| Aims: To prospectively explore the possible relationship of serum uric acid with newly developed nonalcoholic fatty liver disease(NAFLD) and its progression over DongfengTongji(DFTJ) cohort.Methods: The DFTJ cohort Study is a prospective study with 27,009 participants followed from baseline assessment between 2008 and 2010. Individuals at baseline with any of the following were excluded from the study: fatty liver diagnosed by abdominal B-type ultrasound, excessive alcohol consumption, the presence of chronic hepatitis or hepatic cirrhosis, the use of medications associated with NAFLD within the past two weeks, the presence of hepatitis B surface antigen positive, data missing at baseline for abdominal Btype ultrasound inspection. A total of 14,821 participants without NAFLD at baseline were included in this follow-up study, and the first follow-up was conducted in 2013. Finally, 8,429 subjects met the inclusion criteria of this study. Each of the subjects was required to take a physical examination to obtain information about height, weight, abdomen B ultrasound and serum biochemical indices, and fill out a semi-structured questionnaire, including the socio-demographic, lifestyle and medical history. Categorical variables and continuous variables were computed by χ2 test and one-way ANOVA analysis, respectively. Logistic regression analysis, covariance, linear regression, and instrumental variables were used to assess associations between uric acid level and(the severity of) NAFLD, and the causal link.Results:(1) Baseline characteristics: this study included 8, 429 participants and the average age of those were 61.7±7.8 years; the sex ratio was 1:1.28(3,700 males, accounted for 43.9% of all study population; 4,729 females, accounted for 56.1% of all study population); the average body mass index(BMI) was 23.3±2.8 kg/m2. Among 8,429 subjects free of NAFLD at baseline, 2,007 participants developed NAFLD after 5 years of follow-up.(2) Association between uric acid levels and the risk of newly developed NAFLD: uric acid levels were divided as four groups by quartiles. After fully adjustment, the odds ratios(ORs) and 95% confidence interval(CI) for the risk of newly developed NAFLD comparing the upper 3 uric acid levels with the lowest uric acid level were 1.31(1.11-1.55), 1.43(1.22-1.69) and 1.71(1.45-2.01), respectively, P for trend < 0.001. Increased uric acid levels in quartiles were associated prospectively with the stepwise increased risk of newly developed NAFLD, more prominently among females or non-overweight population. In addition, when uric acid was used as a continuous variable, the fully adjusted OR for NAFLD was 1.18(95 % CI: 1.12, 1.24, P < 0.001) for per 1 mg/d L increased in uric acid level.(3) Correlation between single nucleotide polymorphism(SNP) and uric acid level: in genetic analyses, both SNPs(rs11722228 to SLC2A9, rs2231142 to ABCG2) were pronounced Ly associated with increased uric acid levels. For rs11722228, making participants with CC genotype as a reference, the uric acid level of participants with CT genotype increased by 5.4% and TT genotype increased by 7.2%. Similarly, uric acid levels were positively associated with the number of T gene for rs2231142. The two SNPs continuously increased with each additional uric acid-increasing allele in the genetic combination. Additionally, there was no evidence for a significant association between the variants and potential confounders of NAFLD.(4) Causal link between uric acid level and NAFLD: In multivariable Logistic regression analysis, comparing CT/TT genotype with CC genotype of rs11722228, the risk of newly developed NAFLD increased and the corresponding OR was 0.95(95% CI: 0.81-1.11,P = 0.53). Similarly, comparing GT/TT genotype with GG genotype of rs2231142, or comparing CT/TT/GT/TT genotype with CC/GG genotype of the combination of rs11722228 and rs2231142, the variation of risks on newly developed NAFLD were no statistical difference. With Mendelian randomization analysis, no association was observed between the uric acidincreasing allele of rs11722228 and the risk of newly developed NAFLD, with an OR of 0.93(95% CI: 0.82-1.05), no significant difference(P = 0.09) from that expected(OR = 1.03, 95% CI: 1.03-1.03). No significant difference on the associations between the uric acid-increasing alleles of rs2231142(or the combination of rs11722228 and rs2231142) and the risk of newly developed NAFLD.(5) Relationship between uric acid level and NAFLD severity: uric acid levels were categorized into four groups by quartiles. With the uric acid level rising, the risk of hepatic inflammation(which was reflected as elevated ALT(Alanine aminotransferase) and GGT(Gamma-glutamyl transferase)) and hepatic fibrosis(which was reflected as elevated APRI and FIB-4) increased. The risk of elevated ALT increased with increasing uric acid levels among newly developed NAFLD. The corresponding ORs with multivariable adjustment of individuals in the higher quartile comparing with those in lowest quartile were 1.08(95% CI: 0.81-1.45), 1.17(95% CI: 0.87-1.57), 1.57(95% CI: 1.17-2.11). A similar pattern was also observed in the association between uric acid with elevated GGT or APRI or FIB-4.Conclusions: Serum uric acid level was positively associated with newly developed NAFLD, especially among female or normal-weight persons. The Mendelian randomization analyses lend no causal evidence between serum uric acid and NAFLD, suggesting high uric acid level may act as a marker not a cause of NAFLD, and further validation based on large population-based study is still needed. In addition, increased uric acid was positively associated with the hepatic inflammation and hepatic fibrosis. |
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