Introduction
Materials and methods
Study population
Smoking history
Metabolome analysis
Non-targeted metabolomics
UHPLC-MS/MS analysis
Identification of metabolites
Genotyping
Statistical analysis
Results
Anthropometric and clinical/biochemical characteristics at the baseline
Total (n = 349) | p | ||
---|---|---|---|
Control (n = 236) | Pancreatic cancer incidence (n = 113) | ||
Age (year) | 52.4 ± 0.588 | 52.7 ± 0.832 | 0.991 |
Male/female n, (%) | 174 (73.7)/62 (26.3) | 87 (77.0)/26 (23.0) | 0.511 |
Current smoker n, (%) | 70 (30.3) | 33 (31.7) | 0.116 |
Body mass index (kg/m2)† | 24.3 ± 0.187 | 24.6 ± 0.256 | 0.238 |
Systolic blood pressure (mmHg)† | 120.8 ± 0.940 | 121.2 ± 1.24 | 0.929 |
Diastolic blood pressure (mmHg)∮ | 75.0 ± 0.701 | 76.7 ± 0.833 | 0.571 |
Glucose (mg/dL)† | 95.6 ± 1.37 | 101.4 ± 2.90 | 0.439 |
White blood cell (103/μL)† | 5.99 ± 0.109 | 8.26 ± 2.14 | 0.536 |
Albumin (g/dL)† | 4.53 ± 0.017 | 4.51 ± 0.027 | 0.199 |
Total cholesterol (mg/dL)∮ | 193.6 ± 2.28 | 192.0 ± 3.27 | 0.669 |
Triglyceride (mg/dL)∮ | 151.5 ± 6.79 | 141.1 ± 7.04 | 0.686 |
HDL-cholesterol (mg/dL)† | 50.3 ± 0.717 | 49.4 ± 1.01 | 0.286 |
LDL-cholesterol (mg/dL)† | 115.8 ± 2.08 | 117.0 ± 2.95 | 0.789 |
AST (IU/L)† | 26.0 ± 1.48 | 24.9 ± 0.847 | 0.986 |
ALT (IU/L)† | 27.4 ± 2.18 | 27.2 ± 1.50 | 0.353 |
GGT (IU/L)† | 41.8 ± 3.44 | 41.8 ± 4.20 | 0.574 |
ALP (IU/L)† | 121.5 ± 4.49 | 131.4 ± 6.84 | 0.223 |
Bilirubin (mg/dL)† | 0.881 ± 0.023 | 0.894 ± 0.040 | 0.710 |
Uric acid (mg/dL) | 5.56 ± 0.092 | 5.39 ± 0.123 | 0.282 |
Blood urea nitrogen (mg/dL)† | 14.6 ± 0.237 | 14.6 ± 0.337 | 0.722 |
Creatinine (mg/dL)† | 1.00 ± 0.013 | 0.998 ± 0.017 | 0.164 |
CA 19–9 (U/mL)† | 8.37 ± 0.526 | 20.0 ± 2.48 | 0.346 |
Discriminant metabolites between the pancreatic cancer incidence and control groups
Putative identification | HMBD ID | m/z | Formula | Feature importance | Pancreatic cancer incidence/control |
---|---|---|---|---|---|
Eicosa-11,14,17-trienoic acid | HMDB0244373 | 306.2560 | C20H34O2 | 6.0 | 1.826 |
Kynurenic acid | HMDB0000715 | 189.0429 | C10H7NO3 | 6.0 | 1.069 |
γ-Glutamyl tyrosine | HMDB0011741 | 310.1166 | C14H18N2O6 | 5.0 | 1.230 |
N(6)-Methyllysine | HMDB0002038 | 160.1214 | C7H16N2O2 | 5.0 | 0.875 |
LysoPE(18:0/0:0) | HMDB0011130 | 481.3170 | C23H48NO7P | 5.0 | 1.040 |
Trans-3'-hydroxy cotinine | HMDB0304504 | 192.0901 | C10H12N2O2 | 4.0 | 1.130 |
Palmitic amide | HMDB0012273 | 255.2563 | C16H33NO | 4.0 | 0.915 |
