TABLE 3.
Least-squares adjusted means (SE) of log-transformed circulating metabolite values across increasing quartiles of dairy intake in the Framingham Heart Study Third Generation cohort, total sample (n = 866)1
| Quartile category of dairy intake | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Metabolite | Unannotated m/z2 | n | Q1 | Q2 | Q3 | Q4 | P-trend | Sig.3 | In Offspring4 |
| Number per quartile category | 216 | 217 | 217 | 216 | |||||
| Total dairy (quartile median, servings/wk) | 4.5 | 8.5 | 12.5 | 23.4 | |||||
| Hippurate | 865 | −0.73 ± 0.19 | −0.86 ± 0.18 | −0.77 ± 0.19 | −0.83 ± 0.19 | 0.48 | N | P = 0.19 | |
| Kynurenic acid | 865 | −0.23 ± 0.10 | −0.24 ± 0.10 | −0.22 ± 0.10 | −0.28 ± 0.10 | 0.25 | N | P = 0.18 | |
| Oxalate | 860 | −0.52 ± 0.10 | −0.50 ± 0.10 | −0.45 ± 0.10 | −0.40 ± 0.10 | 0.004 | Y | P = 0.58 | |
| X1840 | 431.3395 | 864 | 8.50 ± 0.24 | 8.22 ± 0.24 | 8.31 ± 0.24 | 8.03 ± 0.24 | 0.0003 | Y | n/a |
| X1852 | 496.4205 | 855 | 10.10 ± 0.28 | 10.08 ± 0.28 | 10.00 ± 0.28 | 10.14 ± 0.28 | 0.68 | N | n/a |
| X203 | 244.1905 | 846 | 8.85 ± 0.16 | 8.83 ± 0.16 | 8.83 ± 0.16 | 8.90 ± 0.16 | 0.70 | N | n/a |
| X2204 | 431.3388 | 863 | 9.34 ± 0.27 | 9.21 ± 0.27 | 9.35 ± 0.27 | 9.18 ± 0.27 | 0.23 | N | n/a |
| X291 | 214.1787 | 833 | 5.80 ± 0.25 | 5.79 ± 0.24 | 5.85 ± 0.25 | 5.77 ± 0.25 | 0.65 | N | n/a |
| X3341 | 197.0669 | 838 | 10.67 ± 0.31 | 10.58 ± 0.31 | 10.64 ± 0.31 | 10.10 ± 0.32 | 0.0002 | Y | n/a |
| X3517 | 213.0981 | 814 | 10.37 ± 0.35 | 10.24 ± 0.34 | 10.38 ± 0.35 | 9.62 ± 0.35 | 0.00002 | Y | n/a |
| X3726 | 207.1742 | 828 | 7.47 ± 0.22 | 7.39 ± 0.22 | 7.45 ± 0.22 | 7.44 ± 0.22 | 0.79 | N | n/a |
| X4778 | 96.0449 | 841 | 9.93 ± 0.42 | 9.78 ± 0.41 | 9.67 ± 0.42 | 9.27 ± 0.42 | 0.0006 | Y | n/a |
| X6385 | 94.0657 | 849 | 8.63 ± 0.47 | 8.49 ± 0.47 | 8.31 ± 0.47 | 7.95 ± 0.48 | 0.006 | N | n/a |
| X942 | 402.2634 | 862 | 10.33 ± 0.13 | 10.50 ± 0.13 | 10.62 ± 0.13 | 10.74 ± 0.13 | <0.0001 | Y | n/a |
| Milk (quartile median, servings/wk) | 0.0 | 3.0 | 5.5 | 17.5 | |||||
| α-Hydroxybutyrate | 865 | 0.00 ± 0.15 | 0.06 ± 0.15 | 0.01 ± 0.15 | −0.15 ± 0.15 | 0.04 | N | P = 0.99 | |
