| Systemic Lupus Erythematosus (SLE) is an autoimmunity disease with multiple system impairment, both gene and environment play important roles in the development of SLE. With the help of molecular biologic techniques including Polymerase Chain Reaction and Restriction Fragment Length Polymorphism, we applied case-control study and case-only study to explore the association of Methyl-CpG-binding protein-2(MECP2) gene polymorphism,5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, the gene-gene interaction and the gene-environment interaction with SLE among Chinese Han women in South of the Yangtze. Then we further explored the association between MECP2polymorphism, MTHFR polymerphism and SLE phenotypes. The results are as follows:Part Ⅰ The association of Single Nucleotide Polymorphism(SNP) with SLE1.The result from univariate logistic regression indicated that, under additive models, the genotype distribution of rs2239464in MECP2was significant different between case and control (χ2=6.060, P=0.014), with AA genotype as a reference, people with AG genotype had a lower risk of SLE(OR=0.531,95%CI:0.321-0.879); The genotype distribution of rs2239464were also significant different between two groups under dominant models(χ2=6.198,P=0.013), people bearing AG/GG genotype had a lower risk of SLE compared to those with A A genotype(OR=0.511,95%CI:0.301-0.867). There was a significant difference in the distribution of rs2239464allele in MECP2between case and control (χ2=5.515, P=0.019), the G allele might decrease the risk of SLE, as compared to A allele(OR=0.565,95%CI:0.351-0.910).2.The result from univariate logistic regression indicated that, under additive models, the genotype distribution of rs2075596in MECP2was significant different between case and control (x2=10.472, P=0.001), with AA genotype as a reference, people with AG genotype had a lower risk of SLE(OR=0.446,95%CI:0.274-0.728); The genotype distribution of rs2075596was also significant different between two groups under dominant models(x2=10.114,P=0.001), people bearing AG/GG genotype had a lower risk of SLE compared to those with AA genotype(OR=0.430. 95%CI:0.256-0.724). There was a significant difference in the allelic distribution of rs2239464in MECP2between case and control(x2=9.773, P=0.002), the G allele might protect people from SLE, relative to A allele(OR=0.479,95%CI:0.302-0.760).3.The result from univariate logistic regression indicated that, under additive models, the genotype distribution of A1298C in MTHFR was significant different between case and control (x2=7.608,P=0.006), with A A genotype as a reference, people with AC genotype had a higher risk of SLE(OR=1.819,95%CI:1.189-2.782); The genotype distribution of A1298C under dominant models were also significant different between two groups(x2=7.464, P=0.006), people with AC/CC genotype had a higer risk of SLE compared to those with AA genotype(OR=2.005,95%CI:1.217-3.303). There was a significant difference in the allelic distribution of A1298C in MTHFR between case and control(x2=7.967, P=0.005), the C allele might protect people from SLE, relative to A allele(OR=1.839,95%CI:1.205-2.808).4. There were no significant difference in the allelic or genotype distribution of C677T and G1793A sites of MTHFR between cases and controls (P>0.05).5. After adjustment of factors(age, bugantia, damp and UV), the Multiple logistic regression indicated that the rs2075596polymorphism in MECP2was related to SLE under additive and dominant models, as compared to AA genotype, people with AG genotypes (OR=0.448,95%CI:0.267-0.892) or AG/GG genotype (OR=0.447,95%CI:0.237-0.843) had a lower risk of SLE.7. The Multiple logistic regression indicated that the A1298C polymorphism in MTHFR was related to SLE under additive and dominant models, after adjustment of factors (age. bugantia, damp and UV), people with AC genotypes (OR=1.933,95%CI:1.154-3.238) or AC/CC genotype (OR=2.119,95%CI:1.135-3.957) had a higher risk of SLE, taken AA genotype as reference.8. After adjustment of factors (age, bugantia, damp and UV), the Multiple logistic regression failed to find any significant difference between the genotype distribution of rs2239464in MECP2, C667T or G1793A in MTHFR between cases and controls (P>0.05).Part Ⅱ The association of haplotype with SLE1. It was found that there was significant linkage disequilibrium between rs2239464and rs2075596in MECP2gene (x2=189.579,P<0.01). with D’being0.721and r2 being0.455. For MTHFR, C677T and A1298C, C677T and G1793A, A1298C and G1793A were also in linkage disequilibrium (χ2were52.056,23.268,96.041respectively, all P values were less than0.01), with D’being0.936,1.000and0.875; r2being0.146,0.072and0.330, respectively.2. The result from HAPSTAT3.1indicated that, under additive and recessive model, the A-A haplotypes composed of rs2239464and rs2075596in MECP2gene was associated with higher risk of SLE, with no A-A haplotype as reference(additive model:P=0.001, OR=3.139; recessive model:P=0.003, OR=2.075). And the additive model was the optimal model according to the minimum of AIC.3. The result from HAPSTAT3.1indicated that, under additive and dominant model, the C-C-G haplotype composed of C677T, A1298C and G1793A in MTHFR gene was associated with higher risk of SLE, with no C-C-G haplotypes as reference (additive model:P=0.020,OR=2.482; dominant model:P=0.017, OR=2.088); With those without C-A-G haplotypes as reference, the C-A-G haplotype was associated with lower risk of SLE, under recessive model(P=0.037, OR=0.514). And the additive model was the optimal model according to the minimum of AIC4. No significant interactions of haplotype-haplotype or haplotype-environment was found under additive, dominant or recessive model using the software of HAPSTAT3.1.Part Ⅲ The study of interactions between gene-gene and gene-invironment for SLE.1. For case-only study, we