L-Leucine | HMDB0000687 | 131.0949 | C6H13O2 | 4.0 | 1.144 |
Adipic acid | HMDB0000448 | 146.0581 | C6H10O4 | 4.0 | 0.795 |
9-Decenoylcarnitine | HMDB0013205 | 313.2254 | C17H31NO4 | 4.0 | 0.794 |
5α-Pregnane-3,20-dione | HMDB0003759 | 316.2398 | C21H32O2 | 4.0 | 0.845 |
Metabolite-genomewide association analysis
Metabolites | SNP | Position | EA | EAF | Mapped Gene | OR [CI] | p |
---|---|---|---|---|---|---|---|
HMDB0244373 Eicosa-11,14,17-trienoic acid | rs6731366 | chr2:132891267 (GRCh38.p14) | A | 0.053 | NCKAP5 | 1.740 [0.833–3.633] | 0.141 |
rs11860247 | chr16:16071432 (GRCh38.p14) | A | 0.086 | ABCC1 | 1.016 [0.534–1.934] | 0.960 | |
rs201237448 | chr3:157725970 (GRCh38.p14) | A | 0.053 | 0.869 [0.388–1.944] | 0.732 | ||
rs4541064 | chr16:85230276 (GRCh38.p14) | C | 0.487 | GSE1 | 1.037 [0.615–1.748] | 0.892 | |
rs114089627 | chr3:3658708 (GRCh38.p14) | A | 0.016 | 1.106 [0.503–2.432] | 0.802 | ||
rs138810234 | chr4:161529556 (GRCh38.p14) | C | 0.036 | FSTL5 | 1.430 [0.834–2.450] | 0.193 | |
rs77806269 | chr3:12881670 (GRCh38.p14) | T | 0.023 | LINC02022, LOC105376956 | 0.749 [0.363–1.548] | 0.436 | |
rs2370981 | chr14:79402892 (GRCh38.p14) | G | 0.017 | NRXN3 | 0.371 [0.142–0.968] | 0.043 | |
rs117753991 | chr16:77579192 (GRCh38.p14) | G | 0.024 | 0.951 [0.518–1.748] | 0.873 | ||
rs201592606 | chr4:139691697 (GRCh38.p14) | G | 0.050 | MGST2 | 1.089 [0.683–1.738] | 0.720 | |
HMDB0000715 Kynurenic acid | rs73448444 | chr13:28731007 (GRCh38.p14) | G | 0.138 | 1.075 [0.614–1.883] | 0.799 | |
rs200475458 | chr17:16403690–703 (GRCh38.p14) | C | 0.110 | 0.833 [0.463–1.498] | 0.541 | ||
rs187490 | chr5:35045022 (GRCh38.p14) | G | 0.311 | AGXT2 | 1.256 [0.787–2.005] | 0.339 | |
rs604140 | chr2:67422625 (GRCh38.p14) | C | 0.050 | 1.734 [0.834–3.602] | 0.140 | ||
rs78053646 | chr12:231126 (GRCh38.p14) | T | 0.166 | SLC6A13, PARM1 | 1.233 [0.746–2.039] | 0.414 | |
rs890289 | chr4:75,047,822 (GRCh38.p14) | A | 0.054 | LOC107986289 | 0.998 [0.481–2.070] | 0.995 | |
rs9908634 | chr17:79431371 (GRCh38.p14) | T | 0.062 | RBFOX3 | 1.224 [0.603–2.485] | 0.576 | |
rs12909308 | chr15:61777037 (GRCh38.p14) | T | 0.284 | 1.223 [0.770–1.942] | 0.393 | ||
rs10407389 | chr19:36484416 (GRCh38.p14) | G | 0.103 | ZNF566 | 0.996 [0.559–1.775] | 0.990 | |
rs72747726 | chr15:69,899,377 (GRCh38.p14) | G | 0.238 | 1.093 [0.680–1.757] | 0.712 | ||
HMDB0011741 γ-Glutamyl tyrosine | rs59519100 | chr20:33868761 (GRCh38.p14) | T | 0.166 | 1.701 [1.046–2.765] | 0.032 | |
