Table 2.
Associations Between All-Cause Mortality and Serum Metabolitesa in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Finland, 1985–2013
| Metabolite | Chemical Class | Chemical Subclass | HRb | 95% CI | P Value |
|---|---|---|---|---|---|
| N-Acetylvalinec | Amino acid | Valine, leucine, and isoleucine metabolism | 1.28 | 1.14, 1.43 | 2.02 × 10−5 |
| Dimethylglycine | Amino acid | Glycine, serine, and threonine metabolism | 1.26 | 1.13, 1.40 | 4.56 × 10−5 |
| 7-Methylguanine | Nucleotide | Purine metabolism, guanine-containing | 1.31 | 1.15, 1.51 | 8.77 × 10−5 |
| C-Glycosyltryptophan | Amino acid | Tryptophan metabolism | 1.32 | 1.15, 1.51 | 9.18 × 10−5 |
| Taurocholate | Lipid | Primary bile acid metabolism | 1.23 | 1.10, 1.36 | 1.33 × 10−4 |
| N-Acetyltryptophan | Amino acid | Tryptophan metabolism | 1.24 | 1.11, 1.39 | 1.38 × 10−4 |
| Erythronate | Carbohydrate | Aminosugar metabolism | 1.23 | 1.09, 1.39 | 6.62 × 10−4 |
| 4-Androsten-3β,17β-diol disulfate 1 | Lipid | Sterol/steroid | 1.21 | 1.08, 1.36 | 7.46 × 10−4 |
| N-Acetylmethionine | Amino acid | Cysteine, methionine, SAM, taurine metabolism | 1.23 | 1.09, 1.39 | 7.62 × 10−4 |
| 5,6-Dihydrothymine | Nucleotide | Pyrimidine metabolism, thymine-containing | 1.28 | 1.11, 1.48 | 9.46 × 10−4 |
| Hexanoylcarnitine | Lipid | Carnitine metabolism | 1.20 | 1.08, 1.34 | 1.17 × 10−3 |
| Palmitoleate (16:1n7) | Lipid | Long-chain fatty acid | 1.20 | 1.08, 1.35 | 1.26 × 10−3 |
| 5-Dodecenoate (12:1n7) | Lipid | Medium-chain fatty acid | 1.20 | 1.08, 1.35 | 1.29 × 10−3 |
| N-Acetylphenylalanine | Amino acid | Phenylalanine and tyrosine metabolism | 1.20 | 1.07, 1.34 | 1.33 × 10−3 |
| Myristoleate (14:1n5) | Lipid | Long-chain fatty acid | 1.20 | 1.07, 1.35 | 1.37 × 10−3 |
| N1-Methylguanosine | Nucleotide | Purine metabolism, guanine-containing | 1.23 | 1.08, 1.39 | 1.37 × 10−3 |
| Docosadienoate (22:2n6) | Lipid | Long-chain fatty acid; polyunsaturated fatty acid (n3 and n6) | 1.18 | 1.06, 1.32 | 2.70 × 10−3 |
| Taurochenodeoxycholate | Lipid | Primary bile acid metabolism | 1.22 | 1.07, 1.39 | 2.73 × 10−3 |
| Homocitrulline | Amino acid | Urea cycle; arginine and proline metabolism | 1.24 | 1.08, 1.44 | 2.81 × 10−3 |
| 3-Hydroxycotinine glucuronide | Xenobiotics | Tobacco metabolite | 1.26 | 1.08, 1.47 | 2.86 × 10−3 |
| N-Formylmethionine | Amino acid | Cysteine, methionine, SAM, taurine metabolism | 1.20 | 1.06, 1.36 | 3.49 × 10−3 |
| 3-Methyl catechol sulfate 1 | Xenobiotics | Benzoate metabolism | 1.18 | 1.05, 1.32 | 3.86 × 10−3 |
| 4-Acetamidobutanoate | Amino acid | Guanidino and acetamido metabolism; polyamine metabolism | 1.23 | 1.07, 1.41 | 3.88 × 10−3 |
| γ-Glutamyltryptophan | Peptide | γ-Glutamyl amino acid | 1.19 | 1.06, 1.34 | 3.96 × 10−3 |
| Asparagine | Amino acid | Alanine and aspartate metabolism | 0.86 | 0.78, 0.96 | 4.55 × 10−3 |
| N-Acetyltyrosine | Amino acid | Phenylalanine and tyrosine metabolism | 1.16 | 1.05, 1.29 | 5.19 × 10−3 |
| Xylose | Carbohydrate | Pentose metabolism | 1.17 | 1.05, 1.31 | 5.31 × 10−3 |
| 3-Methyl catechol sulfate 2 | Xenobiotics | Benzoate metabolism | 1.22 | 1.06, 1.39 | 5.43 × 10−3 |
| N2,N2-Dimethylguanosine | Nucleotide | Purine metabolism, guanine-containing | 1.20 | 1.05, 1.36 | 5.58 × 10−3 |
| 3-Hydroxybutyrate (BHBA) | Lipid | Ketone bodies | 1.17 | 1.05, 1.30 | 5.78 × 10−3 |
| 4-Vinylphenol sulfate | Xenobiotics | Benzoate metabolism | 1.17 | 1.05, 1.31 | 6.20 × 10−3 |
Abbreviations: CI, confidence intervals; HDL, high-density lipoprotein; HR, hazard ratios; SAM, S-adenosylmethionine; SD, standard deviation.
a Metabolites were natural log-transformed and standardized (mean = 0, variance = 1). All 620 participants were included in each test, except for metabolites 5,6-dihydrothymine, taurochenodeoxycholate, homocitrulline, and 3-hydroxycotinine glucuronide (missing metabolic data from set 1 (n = 186), thus a total of 434 participants were included in these tests), for metabolites N-acetyltryptophan and 3-methyl catechol sulfate (missing metabolic data from set 2 (n = 38): a total of 582 participants were included in these tests). False discovery rate of ≤0.05.
b For each study set, we used attained age as time metric in the Cox proportional hazards regression model, and we adjusted for age at baseline, body mass index, number of cigarettes per day, total cholesterol, HDL cholesterol, history of hypertension (elevated blood pressure), history of diabetes mellitus, and serum creatinine. The reported HR (per SD) and P value were obtained from meta-analysis, which was conducted using a fixed-effects model to pool the study sets estimates.
cN-acetylvaline achieved statistical significance after Bonferroni correction for multiple tests.