| Hippurate | 865 | −0.87 ± 0.18 | −0.77 ± 0.18 | −0.68 ± 0.18 | −0.89 ± 0.19 | 0.40 | N | P = 0.47 | |
| Kynurenic acid | 865 | −0.23 ± 0.10 | −0.24 ± 0.10 | −0.24 ± 0.10 | −0.28 ± 0.10 | 0.19 | N | P = 0.21 | |
| Maleate | 865 | −0.14 ± 0.11 | −0.11 ± 0.10 | −0.25 ± 0.11 | −0.24 ± 0.11 | 0.03 | N | n/a | |
| Quinolinate | 865 | −0.28 ± 0.07 | −0.23 ± 0.07 | −0.25 ± 0.07 | −0.27 ± 0.07 | 0.75 | N | P = 0.70 | |
| X1866 | 308.2218 | 861 | 9.21 ± 0.14 | 9.06 ± 0.13 | 9.13 ± 0.14 | 9.20 ± 0.14 | 0.25 | N | n/a |
| X2920 | 427.3531 | 863 | 10.02 ± 0.16 | 9.96 ± 0.16 | 9.89 ± 0.16 | 9.88 ± 0.17 | 0.22 | N | n/a |
| X3878 | 184.071 | 751 | 5.23 ± 0.45 | 5.20 ± 0.45 | 5.53 ± 0.46 | 5.10 ± 0.47 | 0.82 | N | n/a |
| Cream/butter (quartile median, servings/wk) | 0.5 | 2.9 | 7.0 | 18.0 | |||||
| Indole-3-carboxyl | 865 | −0.12 ± 0.16 | −0.20 ± 0.16 | −0.22 ± 0.17 | −0.20 ± 0.16 | 0.38 | N | n/a | |
| Pantothenate | 865 | −0.15 ± 0.11 | −0.20 ± 0.11 | −0.26 ± 0.11 | −0.29 ± 0.11 | 0.01 | N | P = 0.035 | |
| Taurine | 865 | 0.03 ± 0.23 | 0.14 ± 0.23 | 0.04 ± 0.23 | 0.00 ± 0.23 | 0.47 | N | P = 0.21 | |
| X5942 | 510.3926 | 864 | 11.63 ± 0.10 | 11.70 ± 0.10 | 11.70 ± 0.10 | 11.82 ± 0.10 | 0.0002 | Y | n/a |
| X1427 | 445.2948 | 766 | 8.16 ± 0.45 | 7.63 ± 0.46 | 7.74 ± 0.46 | 7.40 ± 0.46 | 0.001 | Y | n/a |
| X250 | 96.045 | 704 | 7.79 ± 0.45 | 7.76 ± 0.46 | 7.60 ± 0.46 | 8.38 ± 0.45 | 0.001 | Y | n/a |
| X2979 | 210.1488 | 864 | 10.28 ± 0.19 | 10.22 ± 0.19 | 10.41 ± 0.19 | 10.86 ± 0.19 | <0.0001 | Y | n/a |
| X3632 | 144.1019 | 864 | 9.46 ± 0.11 | 9.45 ± 0.11 | 9.47 ± 0.12 | 9.72 ± 0.11 | <0.0001 | Y | n/a |
| X4249 | 221.0643 | 842 | 10.17 ± 0.26 | 10.20 ± 0.27 | 10.58 ± 0.27 | 10.96 ± 0.26 | <0.0001 | Y | n/a |
| X4259 | 181.0719 | 834 | 9.12 ± 0.27 | 9.19 ± 0.28 | 9.45 ± 0.28 | 9.93 ± 0.27 | <0.0001 | Y | n/a |
| X4778 | 96.0449 | 841 | 9.30 ± 0.40 | 9.17 ± 0.40 | 9.64 ± 0.41 | 10.53 ± 0.40 | <0.0001 | Y | n/a |
| X5033 | 797.622 | 864 | 12.51 ± 0.04 | 12.55 ± 0.04 | 12.55 ± 0.04 | 12.60 ± 0.04 | <0.0001 | Y | n/a |
| X5146 | 692.5573 | 864 | 11.86 ± 0.09 | 11.99 ± 0.09 | 12.02 ± 0.09 | 12.11 ± 0.09 | <0.0001 | Y | n/a |