rs193488 | chr5:136703440 (GRCh38.p14) | G | 0.053 | 1.920 [0.948–3.890] | 0.070 | ||
rs202074299 | chr13:90,574,203 (GRCh38.p14) | T | 0.165 | 1.126 [0.689–1.839] | 0.637 | ||
HMDB0002038 N(6)-Methyllysine | rs200559669 | chr6:123584482 (GRCh38.p14) | C | 0.481 | TRDN | 0.685 [0.415–1.131] | 0.139 |
rs918171 | chr19:3336541 (GRCh38.p14) | C | 0.370 | 0.947 [0.599–1.499] | 0.817 | ||
rs2374205 | chr4:113984965 (GRCh38.p14) | G | 0.143 | LOC124900762 | 0.893 [0.523–1.524] | 0.677 | |
rs116931887 | chr6:143808387 (GRCh38.p14) | C | 0.384 | PHACTR2 | 0.971 [0.612–1.241] | 0.900 | |
HMDB0011130 LysoPE(18:0/0:0) | rs11083238 | chr18:27943526 (GRCh38.p14) | T | 0.135 | CDH2 | 1.299 [0.744–2.267] | 0.358 |
rs6731366 | chr2:132891267 (GRCh38.p14) | A | 0.053 | NCKAP5 | 1.329 [0.615–2.874] | 0.469 | |
rs12059514 | chr1:102370790 (GRCh38.p14) | C | 0.181 | 0.987 [0.571–1.706] | 0.964 | ||
rs28565987 | chr15:88048299 (GRCh38.p14) | A | 0.097 | NTRK3 | 0.829 [0.432–1.590] | 0.573 | |
rs2505110 | chr10:30181971 (GRCh38.p14) | G | 0.248 | 0.843 [0.514–1.384] | 0.500 | ||
rs62525721 | chr8:129066916 (GRCh38.p14) | T | 0.052 | 0.986 [0.430–2.259] | 0.973 | ||
rs8052560 | chr16:88710834 (GRCh38.p14) | C | 0.082 | CTU2 | 1.391 [0.734–2.636] | 0.312 | |
rs117723718 | chr4:40487925 (GRCh38.p14) | G | 0.057 | RBM47 | 1.050 [0.489–2.254] | 0.901 | |
rs28705703 | chr6:167502412 (GRCh38.p14) | G | 0.066 | 1.650 [0.823–3.306] | 0.158 | ||
rs9829051 | chr3:31491669 (GRCh38.p14) | G | 0.122 | 1.149 [0.628–2.102] | 0.652 | ||
rs375927045 | chr7:16220625 (GRCh38.p14) | C | 0.208 | CRPPA | 0.624 [0.370–1.052] | 0.077 | |
rs881433 | chr18:44864508 (GRCh38.p14) | A | 0.262 | SETBP1 | 1.293 [0.799–2.092] | 0.295 | |
rs11164375 | chr1:102083600 (GRCh38.p14) | T | 0.080 | 2.194 [1.095–4.394] | 0.027 | ||
rs117753153 | chr3:24689035 (GRCh38.p14) | G | 0.050 | 1.041 [0.446–2.427] | 0.927 | ||
rs1923773 | chr13:53176219 (GRCh38.p14) | G | 0.148 | 0.999 [0.576–1.732] | 0.996 | ||
rs141483946 | chr11:13570434 (GRCh38.p14) | A | 0.079 | 1.472 [0.751–2.884] | 0.260 | ||
rs9345335 | chr6:93188629 (GRCh38.p14) | G | 0.400 | 0.999 [0.605–1.651] | 0.998 | ||
rs78505433 | chr15:49737092 (GRCh38.p14) | T | 0.053 | 1.642 [0.761–3.547] | 0.207 | ||
rs57966757 | chr18:5919654 (GRCh38.p14) | A | 0.076 | LOC121725015 | 0.938 [0.477–1.844] | 0.853 | |
rs4727289 | chr7:93397016 (GRCh38.p14) | G | 0.120 | 0.743 [0.407–1.356] | 0.333 | ||
rs55721115 | chr14:34277292 (GRCh38.p14) | G | 0.054 | 0.515 [0.212–1.250] | 0.143 | ||
