| Background and Purpose:Parkinson’s disease(PD)is the second most common neurodegenerative disorder after Alzheimer’s disease.It is characterized by static tremor,bradykinesia,rigidity,and postural instability.The pathological features of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)and the formation of Lewy bodies(LB)containing α-synuclein.At present,the pathogenesis of PD is still unclear,mainly involving neuroinflammation,oxidative stress,mitochondrial dysfunction,autophagy-lysosomal disorders,protein homeostasis,and apoptosis.Age,gender,race,drugs,brain damage,and environmental factors all may affect the development of PD.With the development of gene sequencing technology,there are increasing evidences showing that genetic factors play an important role in the pathogenesis of PD.Recently,a meta-analysis identified a new set of Genome-wide association studies-related loci whose ability to predict PD in Caucasians cannot be ignored.However,whether these loci are related to the risk of PD in the Chinese Han population is still controversial.In order to further confirm the PD susceptible sites in Chinese Han population,we conducted a case-control study that explore whether the 15 loci polymorphisms were related to PD risk.And we tried to find the relationship between these genes and PD.Methods:1.This study is a case-control study.2.We enrolled 492 Chinese Han PD patients as the case group and 524 age-and gender-matched healthy adults as the control group.All data were extracted from the PD database of the Department of Neurology,the First Affiliated Hospital of Zhengzhou University from July 2012 to September 2019.3.Based on the 1000 Genomes Project,we looked up the information of 15 single nucleotide polymorphisms to be genotyped,including rs13294100(SH3GL2),rs12497850(NCKIPS/CDC71),rs10906923(FAM171A),rs2280104(BIN3),rs2694528(ELOVL7),rs34043159(IL1R2),rs353116(SCN3A),rs4073221(SATB1),rs4653767(ITPKB)rs11343(COQ7),rs143918452(ALAS1),rs2740594(CTSB),rs601999(ATP6V0A1)and rs78738012(ANK2/CAMK2D).4.After all participants signing the informed consent,peripheral venous blood DNA was extracted.The improved multiple ligase detection reaction(iMLDR)technology was used to genotype the above loci.5.Statistical analyses were performed using IBM SPSS Statistics 23.0 software.Pearson χ2 test was used to verify whether the genotypes of the 15 loci in the healthy control group abide by the Hardy-Weinberg equilibrium.The Student t test was used to compare the the mean age of two groups and Pearson χ2 test was used to compare gender ratio composition of two groups.Single-factor Logistic analyses were used to identify PD-related loci.Multi-factor logistic regression analyses were used to eliminate the interference of confounding factors,such as age and gender.Subgroup analyses of 15 loci by age-at-onset and gender were performed to further understand the relationship between genes and PD.Results:1.This study included 492 PD patients and 524 healthy controls.There was no significant difference in the mean age(P=0.143)and gender ratio composition(P=0.785)between the PD group and the control group.2.The distribution of genotype frequencies of 15 loci in the control group were in accordance with Hardy-Weinberg equilibrium(P>0.05).The minor allele frequencies of 5 loci were less than 0.05,including rs11343(COQ7),rs143918452(ALAS1),rs2740594(CTSB),rs601999(ATP6V0A1)and rs78738012(ANK2/CAMK2D).3.IMLDR technology was used for genotyping successfully,and the polymorphisms of 15 loci were confirmed.4.Single-factor logistic regression analyses showed that rs34043159(ILIR2)was significantly correlated with PD in the dominant model(TT+CT vs.CC:P=0.021,OR 95%CI 0.714(0.536-0.951)).After adjusting gender and age by multi-factor logistic regression,the dominant model of rs34043159(IL1R2)was still associated with PD(P=0.011,OR 95%CI 0.577(0.378-0.880)).Bonferroni correction showed that there was no significant difference of this locus between the case group and the control group(Pcorr=0.003).5.Single-factor logistic regression analyses showed that rs4073221(SATB1)was significantly correlated with PD in the allele model(G vs.T:P=0.001,OR 95%CI 0.542(0.371-0.792)),the dominant model(GG+GT vs.TT:P=0.043,OR 95%CI 0.656(0.436-0.988)),and the recessive model(GG vs.GT+TT:P<0.001).After adjusting for gender and age by multi-factor logistic regression,the dominant model of rs4073221(SATB1)still showed a correlation with PD(P=0.049,OR 95%CI 0.581(0.345-0.998)),while the recessive model of rs4073221(SATB1)had nothing to do with PD(P=0.999).Bonferroni corrections showed that there was no significant difference in this locus between the case group and the control group(Pcorr=0.003).6.In the subgroup of age-at-onset≥50 years,the frequency of genotype distribution of rs34043159(IL1R2)(χ2=7.971,P=0.019)and rs4073221(SATB1)(χ2=12.673,P=0.001)was statistically different between the case group and the control group.In the subgroups with age-at-onset<50 years,there was no significant difference in the genotype frequency distribution of rs34043159(IL1R2)(χ2=0.401,P=0.818)and rs4073221(SATB1)(χ2=4.102,P=0.120).7.In the female PD subgroup,the genotype frequency distribution of rs34043159(IL1R2)between the case group and the healthy control group was significantly different(χ2=7.227,P=0.027).In the male PD subgroup,the genotype frequency distribution of rs34043159(IL1R2)was not significantly different between the case group and the healthy control group(χ1=1.100,P=0.577).While the genotype frequency distribution of rs4073221(SATB1)between the case group and the healthy group was significantly different both in the male PD subgroup(χ2=10.270,P=0.005)and the female PD subgroup(χ2=7.050,P=0.022).Conclusion:1.The polymorphisms of rs34043159(IL1R2)and rs4073221(SATB1)are associated with the risk of late-onset PD in Chinese Han population.2.The polymorphisms of rs34043159((IL1R2)are associated with the risk of female PD in Chinese Han population.3.The polymorphisms of rs4073221(SATB1)are associated with the risk of male PD and female PD in Chinese Han population. |
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