The Association Between Low Frequency Mutations And Genetics Of "High Purine,Low Uric Acid" Population

Objective: To explore the specific genetic mechanism of low frequency mutation loci in the phenomenon of "high purine,low uric acid" in Kazakhs from a genetic perspective,and to provide a basis for early warning of disorders of uric acid metabolism.Methods: General clinical indices and blood biochemical indices were measured in 3097 Kazakh healthy physical examination population by using a current survey;retrospective dietary survey was conducted by screening low uric acid and its uric acid normal population by semi-quantitative food frequency questionnaire and purine intake was calculated;single nucleotide polymorphisms of genes related to common uric acid metabolism disorders were detected by multiplex high temperature ligase assay reaction;whole exon sequencing was performed on selected members of low uric acid family lines by using sequence capture technology to find low frequency mutation loci associated with low uric acid in Kazakhs,and Sanger sequencing technology was used for population validation and bioinformatics analysis.Results:(1)The mean blood uric acid level in the surveyed population of 3097 Kazakhs was 260.41±71.99μmol/L,and it tended to increase with age,among which the mean blood uric acid level was 298.22±69.57μmol/L in men and 236.17±62.44μmol/L in women,and the difference was statistically higher in men than in women(P<0.05);the detection rate of low uric acid was 11.1%,including 2.6%in men and 16.6% in women.(2)The dietary survey found that the average daily intake of livestock meat,cereals,milk and dairy products of the Kazakh population was significantly higher than the recommended value of the average diet of Chinese residents;the total daily intake of purine per standard person was 521.67 mg,of which 704.44 mg for men and 352.97 mg for women,and the daily intake of purine for men was significantly higher than that of women.The total daily purine intake per standard person was521.67 mg,of which 704.44 mg for men and 352.97 mg for women,with men being significantly higher than women,and both higher than the daily per capita purine intake of319.0mg for Chinese residents in 2002.(3)The differences between common mutations SLC2A9 gene rs13101785,rs13137343,rs7679916,rs938557 and SLC22A12 gene rs505802,rs524023 SNP loci with different genotypes and alleles in Kazakh low uric acid and normal control population were not statistically significant(P > 0.05);in The association differences between SLC2A9 gene rs13101785,rs13137343,rs7679916,rs938557 and SLC22A12 gene rs505802,rs524023 SNP locus polymorphisms and Kazakh population with low uric acid were not statistically significant under dominant,recessive and co-dominant models(P>0.05).There was no statistically significant difference(P>0.05)between the general clinical indices of the SLC2A9 gene rs13101785,rs13137343,rs7679916,rs938557 and SLC22A12 gene rs505802,rs524023 SNP loci with different genotypes in the low uric acid and normal control populations,excluding the above common The association between mutations in the above common loci and "high purine,low uric acid" in this study population was excluded.(4)Whole-exome sequencing was performed on the low uric acid and normal uric acid members of the six screened low uric acid families,and no mutations related to low uric acid were detected by comparing the identified mutation loci of genes related to uric acid metabolism;and eight low frequency mutated genes were initially screened by comparing with known public databases and combining with the genetic characteristics of the families: TXNIP,PCK2,HOGA1,ANK1,ALPK3,MYOM2,LRRC52,CFAP47.ALPK3,MYOM2,LRRC52,and CFAP47;only the TXNIP gene was found to be associated with low uric acid levels in the family through literature review and interaction analysis with genes related to purine metabolism;genome-wide exon sequencing analysis showed that the TXNIP low-frequency mutation loci were co-existing in two families,A and E,in which the low uric acid person in family A was found in the TXNIP gene(NM The heterozygous mutation A>G at amino acid169 in exon 1 of TXNIP gene(NM006472),which mutates the methionine at position 57 to valine,was absent in normal controls.A heterozygous G>A mutation at amino acid position 530 in exon 4 of the TXNIP gene(NM＿001313972),which mutates arginine to glutamine at position 177 of the TXNIP gene,is absent in the normal control.(5)Sanger sequencing population validation revealed two TXNIP low-frequency mutation loci consistent with family co-segregation in the A and E families,while the uric acid normal population did not have these two mutations.Conclusion: In this study,we found that the Kazakh population is characterized by "high purine and low uric acid",and the genetic study excluded the association of mutations in genes commonly associated with uric acid metabolism disorders with low uric acid levels in this population.It is hypothesized that the low frequency mutations in this gene may be a protective factor for uric acid metabolism in Kazakhs,which explains the possible genetic mechanism of the phenomenon of "high purine,low uric acid" in this ethnic group,and whether TXNIP can be used as a drug target or a candidate gene for gene therapy provides important clues for further exploration of the treatment of hyperuricemia and gout.The genetic mechanism of TXNIP as a drug target or gene therapy candidate provides important clues for further exploration of the treatment of hyperuricemia and gout.