| ObjectiveThe incidence of gout had increased significantly in recent years,especially in coastal areas.Clinical observation found that the incidence of the disease was significantly different between male and female.The onset of gout became younger gradually and had the tendency of familial aggregation.In addition,the gout gave the patient a heavy psychological burden.Gout patients often suffer from obesity,lipid metabolism disorder,insulin resistance,hyperinsulinemia,diabetes,hypertension and even coronary heart disease at the same time.But the relevant mechanism had not been completely analyzed,so it is important to study the genetic susceptibility and pathogenesis of gout.As a polygenic disease,its genetic susceptibility derives from a series of susceptible genes.In other words,not a single gene but multiple susceptible genes lead to gout together.With more and more researches on the pathogenesis of gout,there was a series of new discovery of gout related genes.Most of the gout susceptibility genes that have been found are related to the reabsorption and secretion of uric acid in the kidney.The epidemiological studies of our group and other research teams all show that the gout has obvious epidemiological characteristics and there are significant differences in gender.Genome-wide association studies(GWAS)have identified dozens of hyperuricemia /gout susceptibility genes.At present,three genes(SLC2A12,ABCG2 and SLC2A9)are confirmed repeatedly in multiple ethnic groups such as Chinese,Korean and Japanese populations in Asia,the Caucasian population in Europe,and Mexican Americans.A large-scale meta-analysis detected nine single nucleotide polymorphisms(SNPs)associated with serum uric acid concentrations.Studies have shown significant gender differences in gout genetic pathogenesis.We previously investigated the relationship between the eight SNPs(rs734553(SLC2A9),rs12356193(SLC16A9),rs1183201(SLC17A1),rs17300741(SLC22A11),rs505802(SLC22A12),rs780094(GCKR),rs742132(LRRC16A)and rs12129861(PDZK))and gout in Chinese Han male population and three SNPs(rs1183201,rs780094 and rs505802)were successfully replicated.Therefore,it is necessary to repeat the study on these SNPs and detect biochemical indicators related to the metabolic syndrome,to clarify the correlation between serum uric acid metabolism and glucose-lipid metabolism abnormalities,as well as gender differences.In this study,we aim to determine whether the eight SNPs are significantly associated with gout in females.MethodPolymerase chain reaction(PCR),sequencing technology and Genemapper software were used to genotype age-matched 318 female cases and 682 female normal volunteers long living in Shandong coastal areas.Then,clarify whether these SNPs were associated with gout in Han Chinese females and whether allele distributions of these SNPs were different between females and males.Result1.The body mass index of the gout groupwas higher than the control group(P =0.025).The systolic and diastolic blood pressure of the gout group were significantly higher than that of the control group(P = 0.002 and P < 0.001).The serum triglyceride in the gout groupwas significantly higher than that in the control group(P < 0.001).The serumurea nitrogen and creatinine level in the gout groupwere significantly higher than that in the control group(P = 0.003 and P < 0.001).While the serum glucose in the gout group was lower than that in the control group,but there is no statistical difference(P =0.058),as well as cholesterol level(P = 0.065).Both indexes were inconsistent with the previousresearch results of female gout.2.We also compared the basic body and biochemical indexes beween male and female.The average age and onset age of female gout were significantly higher than male,and body mass index is significantly lower(P < 0.001).The incidence of hypertension in femle gout patients was significantly higher than that in male gout patients(P = 0.006),with the systolic blood pressure significantly higher than male(P = 0.006),and the diastolic blood pressure significantly lower(P < 0.001).In metabolic indexes,female gout patients had lower levels of blood glucose,triglyceride and uric acid(P < 0.001,P =0.002 and P < 0.001),and a higher level of blood cholesterol(P < 0.001).The incidence of gouturatoma in female patients was significantly lower than that of male gout cohort(P= 0.019).But there was no significant difference in serum creatinine between the two cohorts(P = 0.215),which was not consistent with previous studies.3.There was no significant difference in the incidence of the plantar joint as the first gout joint between male and female gout(P = 0.692).The probability of dorsum of the foot and the ankle joint involved by uratoma in female gout cohortwas significantly lower than male(P = 0.002 and P < 0.001)?4.The eight SNPs in the control cohort were tested by genetic balance test and all P values were larger than 0.05,indicating the accordance with Hardy-Weinberg equilibrium.5.Minor allele frequency(MAF)of rs734553 in gout and normal controls is 0.006 and 0.016,respectively and that of rs12356193 in gout and normal controls is 0 and 0.002,respectively.Both are rare SNPs and the others are common SNPs with MAF greater than0.05.6.No statistically significance was found in rs1183201 genotype frequency distribution(P = 0.072,FDR = 0.287);And its allele frequency distribution wassignificantly different(P = 0.026)with minor allele T allele conferred to be a protective factor(ORs and 95% CI: 0.759,0.595 ~ 0.968),but this significance was subsequently eliminated after multiple correction(P = 0.210).7.Other SNPs had no significant difference in case-controls(P > 0.05).8.The testing power of the eight SNPs is 0.223,-,0.344,0.052,0.106,0.074,0.050 and 0.103 successively.9.Allele and genotype frequencies were basically the same in female gout and male gout(P> 0.1);rs780094 locus allele frequency and genotype frequency were significantly different in female controls and male controls(P = 0.025 and 0.033,respectively),but this significance was subsequently eliminated after multiple correction(P = 0.201 and 0.236,respectively).10.Rs1183201 and rs742132 were located in the same chromosome region 6p22.2.Haplotype analysis were performed in these two SNPs and three haplotypes were detected:AT,TT and AC(P > 0.03).The frequency distribution in female gout and female controls were similar,with no significant difference(P > 0.05).In the haplotype analysis of rs17300741-rs505802,three haplotypes were also detected: AA,AG,and GG(P > 0.03).The frequency distributions in female gout and female controls were also similar,with no significant difference(P > 0.05).11.Rs1183201 were significantly correlated with triglyceride level(P = 0.03 after FDR),and the mean values of TT genotype,AT genotype and AA genotype were1.91±1.18 ? 1.35±0.69 and 1.53±0.99.There were no significant associations between other SNPs and basic biochemical indexes(P > 0.05 after FDR).Conclusion1.There were significant differences in body mass index,systolic and diastolic blood pressure,serum triglyceride,urea nitrogen and creatinine between the female gout cohort samples and the control group,which basically met the results of several epidemiological and clinical studies.But there was no significant difference in serum glucose and cholesterol.2.The average age,onset age,systolic blood pressure,incidence of hypertension and serum cholesterol level of Chinese female gout patients were significantly higher than those of male.And body mass index,diastolic blood pressure,incidence of uratoma,serum glucose,triglyceride and uric acid of female were significantly lower than male.All these were basically consistent with previous studies.But there was no significant difference in serum creatinine level,which is different from previous studies.3.The first gout joint in female was the first plantar joint,while the uratoma in male was more likely to locate in the dorsal joint of the foot and the ankle joint,that was not completely in line with previous statistics.4.Both rs734553 and rs12356193 were rare mutations in the eight SNPs.Therelationship between rs1183201 and primary female gout was strongest,but still not significant.The rs780094 had a bit of difference between healthy male and female,but the correlation was not significant.5.The association between serum uric acid-correlated SNPs and female gout is not confirmed.These SNPs distribution in females and male is also not found.Small sample size leading to low testing power may explain this and larger sample size is needed to further clarify the association. |
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