| BackgroundWith the improving quality of life, the world has seen increasing prevalence of gout and hyperuricemia. Both epidemiology and bench work have demonstrated significant association between hyperuricemia and cardiovascular disease. We found a family characterized with three female gout patients attacked before menopause, which was in contrast with the well-known risk factors of gout and hyperuricemia that women usually do not have gout until menopause, particularly one patient had gout attack as early as16years, highly implicating the involvement genetic factors.Genetic are important risk factors for hyperuricemia and gout, and possibly one of the reasons that cause the variation of gout disease. Genome-Wide Association Study (GWAS) have identified multiple loci associated with gout and hyperuricemia. However what we see in the clinic is often the result of both nature and nurture, and more often than not, nurture is more predominant. Therefore, there are still gap between the findings of GWAS and its application in a specific population, and even further to be transformed into clinical practice. In light of these, we performed the following series of work.Object:1) To explore the genetic factors related to gout and hyperuricemia in a female premenopausal gout family.2) To explore the association between gout risky loci ABCG2rs2231142polymorphism and hyperuricemia in a population, and the possible interaction between other risk factors and genetic factors.Method:1) Collecting medical history, physical examination and laboratory examination of this family. Allele sharing examination and exon sequencing were applied to study the causative genes of familial juvenile hyperuricemia nephropathy, including UMOD, RENIN, HNF1B and HNFJ3, as well as the causative gene of Lesch-Nayhn syndrome-HPRT1. ABCG2, SLC2A9, and SLC22A12were screened by exon sequencing.2) Based on the cohort of the2008faculty annual health examination of PUMCH, exclude hyperuricemia with GFR less than30ml/min/1.73m2(NHUA), normal uricemic control group (NUA) were randomly selected after matching with the NHUA group by sex, age, CKD and BMI. SNP rs2231142were identified by ARMS-PCR. Paired logistic regression and interaction analysis were used to study the genotype distribution of rs2231142, the A allele frequency, the association between A allele and hyperuricemia, and the interaction of other risk factors with the rs2231142risk A allele.Results:1) The family was composed of4generations with21family members, clinical information and genetic study was focused on11members, including6male members and5female members. All three gout patients were female, attacked before menopause; and none of the male family members were affected. RENIN gene was found to be shared in this family by allele sharing experiment, but was found to be normal by exon sequencing. UMOD was not shared and found to be spared with mutations by exon sequencing. HPRT1gene was proved to be normal. Multiple single nucleotide polymorphisms of gene ABCG2, SLC2A9and SLC22A12were found in the one patient, including one locus known to be highly associated with gout, the SNP rs2231142of the gene ABCG2. Nearly all of the family members carry this risk allele.2) A total of296were found to be hyperuricemia in the total cohort. After excluding those with GFR<30ml/min/1.73m2,196hyperuricemic samples were enrolled in the pair group (NHUA);288normal uricemic controls were selected (NUA), matched with hyperuricemic group by sex, age, CKD and BMI. The total A allele frequency of the pair group were30.79%. The A allele frequency was significantly higher in the NHUA group than the NUA group (39.03%v.s.25.17%, p<0.001). The A allele were significantly associated with hyperuricemia (OR=3.35,95%CI2.10-5.33, p<0.01); compared to CC genotype, the risk of hyperuricemia rendered by CA genotype and AA genotype were3.19(95%CI:1.99-5.12, p<0.01) and4.85(95%CI2.13-11.00, p<0.01). After adjustment of dyslipidemia, hypertension and hyperglycemia, the OR of A allele was3.37(95%CI2.07-5.47, p<0.01). Subgroup analysis showed that in young male, old female, those in CKD3and those with BMI<28kg/m2, the relative risk contributed by A allele was more significant, but the increased risk by A allele was not so obvious in young female. Conclusion:1) In this premenopausal gout family, all the known gout causative genes were excluded as the culprit of this family. ABCG2SNP rs2231142was found in both the female patients and male healthy members of this family.2) In this nested case-control study, after matching with sex, age, CKD and BMI, ABCG2SNP rs2231142A allele was proved to be an independent risk factor for hyperuricemia, and the risk of hyperuricemia tends to increase with increasing number of the risk A allele. Sex, age, CKD and BMI might modify the risk conducted by A allele.3) The risk conducted by A allele toward hyperuricemia was relatively insignificant in young female, indicating a protective factor that might overwhelm the risk of SNP rs2231142A allele. |
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