| Backgroud Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies and the formation of immune complexes (ICs). The deposit of autoantibodies and ICs can lead to inflammtion and injury of multiorgans, which causes disease at last. The clinic manifestations of SLE are variable including glomerulonephritis, dermatitis, vasculitis, epileptic seizure, arthritis and so on, so SLE is an type of complex diseases and regarded as the multifactorial disease. Nowadays there have been a lot of hypothesizes about the etiology and pathogenesis of SLE, such as immunology theory, the genetics theory and the theory of the interaction between environment and genetics. But the exact development mechanisms of SLE remains unclear, and many scholars are agreed that the genetic factors play an important role in the onset of SLE. A large number of domestic and overseas studies have found several genetic loci associated with the susceptibility to SLE through linkage analysis.Objective Through the large scale epidemilolgy survey of families with SLE and making use of the research results of Human Genome Plan, our study are aimed to search the genetic relationship with SLE of specific single nucleotide polymorphisms (SNPs) and hplotypes in the susceptible genes (signal transducers and activators of transcription gene) at some susceptible loci of Han ethnics among Chinese and finding the SNPs and haplotypes which have the statistically significant association with SLE. And the interaction between genetics and environment was discussed preliminarily in the study. Methods Through the SLE patients collecting network (constituted with the rheumatology department of the Anhui Provincial Hospital and the first affiliated hosptital of Anhui Medical University), the blood samples containing DNA and epidemiological statistics of 332 patients were collected from 100 families (including 87 nuclear families). The database about the information was set up using EPI DATA 3.0 software and then the data were analyzed by Statistical Package for the Social Science (SPSS) 10.01 and the biostatistical analysis software, the Family Base-Association Test (FBAT) v1.7.3, after having been checked and sorted. And the possible interaction between genes and environment on SLE were analyzed with conditional logistic regression method.Results A total of 332 subjects from 100 qualifiedr families (including 87 nuclear families) (58 [66.7%] families had both parents, 20 [23.0%] families had one single parent and 9 [10.3] had no available parents) were finally recruited. The family criteria for subject selection were used as follows: (1) at least two parents, (2) at least two siblings, and (3) at least one parent and one additional sibling. the mean age is 44.20±15.50 years (minimum 13, and maximum 86).In the STAT4 gene, we selected 4 SNP loci according to the information (rs10181656, rs11889341, rs7574865 and rs8179673) from the NCBI page, and they all have polymorphism in Chinese population. Among 87 SLE patients, the frequencies of rs10181656 CC, CG and GG genotypes were 48.7%, 9.8% and 41.5%, respectively. The frequencies of rs11889341 CC, CT and TT genotypes were 4.7%, 94.9% and 0.3%, respectively. The frequencies of rs7574865 GG, GT and TT genotypes were 53.1%, 21.3% and 25.6%, respectively. The frequencies of rs8179673 CC, CT and TT genotypes were 18.3%, 21.8% and 59.9%, respectively. Univariate (single-marker analysis) family-based association test (FBAT) demonstrated that variant alleles at four SNPs were significantly associated with genetic susceptibility to SLE in dominant model (rs11881656, Z=3.521, P=0.00043, rs11889341, Z=2.110, P=0.034899, rs7574865, Z=3.120, P=0.001811, rs8179673, Z=3.821, P=0.000133). Four haplotypes (rs10181656, rs11889341, rs7574865 and rs8179673), CTGT(23.8%), GCTC(22.4%), CCGT(21.7%) and GTTC(15.6%) were reconstructed. The haplotype in the STAT4 gene specific FBAT showed GTTC(15.6%) haplotype was more frequently transmitted in SLE than other haplotypes (Z=3.375, P=0.000737).In addition, about the possible gene-environment interaction, we use the design of case-control study in family according to the icdicated age. Total 58 pairs of patient and his normal sibling were selected, the conditional logistic regression model was used to analyse the data. The environmental factors were significant between the SLE cases with their normal siblings, such as sex (OR=38.294, CI=3.333-440.007), hypersensitiveness (OR=12.393, CI=2.958-51.928). In addition, the conditional logistic regression model was used to explore the interaction of rs11889341 with hypersensitiveness. The positive interaction of hypersensitiveness with rs11889341 was found.Conclusions In conclusion, the STAT4 gene (located 2q32) may be susceptibility loci in the Chinese Han SLE Population, meantime, have the action with the environment and the interaction of gene-environment. The present study has demonstrated that four STAT4 polymorphisms and one haplotype were significantly with genetic susceptibility to SLE in Chinese population by family-based association test.
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