsychiatric lupus?anti-SSA?anti-SSB?anti-Sm?anti-RNP?anti-dsDNA and low complement?.Rs8023715 at SPATA8 was related to anti-RNP antibody positive and anti-Sm antibody positive SLE.Rs3803800 at APRIL was related to anti-SSA negative?anti-SSB negative?anti-RNP negative and anti-dsDNA negative SLE.4.The haplotype?AA?formed by rs3792189 and rs3792192 at PLA2R1 was associated with SLE.5.Cerebrospinal fluid is the most basic and important examination for the diagnosis of CNS–SLE.Positive anti-SSA?anti-RNP and anti-rRNP antibodies were risk factors for CNS–SLE.Significance.This is the first report which indicates PLA2R1 might be a susceptibility gene for SLE/LN in a north China han population.Our research give us more evidence that systemic lupus erythematosus?SLE?is a kind of disease related to various genetic factors and certain genetic factors have been implicated in its pathogenesis,clinical expression,and production of its characteristic autoantibodies.TMEM39A?APRIL?SPATA8?PDGFRA and POLB were all susceptibility genes of SLE and LN as that previous genome-wide association study?GWAS?had reported,but we found no significant correlation with SLE in our north China han population,from which we can find that genetic mechanism is different in different ethnic groups with SLE.Moreover,PLA2R1was related to membranous nephropathy?IMN?and APRIL was related to IgA nephropathy as reported from some GWAS and replication studies,both IMN and IgA nephropathy are the common diagnosis in adults with the nephrotic syndrome and both of them are autoimmune diseases of the kidney similar to lupus nephritis?LN?.Our study aimed to investigate the association between the genes of PLA2R1and APRIL with SLE and LN,and from this study we can also find that LN and IMN may share common disease mechanisms that overlap with genetic susceptibility but the genetic mechanisms of LN and IgA nephropathy maybe different. |
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