The Study Of Genetic And Environmental Risk Factors And Gene-environment Interaction For SLE

Systemic lupus erythematosus(SLE) is a multifactorial inheritance disease,both genetic and environmental factors play an important role in the development of SLE. In order to explore the association of genetic and environmental factors as well as their interactions with SLE and SLE's phenotype,we applied case-control study and case-only study design in Southern Chinese han population with the aid of some molecular biologic techniques,such as polymerase chain reaction(PCR) and restriction fragment length polymorphism(RFLP).The results are as follows:PartⅠEnvironmental risk study of SLE1.With the univariate logistic regression analysis,the results showed that bugantia may be SLE's concomitant facter(OR=9.53,95%CI:5.58-16.28),damp of inhabited environment,ultraviolet exposure,allergy to sunlight,measles,herpes,injurant exposure,fatty food intake,medication hypersusceptibility and family history were related to SLE,with the odds ratios(ORs) of 7.85(95%CI:3.23-19.05),3.80(95%CI: 1.96-7.36),7.05(95%CI:3.88-12.79),11.95(95%CI:1.60-4.90),4.08(95%CI:1.62-10.26), 5.72(95%CI:2.86-11.43),1.81(95%CI:1.05-3.13),2.80(95%CI:1.6.0-4.90)and 76.64 (95%CI:10.46-561.36),respectively.2.With multiple logistic regression analysis,it showed that bugantia,damp of inhabited environment,allergy to sunlight,ultraviolet exposure,measles,injurant exposure and family history were responsible for SLE,with the odds ratios(ORs) of 7.09(3.71-13.53),6.59(2.18-19.75),3.81(1.81-8.02),2.94(1.21-7.11),11.96(2.24-63.82), 3.02(1.21-7.53) and 49.23(6.28-385.68),respectively.3.For female subjects,the results from multiple logistic regression analysis showed that bugantia,damp of inhabited environment,allergy to sunlight,ultraviolet exposure, measles,injurant exposure and family history were also responsible for SLE,with the odds ratios(ORs) of 8.00(4.04-15.84),6.51(1.93-21.92),3.23(1.49-6.99),4.31(1.63-11.35),12.70(2.37-68.22),2.81(1.09-7.21) and 51.76(6.56-408.72),respectively. PartⅡThe study on genetic susceptibility to SLE1.For locus PDCD1-PD12A＞G,the results showed that genotypic frequencies of A/A, A/G and G/G in case groups were significantly different from controls (χ~2 =9.049,P=0.011).Individuals with genotype A/G had a higher onset risk of SLE as compared with genotype A/A,with the OR=2.00(95%CI:1.27-3.45).A/G or G/G genotype carriers' OR merged together were 1.84(95%CI:1.19-2.85).For the allelic frequencies of PD12A＞G,there was also significant difference between patients and controls(χ~2 =4.273,P =0.039),and there was a higher propotion of allele G in SLE patients than that in controls(28.7%vs 21.7%).2.For locus PDCD1-PD16A＞G,the results showed that genotypic frequencies of A/A, A/G and G/G in case groups were significantly different from controls(χ~2 =10.094, P=0.006).Individuals with genotype A/G had a higher onset risk of SLE as compared with genotype A/A,with the OR=1.70(95%CI:1.08-2.70).A/G or G/G genotype carriers' OR merged together were 1.70(95%CI:1.10-2.62).For the allelic frequencies of PD16A＞G,there was also significant difference between patients and controls (χ~2=8.689,P =0.003),and there was a higher propotion of allele G in SLE patients than that in controls(28.4%vs 18.0%).3.For locus PDCD1-PD15C＞T,the results showed that genotypic frequencies of C/C,C/T and T/T in case groups were significantly different from controls (χ~2 =16.031,P=0.000).Individuals with genotype C/T had a higher onset risk of SLE as compared with genotype C/C,with the OR=2.48(95%CI:1.59-3.89).C/T or T/T genotype carriers' OR merged together were 2.49(95%CI:1.59-3.89).For the allelic frequencies of PD15C＞T,there was also significant difference between patients and controls(χ~2=12.084,P =0.001),and there was a higher propotion of allele G in SLE patients than that in controls(27.0%vs 15.8%).4.On polymorphic site CD22-BSP A＞T for CD22 gene,there were significant differences of the genotypic frequencies of T/T,A/T and A/A between patients and controls(χ~2=8.085,P =0.018).Individuals with genotype A/T had a higher SLE onset risk as compared with genotype T/T,and OR was 1.98(95%CI:1.20-3.27).A/T or A/A genotype carriers' OR merged together were 1.99(95%CI:1.24-3.20).For the allelic frequencies of CD22-BSP A＞T,there was also significant difference between patients and controls(χ~2=4.273,P =0.024),and there was a higher propotion of allele A in SLE patients than that in controls(19.9%vs 13.4%).5.On polymorphic site CD22-Cail C＞G for