HMDB0304504 Trans-3′-hydroxy cotinine | rs74600139 | chr5:44446171 (GRCh38.p14) | C | 0.249 | 0.845 [0.531–1.344] | 0.477 | |
rs8100204 | chr19:19282905 (GRCh38.p14) | A | 0.201 | SUGP1 | 0.763 [0.472–1.234] | 0.270 | |
rs148195640 | chr20:59240551 (GRCh38.p14) | T | 0.053 | ZNF831 | 0.754 [0.435–1.306] | 0.313 | |
rs4308248 | chr3:134302128 (GRCh38.p14) | G | 0.129 | 0.729 [0.327–1.621] | 0.438 | ||
HMDB0012273 Palmitic amide | rs13043798 | chr20:23283897 (GRCh38.p14) | A | 0.269 | 0.709 [0.446–1.127] | 0.146 | |
rs13132855 | chr4:44399250 (GRCh38.p14) | A | 0.085 | KCTD8 | 1.038 [0.551–1.954] | 0.908 | |
rs7949816 | chr11:60278427 (GRCh38.p14) | A | 0.130 | 0.778 [0.453–1.338] | 0.364 | ||
rs2724067 | chr7:93831676 (GRCh38.p14) | A | 0.246 | 0.877 [0.552–1.393] | 0.579 | ||
rs149210546 | chr4:8824426 (GRCh38.p14) | C | 0.391 | 1.458 [0.896–2.375] | 0.129 | ||
rs76582834 | chr4:164383443 (GRCh38.p14) | C | 0.076 | MARCHF1 | 0.568 [0.280–1.152] | 0.117 | |
HMDB0000687 l-Leucine | rs76417681 | chr2:61231241 (GRCh38.p14) | C | 0.062 | USP34 | 0.610 [0.271–1.371] | 0.232 |
rs17684350 | chr10:18374682 (GRCh38.p14) | C | 0.080 | CACNB2 | 1.597 [0.814–3.133] | 0.173 | |
rs55828915 | chr1:207785790 (GRCh38.p14) | T | 0.060 | CD46 | 0.742 [0.335–1.642] | 0.462 | |
rs57192942 | chr10:127846701 (GRCh38.p14) | T | 0.265 | 1.415 [0.863–2.320] | 0.169 | ||
rs72709073 | chr9:69206346 (GRCh38.p14) | C | 0.054 | TJP2 | 0.749 [0.331–1.696] | 0.488 | |
rs7182182 | chr15:54,330,440 (GRCh38.p14) | A | 0.064 | UNC13C | 0.848 [0.395–1.822] | 0.673 | |
rs11525305 | chr10:6632812 (GRCh38.p14) | A | 0.073 | LINC02648 | 1.365 [0.688–2.708] | 0.373 | |
rs74724211 | chr19:44209431 (GRCh38.p14) | G | 0.097 | ZNF227 | 0.847 [0.447–1.605] | 0.610 | |
rs79500165 | chr2:141763014 (GRCh38.p14) | T | 0.056 | LRP1B, LOC107985779 | 0.663 [0.271–1.626] | 0.370 | |
rs72805402 | chr10:75306714 (GRCh38.p14) | A | 0.152 | ZNF503 | 2.150 [1.258–3.674] | 0.005 | |
rs687168 | chr17:14441416 (GRCh38.p14) | C | 0.172 | 1.281 [0.657–2.495] | 0.467 | ||
rs13388819 | chr2:64599202 (GRCh38.p14) | T | 0.099 | LOC105374773 | 1.278 [0.681–2.398] | 0.445 | |
rs77464636 | chr7:2301325 (GRCh38.p14) | A | 0.103 | SNX8 | 0.85 [0.459–1.574] | 0.605 | |
rs7525555 | chr1:202170575 (GRCh38.p14) | G | 0.138 | PTPRVP | 0.747 [0.420–1.329] | 0.321 | |
rs7175639 | chr15:50210373 (GRCh38.p14) | C | 0.206 | SLC27A2 | 1.005 [0.609–1.660] | 0.983 | |