explored the interactions of gene-gene and gene-environment through log-linear model under additive, dominant and recessive model. And no significant interactions were found.2. Logistic regression was used to explore the interactions between gene-gene and gene-environment for case-control study under additive, dominant and recessive model. The result indicated that there was significant interactions between AG/AA genotype of G1793A and UV (β=-1.802,.P=0.030) under dominant model. We failed to find any other significant interactions between gene-gene or gene-environment.Part Ⅳ The association of genes with SLE phenotype1. The result of x-test indicated that the polymorphism of rs2239464in MECP2were association with renal manifestations and hematologic system abnormal in SLE cases. Taken AA genotype or A allele as reference, there were lower frequencies of AG/GG genotype (P=0.014, OR=0.386,95%CI:0.179-0.832) or G allele (P=0.006, OR=0.387.95%CI:0.193-0.775) in patients with renal manifestations. The frequency of G allele is lower in Patients with hematologic system abnormal than those without (P=0.049,OR=0.463,95%CI:0.215-0.996),when taken A allele as reference. We failed to find any association of rs2239464polymorphism with other organ damage. And there were no significant association of rs2075596with organ damage.2. The result of Χ2test indicated that the polymorphism of rs2239464and rs2075596in MECP2were association with anti-RNP in SLE patients. Patients with positive anti-RNP had higher frequencies of AG/GG genotypes (P=0.034, OR=2.590,95%CI:1.054-6.367) or G allele (P=0.011, OR=2.560,95%CI:1.215-5.393) in rs2239464than those without, taken AA genotype or A allele as reference. There were also higher frequencies of AG/GG genotypes (P=0.038,OR=2.583,95%CI:1.032-6.465) or G allele (P=0.011, OR=2.640,95%CI:1.222-5.703) in rs2075596among those with positive anti-RNP. We failed to find any significant association of rs2239464or rs2075596in MECP2with other indexes of immunological.3. The result of χ2test indicated that the polymorphism of A1298C in MTHFR were association with skin or mucosa abnormal in SLE patients. When taken AA geno-type or A allele as reference, patients with skin or mucosa abnormal had higher frequencies of AC/CC genotypes (P=0.043, OR=4.378,95%CI:1.051-18.240) or C allele (P=0.044, OR=4.067,95%CI:1.041-15.890). There were no associations of A1298C with other organ damage. And we failed to find any significant associations of C677T or G1793A with organ damage in SLE patients either.4. The result of χ2test indicated that the polymorphism of A1298C and G1793A in MTHFR were association with decline of C3C4in SLE patients. Compared to AA genotype or A allele, patients with decline of C3C4had higher frequencies of AC/CC genotypes (P=0.007, OR=2.745,95%CI:1.294-5.820) or C allele (P=0.007, OR=2.405,95%CI:1.253-4.614) in A1298C than those without. There were higher frequencies of AG/GG genotypes (P=0.037, OR=3.211,95%CI:1.028-10.028) or G allele (P=0.034,OR=3.125.95%CI:1.038-9.409) in G1793A among those with decline of C3C4when taken GG genotype or G allele as references. No associations of A1298C or G1793A with other indexes of immunological had been found. And we could not find any significant association of C677T with indexes of immunological in SLE patients either. 5. The result from HAPSTAT3.1indicated that the A-A haplotype of MECP2was associated with renal manifestation in SLE patients under additive model, patients with renal manifestation had higher frequencies of A-A haplotype when taken no A-A haplotypes as reference(P=0.022, OR=2.115,95%CI:1.105-4.047).No significant association of A-A haplotype with renal manifestation had been found under dominant or recessive models. And the additive model was the optimal model according to the minimum of AIC. We failed to find any significant association of A-A haplotype with other organ damage in SLE cases.6. The result from HAPSTAT3.1indicated that the A-A haplotype of MECP2was associated with anti-RNP in SLE patients under additive and recessive model, patients with positive anti-RNP had lower frequencies of A-A haplotype when taken no A-A haplotypes as reference(additive:P=0.006, OR=0.368,95%CI:0.179-0.757; recessive:P=0.014, OR=0331,95%CI:0.137-0.803). The additive model was the optimal model according to the minimum of AIC. No significant associations of A-A haplotype with other index of indexes of immunological in SLE patients had been found.7. We failed to find any significant association of C-A-G or T-A-G haplotypes in MTHFR with organ damages in SLE patients under additive, recessive or dominant models.8. The result from HAPSTAT3.1indicated that the C-A-G haplotype of MTHFR was associated with anti-SSA and anti-SSB in SLE patients under additive model, patients with positive anti-SSA(P=0.035,OR=0.494,95%CI:0.515-0.803) and anti-SSB (P=0.042, OR=0.441,95%CI:0.199-0.977) had lower frequencies of C-A-G haplotype when taken no C-A-G haplotypes as reference. No significant association of C-A-G haplotype with anti-SSA and anti-SSB were found under recessive or dominant models. And the additive model was the optimal model according to the minimum of AIC. We also found significant association of C-A-G and T-A-G haplotypes of MTHFR with decline of C3C4in SLE patients under additive modles, the C-A-G haplotype (P=0.034, OR=0.459,95%CI:0.221-0.951) and T-A-G haplotype (P=0.033, OR=0.467,95%CI:0.230-0.949) showed protective effective on decline of C3C4. We failed to find any significant association of C-A-G or T-A-G haplotype with decline of C3C4under recessive or dominant models. And the additive model was regarded as the optimal model according to the minimum of AIC. No significant association of C-A-G or T-A-G haplotype with other indexes of immunological in SLE patients had been found. |
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