CD22 gene,there were significant differences of the genotypic frequencies of C/C,C/G and G/G between patients and controls(χ~2=14.143,P =0.001).Individuals with genotype C/G and G/G had a higher onset risk of SLE as compared with genotype T/T,and ORs were 1.97(95%CI:1.22-3.18), 5.23(95%CI:1.70-16.08),respectively.C/G or G/G genotype carriers' OR merged together were 2.27(95%CI:1.44-3.58).For the allelic frequencies of CD22-Cail C＞G, there was also significant difference between patients and controls(χ~2=16.140,P =0.000),and there was a higher propotion of allele A in SLE patients than that in controls(27.8%vs 14.9%).PartⅢHaplotype analysis of genesLinkage disequilibrium testThe calculation of the ambi-matched-pairs linkage disequilibrium parameter and the hypothesis tests were conducted using the Haploview4.0 software,It was found that there were low linkage disquilibriums(LD) among three polymorphic sites of PDCD1 gene as well as between two polymorphic sites of CD22 gene.The analysis of association of haplotype with SLEHaplotype association test was done by the use of SPSS13.0 after the assessment of haplotype structure for every individual done by PHASE2.1 software.It was found that the ACA and GTA haplotypes in PDCD1 gene were significantly different between SLE patients and controls(P=0.000,P=0.001).The haplotype of GTA in PDCD1 gene had a higher onset risk of SLE,while the haplotype of ACA and GCA may have a protective effect on SLE.The frequencies of TC and AG haplotypes in CD22 gene also had significant differences between SLE patients and controls (P=0.006,P=0.001).The haplotype of TC in CD22 gene may be protective for SLE with a recessive model,while the AG may be SLE's risk hapolotye with a dominant model.PartⅣInteractions between gene and environmental factors 1.The Multiple logistic regression analysis of genes and environmental factors showed that PD12,PD15 and CD22-Cail were associated with SLE for the genetic aspect,while bugantia,damp of inhabited environment,allergy to sunlight,ultraviolet exposure,measles,injurant exposure and family history were responsible for SLE from environmental perspective.2.Logistic regression analysis showed that there was no interaction between environmental risk factors,genetic risk factors,and gene-environment interaction was also not found.3.In case-only study,we performed log-linear model analysis,the results showed that there were interactions between PD12 and CD22-Cail(P=0.029),so were the case between CD22-BSP and CD22-Cail(P=0.000).Both interacton coefficients were positive.4.The log-linear model analysis showed that both PDCD1 and CD22 gene were not interacted with environmental risk factors in the development of SLE.5.The study of gene-phenotype association showed that PD12 was associated with skin manifestation(χ~2=5.878,P =0.015) and nerve system abnormity(χ~2=6.757,P =0.009),with ORs of 0.19(95%CI:0.05-0.73) and 0.33(95%CI:0.14-0.76) while taken A/A phenotype as reference.CD22-Cail was also associated with skin manifestation(χ~2=5.427,P =0.020),with OR of 4.86(95%CI:1.29-18.38) while taken C/C phenotype as reference.6.The study of environment-phenotype association showed that allergy to sunlight was associated with skin manifestation and anti-RNP antibody with the ORs of 12.52(95%CI:1.61-97.45)and 2.41(95%CI:1.18-4.93),bugantia and measles were associated with joint abnormity with the ORs of 1.94(95%CI:1.03-3.67)and 5.03(95%CI:1.42-17.78),herpes was associated with chorion manifestation with the OR of 3.04(95%CI:1.05-8.85),ultraviolet exposure was associated with kidney damage and nerve system abnormity with the ORs of 2.99(95%CI:1.43-6.22)and 2.46(95%CI:1.02-5.95),family history was also associated with kidney damage with the OR of 2.81(95%CI:1.44-5.49),injurant exposure was associated with nerve system abnormity and the decrease of C3 and C4 with the ORs of 3.40(95%CI:1.47-7.86)and 2.00(95%CI:1.00-4.12) respectively,fatty food intake was negatively associated with anti-Sm antibody and anti-RNP antibody with the ORs of 0.44(95%CI:0.22-0.91)and 0.14(95%CI:0.04-0.49) respectively.7.In case-only study,there was also no interaction of genetic and environmental risk factors with phenotypes of SLE.In conclusion,environmental and genetic factors may both play a role in the development of SLE and SLE's phenotype.Gene-gene interaction may be associated with SLE's phenotype,but we should do further research on the association of environment-environment interaction and gene-environment interaction with SLE and SLE's phenotype.