rs117920703 | chr9:34250372 (GRCh38.p14) | A | 0.060 | UBAP1 | 0.449 [0.185–1.093] | 0.078 | |
rs28438600 | chr8:15523840 (GRCh38.p14) | A | 0.050 | 0.598 [0.252–1.418] | 0.243 | ||
rs17134252 | chr11:99717399 (GRCh38.p14) | A | 0.059 | CNTN5 | 0.978 [0.448–2.133] | 0.955 | |
rs55870181 | chr14:84615718 (GRCh38.p14) | T | 0.272 | 1.821 [1.123–2.951] | 0.015 | ||
rs147699000 | chr22:44353381 (GRCh38.p14) | A | 0.070 | 0.901 [0.428–1.899] | 0.785 | ||
rs8074518 | chr17:14443114 (GRCh38.p14) | G | 0.338 | 0.970 [0.526–1.792] | 0.924 | ||
rs73497629 | chr9:100688200 (GRCh38.p14) | C | 0.242 | 1.258 [0.768–2.060] | 0.362 | ||
rs12429312 | chr13:22915866 (GRCh38.p14) | A | 0.212 | LINC00621 | 0.908 [0.539–1.530] | 0.717 | |
rs149903005 | chr13:66587358–64 (GRCh38.p14) | C | 0.126 | PCDH9, LOC105370247 | 1.133 [0.639–2.011] | 0.669 | |
HMDB0000448 Adipic acid | rs6057003 | chr20:9908557 (GRCh38.p14) | C | 0.179 | 0.853 [0.520–1.400] | 0.529 | |
rs10846689 | chr12:124601819 (GRCh38.p14) | T | 0.198 | 1.056 [0.610–1.826] | 0.847 | ||
rs73608605 | chr8:39240193 (GRCh38.p14) | G | 0.086 | ADAM32 | 1.357 [0.730–2.521] | 0.334 | |
rs12361624 | chr11:30658520 (GRCh38.p14) | G | 0.153 | 1.422 [0.859–2.354] | 0.171 | ||
rs837465 | chr12:124534405 (GRCh38.p14) | A | 0.188 | NCOR2 | 0.943 [0.539–1.647] | 0.835 | |
rs6964529 | chr7:54293427 (GRCh38.p14) | C | 0.085 | 1.064 [0.567–1.993] | 0.848 | ||
rs6739384 | chr2:56142078 (GRCh38.p14) | A | 0.064 | LOC105374690 | 0.527 [0.248–1.124] | 0.097 | |
rs9291437 | chr4:22163632 (GRCh38.p14) | C | 0.426 | 1.163 [0.710–1.907] | 0.548 | ||
HMDB0013205 9-Decenoylcarnitine | rs117445640 | chr4:179766591 (GRCh38.p14) | T | 0.116 | 0.963 [0.556–1.669] | 0.894 | |
rs17116178 | chr11:113956604 (GRCh38.p14) | T | 0.107 | 0.787 [0.442–1.399] | 0.414 | ||
rs2836817 | chr21:39001801 (GRCh38.p14) | C | 0.193 | LINC02940 | 0.639 [0.390–1.049] | 0.077 | |
rs71364155 | chr17:12218522 (GRCh38.p14) | T | 0.380 | 1.101 [0.688–1.762] | 0.688 | ||
rs1532216 | chr12:99210187 (GRCh38.p14) | A | 0.063 | ANKS1B | 1.186 [0.605–2.325] | 0.619 | |
HMDB0003759 5a-Pregnane-3,20-dione | rs74869776 | chr12:30963077 (GRCh38.p14) | G | 0.050 | TSPAN11 | 0.716 [0.319–1.607] | 0.418 |
rs79255083 | chr4:66526962 (GRCh38.p14) | C | 0.069 | 1.104 [0.561–2.173] | 0.775 | ||
rs7760758 | chr6:24036861 (GRCh38.p14) | A | 0.062 | 0.636 [0.295–1.369] | 0.247 | ||
rs9792660 | chr9:29371008 (GRCh38.p14) | T | 0.205 | 0.802 [0.497–1.295] | 0.367 |