Association Of Serum Uric Acid With Increased Risk Of Cancer And Possible Modification Effect Of Folic Acid Supplementation Among Hypertensive Chinese

Background:Cancer poses a major threat to public health worldwide as well as China.It has become the leading cause of mortality ranking second only to cardiovascular disease.Multiple factors including genetic,environmental,and nutritional status are associated with cancer incidence and mortality.Serum uric acid(SUA)is an abundant metabolic product in physiological condition in human body.It has been proposed that the antioxidant properties of SUA may play a crucial role in cancer etiology by acting as a scavenger of oxygen free radicals,thereby protecting against carcinogenesis.However,evidence of a relationship between serum uric acid(SUA)and the risk of cancer incidence is limited and inconclusive among large epidemiological prospective investigations.Besides,most studies demonstrated that increased SUA increased the risk of cancer related mortality.Up to now,the relationship between SUA levels and cancer incidence and mortality is unknown in populations from mainland China.Meanwhile,the impact of folic acid supplementation on cancer risk is uncertain,and whether folic acid supplementation could modify the cancer risk associated with SUA is unclear yet as lack of large epidemiological studies.Study aim:To explore the potential role of SUA on cancer incidence and mortality regarding gender-specific differences,as well as the possible modification effect of folic acid supplementation on cancer risk associated with SUA in China.Study participants and method:We conducted a detailed analysis of cancer as a pre-specified endpoint using data from the China Stroke Primary Prevention Trial(CSPPT).CSPPT is a multi-community,double-blinded,randomized controlled trial,randomized,double-blind clinical trial conducted from May19,2008,to August 24,2013,in 32 communities in the Lian Yungang,Jiangsu and An Qing,Anhui provinces of China.Eligible participants were essential hypertensive men and women aged 45 to 75 years old.Patients with a physician diagnosed history of stroke,myocardial infarction,heart failure,coronary revascularization,or congenital heart disease were excluded.20702 participants were eligible for CSPPT,stratified by MTHFR C677T genotype,and randomized assigned to receive a double-blind treatment of either 10mg enalapril(n=10356)or 10.8mg enalapril-folic acid(n=10348).We excluded 125 participants without SUA measurements at baseline,leaving 20577 adult hypertensive patients with valid SUA measurements for final analysis.The trial consisted of 3 stages;screening and recruitment during which blood and urine sample was collected,a 3-week run-in treatment period during which MTHFR C677T genotype was detected,and a 5-year randomized treatment period.Cancer and death was recorded during the follow-up period.Cox proportional hazards models were used to calculate hazards ratios(HR)of cancer risk associated with SUA.Results:A total of 232 participants developed cancer.After adjusting for age,sex,body mass index,study center,disease of diabetes mellitus,smoking and drinking status,systolic blood pressure during follow-up period,baseline estimated glomerular filtration rate,total cholesterol,falate,homocysteine,vitamin B12 and MTHFR C677T genotype,SUA was independently associated with increased cancer risk in the enalapril group[HR:1.12,(95%CI:1.03-1.22),p= 0,006].Compared to the lowest tertile,combined subjects with SUA levels from upper two tertiles had a higher risk of cancer in the enalapril group[T2+T3:HR:1.58,(95%CI:1.02-2.47)].In cancer site-specific analyses,a positive association of SUA levels with digestive cancer and all fatal cancer was also observed[HR:1.18,(95%CI:1.09-1.27);HR:1.15,(95%CI:1.03-1.28),respectively]in enalapril group.Interestingly,SUA levels were no longer associated with the risk of cancer or related mortality in the enalapril folic acid group(P value>0.05).Folic acid supplementation could modify the association between overall cancer risk and SUA levels(P for interaction<0.05).Conclusion:Our results suggest that elevated SUA is independently and positively associated with the risk of total cancer incidence,digestive cancer incidence and cancer mortality among hypertensive Chinese.It seems that there is an interaction effect of folic acid supplementation on cancer risk associated with SUA.Trial registration:Clinicaltrials.gov Identifier:NCT00794885.