A prospective evaluation of serum kynurenine metabolites and risk of pancreatic cancer

<div><p>Background</p><p>Serum pyridoxal 5’-phosphate (PLP), the active form of vitamin B₆, is associated with reduced risk of pancreatic cancer. Data on functional measures of vitamin B₆ status and risk of pancreatic cancer is lacking.</p><p>Methods</p><p>A nested case-control study involving 187 incident cases of pancreatic cancer and 362 individually matched controls were conducted within two prospective cohorts to evaluate the associations between kynurenine metabolites in pre-diagnostic serum samples and risk of pancreatic cancer.</p><p>Results</p><p>Higher serum concentrations of 3-hydroxyanthranilic acid (HAA) and the HAA:3-hydroxykynurenine (HK) ratio (a measure for <i>in vivo</i> functional status of PLP) were significantly associated with reduced risk of pancreatic cancer. Compared with the lowest tertile, odds ratios (95% confidence intervals) of pancreatic cancer for the highest tertile was 0.62 (0.39, 1.01) for HAA, and 0.59 (0.35–0.98) for the HAA:HK ratio, after adjustment for potential confounders and serum PLP (both <i>P</i>s for trend<0.05). The kynurenine:tryptophan ratio or neopterin was not significantly associated with pancreatic cancer risk.</p><p>Conclusions</p><p>The inverse association between HAA or the HAA:HK ratio and risk of pancreatic cancer supports the notion that functional status of PLP may be a more important measure than circulating PLP alone for the development of pancreatic cancer.</p></div

Associations of tryptophan, kynurenines, and neopterin with pancreatic cancer risk in both Shanghai and Singapore cohorts combined (187 cases and 362 controls).

<p>Associations of tryptophan, kynurenines, and neopterin with pancreatic cancer risk in both Shanghai and Singapore cohorts combined (187 cases and 362 controls).</p

The schematic metabolic pathway of tryptophan and kyurenine.

<p>The schematic metabolic pathway of tryptophan and kyurenine.</p

Median (5^th– 95^th percentile) values of serum biomarkers of tryptophan, kynurenines and neopterin in pancreatic cancer cases and control subjects, the Shanghai Cohort Study and the Singapore Chinese Health Study.

<p>Median (5^th– 95^th percentile) values of serum biomarkers of tryptophan, kynurenines and neopterin in pancreatic cancer cases and control subjects, the Shanghai Cohort Study and the Singapore Chinese Health Study.</p

Beta coefficients^a for tryptophan and kynurenine metabolites derived from linear regression models on smoking status (current or former versus never smokers), cotinine, body mass index (BMI), and pyridoxal 5’-phosphate (PLP) among all controls (N = 362).

<p>Beta coefficients<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196465#t003fn002" target="_blank">^a</a> for tryptophan and kynurenine metabolites derived from linear regression models on smoking status (current or former versus never smokers), cotinine, body mass index (BMI), and pyridoxal 5’-phosphate (PLP) among all controls (N = 362).</p

Association of tobacco smoking with risk of cause-specific death by study populations in Asia.

a<p>Number of deaths among ever-smokers/never-smokers are presented.</p>b<p>HRs estimated for ever-smokers compared with never-smokers and adjusted for age, education, rural/urban residence, marital status, and body mass index; data from participants with <1 y of follow-up are excluded.</p><p>Analyses were conducted among those age 45 y or older.</p>c<p>HR not estimated because of small sample size.</p><p>CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease.</p

Association of tobacco smoking with risk of death from all causes in selected study populations in Asia.

a<p>Adjusted for age, education, rural/urban resident, marital status, and body mass index; data from participants with <1 y of follow-up are excluded.</p><p>Analyses were conducted among those age 45 y or older.</p>b<p>Including data from mainland China, Taiwan, Singapore, Republic of Korea, and Japan.</p>c<p>Including data from India and Bangladesh.</p

Association of tobacco smoking with risk of death from all causes, cardiovascular diseases, cancer, or respiratory diseases in major East Asian female populations.

a<p>Excluding participants with less than 1 y of follow-up.</p>b<p>Adjusted for age, education, rural/urban resident, marital status, and body mass index.</p><p>Analyses were conducted among those age 45 y or older.</p>c<p>Excluding current smokers with missing information on pack-years of smoking.</p

Smoking prevalence, population attributable risk, and number of deaths due to tobacco smoking in selected Asian populations.

<p>Estimates are provided for populations age 45 y or older.</p>a<p>Because of the small sample size in the current study for these populations, data for smoking prevalence rates were obtained from other sources: Bangladeshi men and women: <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001631#pmed.1001631-Giovino1" target="_blank">[12]</a>, Taiwanese women: <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001631#pmed.1001631-Liaw1" target="_blank">[19]</a>, and Korean women: <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001631#pmed.1001631-Jee1" target="_blank">[34]</a>.</p>b<p>PARs were estimated using HRs derived from all South Asian cohorts combined because of unstable HR estimates using Bangladeshi data alone.</p>c<p>Mortality data for Taiwan were obtained from <a href="http://www.mohw.gov.tw/CHT/Ministry/Index.aspx" target="_blank">http://www.mohw.gov.tw/CHT/Ministry/Index.aspx</a>.</p>d<p>PARs were estimated using weighted HRs and smoking prevalence of the study populations.</p><p>Thus, the number of deaths attributable to smoking in these populations may not be equal to the sum of the numbers of deaths from the countries in the population areas. East Asia: mainland China, Taiwan, Singapore, Republic of Korea, and Japan. South Asia: Bangladesh and India. All populations: all seven countries/regions listed above.</p