Association Study Of LEP And LEPR Gene Single Nucleotide Polymorphisms With Genetic Susceptibility To Systemic Lupus Erythematosus

BackgroundSystemic lupus erythematosus(SLE)is a compelx connective tissue disease,characrterized by producing a large number of autoantibodies,involving multi-system organs and arising immune complex deposition,also known as a kind of systemic autoimmune diseases.This disease not only affects the blood vessel walls and skin tissues,but also changes the functional of various organs,like joints,kidneys,blood system,and the nervous system.Now,it is well known that the incidence of SLE varies with different regions,ethnic groups,and gender.Over 90 precent of SLE patients is women,and the onset age of most SLE patients focused on 25 ~ 45 years old.The incidence of SLE in the women of our contry is probably 110/100 000.This disease has seriously affected the physical and mental health of childbearing age women.Though the etiology and pathogenesis of SLE is not yet clear,it may be influenced by genetic factors and environmental factors.Leptin is a protein encoding by leptin gene(LEP),and involved in a variety of immune inflammatory process in the body.Leptin can exert it biological function via combined with leptin receptor to activiate different signaling pathways such as JAK2/STAT3 and mTOR.In addition,Leptin could participate in the immune regulation process by promoting T cell proliferation,inhibiting T cell apoptosis,inducing the expression of a variety of cytokines such as interleukin 1(IL-1),IL-6,tumor necrosis factor?(TNF-?),and promoting helper T cells differentiation toward T-helper 1(Th1)cells.Recent studies demonstrated that leptin and leptin receptor gene polymorphism and leptin levels are associated with the development of variousautoimmune diseases such as SLE and rheumatoid arthritis(RA).At present,there have some controversial conclusions among the researches about the leptin expression levels in SLE,and the studies are still limit which involved the association between leptin and leptin receptor gene polymorphism and genetic susceptibility to SLE in Chinese Han population.ObjectiveWe aimed to explore the association of leptin gene(LEP)and leptin receptor gene(LEPR)single nucleotide polymorphisms(SNPs)with genetic susceptibility to SLE in a Chinese population,and analyze the association between SNPs and clinical features,disease activity and serum leptin levels in SLE patients.MethodsIndependent case-control studies were conducted in unrelated ethnic Han Chinese population.A total of 633 patients with SLE were recruited from department of Rheumatology at Anhui Provincial Hospital,the First Affiliated Hospital of Anhui Medical University and Anqing Hospital.All patients met the 1997 revised criteria of the American College of Rheumatology for the classification of SLE.A total of 559 healthy volunteers recruited from Physical Examination Center of the First Affiliated Hospital of Anhui Medical University were included as healthy controls.Four LEP SNPs(rs11761556,rs12706832,rs2071045,rs2167270)and nine LEPR SNPs(rs10749754,rs1137100,rs1137101,rs13306519,rs8179183,rs1805096,rs3790434,rs3806318,rs7518632)were genotyped using improved multiple ligase detection reaction(iMLDR)genotyping assays.The serum leptin levels of SLE patients were detected by enzyme linked immunosorbent assay(ELISA).ResultsNo significant differences were detected for the distribution of allele and genotype frequencies of all 13 SNPs between SLE patients and controls(all P>0.05).After adjust sex and age,the genotype frequencies of the LEPR rs1137100 has statistically difference between two groups(GG vs.AA:?2= 3.904,P= 0.048,OR=1.948,95% CI : 1.005-3.776).The genotype effects of recessive,dominant and additive models were also analyzed,but no significant evidence for association was detected(all P>0.05).After adjust sex and age,the genotype effects of recessive and additive models in LEPR rs1137100 were significantly different in two groups(GA+GG vs.AA:?2= 4.365,P= 0.037,OR= 0.496,95% CI:0.257-0.958;GG vs.AA:?2= 3.871,P= 0.049,OR= 0.514,95% CI:0.265-0.997).However,in LEP,further analysis in SLE patients showed that the TT genotype and T allele frequencies of the rs2071045 were significantly higher in patients with pericarditis(?2= 8.811,P= 0.012;?2= 6.432,P= 0.011).The allele frequencies of the rs11761556 were associated with SLE patients who combined with malar rash(?2=4.067,P= 0.044).In LEPR,the GG/GA genotype and G allele frequencies of the rs3806318 achieved the significant difference in patients with photosensitivity(?2=8.693,P= 0.013;?2= 6.948,P= 0.008),and the genotype frequencies of rs3806318 also correlated with arthritis(?2= 6.204,P= 0.045).Moreover,we found that the AA/GA genotype and A allele distribution of rs1137100 was significantly associated with photosensitivity in the SLE patients(?2= 6.272,P= 0.043;?2= 5.609,P= 0.018).In halpotype analysis,ACGCAGCAA halpotype formed by LEPR gene polymorphisms were significantly lower in SLE than in controls(?2= 9.038,P=0.003,OR= 0.745,95% CI:0.615-0.903),while ATGCAGCAA halpotype in SLE patients were significantly higher than those in controls(?2= 4.327,P= 0.038,OR=1.390,95% CI:1.018-1.897).Serum leptin levels had no significant association with the 13 SNPs in SLE patients(all P>0.05).ConclusionsIn summary,LEP and LEPR SNPs are not associated with genetic susceptibility to SLE,and they are also not associated with the serum leptin levels in SLE patients.However,after adjust sex and age,the genotype frequencies of the LEPR rs1137100 has statistically difference between two groups.And some SNPs may contribute to some specific clinical phenotype of this disease.