| X6385 | 94.0657 | 849 | 7.95 ± 0.45 | 7.71 ± 0.46 | 8.15 ± 0.46 | 9.44 ± 0.45 | <0.0001 | Y | n/a |
| Cheese (quartile median, servings/wk) | 0.9 | 3.0 | 3.5 | 7.5 | |||||
| X2459 | 165.1257 | 850 | 6.29 ± 0.41 | 6.36 ± 0.41 | 6.36 ± 0.41 | 6.55 ± 0.41 | 0.18 | N | n/a |
| Yogurt (quartile median, servings/wk) | 0.0 | 0.0 | 1.0 | 3.0 | |||||
| X678 | 624.5547 | 865 | 11.72 ± 0.09 | 11.69 ± 0.09 | 11.62 ± 0.09 | 11.52 ± 0.09 | 0.00001 | Y | n/a |
| X580 | 625.5589 | 865 | 10.59 ± 0.12 | 10.56 ± 0.12 | 10.48 ± 0.12 | 10.36 ± 0.12 | 0.00002 | Y | n/a |
| X597 | 598.5389 | 864 | 10.63 ± 0.12 | 10.58 ± 0.12 | 10.49 ± 0.12 | 10.39 ± 0.12 | 0.00003 | Y | n/a |
| X596 | 596.524 | 865 | 11.60 ± 0.10 | 11.55 ± 0.10 | 11.50 ± 0.10 | 11.39 ± 0.10 | 0.00004 | Y | n/a |
| X671 | 581.511 | 865 | 12.32 ± 0.11 | 12.24 ± 0.11 | 12.19 ± 0.12 | 12.08 ± 0.12 | 0.00004 | Y | n/a |
| X608 | 570.5088 | 864 | 10.37 ± 0.12 | 10.35 ± 0.12 | 10.28 ± 0.12 | 10.15 ± 0.12 | 0.00007 | Y | n/a |
| X843 | 565.4456 | 865 | 11.56 ± 0.11 | 11.45 ± 0.12 | 11.43 ± 0.12 | 11.31 ± 0.12 | 0.0001 | Y | n/a |
| X717 | 235.2418 | 865 | 10.01 ± 0.12 | 9.98 ± 0.12 | 9.91 ± 0.12 | 9.81 ± 0.12 | 0.0003 | Y | n/a |
| X634 | 603.496 | 862 | 9.66 ± 0.16 | 9.55 ± 0.17 | 9.48 ± 0.17 | 9.34 ± 0.17 | 0.0005 | Y | n/a |
| X889 | 197.19 | 865 | 9.99 ± 0.11 | 9.91 ± 0.11 | 9.87 ± 0.11 | 9.79 ± 0.11 | 0.0005 | Y | n/a |
| X938 | 425.3626 | 865 | 11.18 ± 0.10 | 11.13 ± 0.10 | 11.06 ± 0.10 | 11.01 ± 0.10 | 0.0007 | Y | n/a |
| X749 | 409.3675 | 864 | 10.08 ± 0.12 | 10.02 ± 0.12 | 10.04 ± 0.12 | 9.89 ± 0.12 | 0.0007 | Y | n/a |
| X795 | 225.1848 | 865 | 12.64 ± 0.09 | 12.57 ± 0.09 | 12.51 ± 0.09 | 12.46 ± 0.09 | 0.0007 | Y | n/a |
| X633 | 535.472 | 864 | 10.23 ± 0.14 | 10.15 ± 0.15 | 10.13 ± 0.15 | 9.98 ± 0.15 | 0.0007 | N | n/a |
| X705 | 419.388 | 865 | 10.63 ± 0.11 | 10.58 ± 0.11 | 10.55 ± 0.11 | 10.44 ± 0.11 | 0.0007 | N | n/a |
| X741 | 614.5347 | 865 | 12.56 ± 0.12 | 12.51 ± 0.12 | 12.44 ± 0.12 | 12.36 ± 0.12 | 0.0008 | N | n/a |
| X695 | 235.2055 | 865 | 11.11 ± 0.09 | 11.06 ± 0.09 | 11.02 ± 0.09 | 10.95 ± 0.09 | 0.0008 | N | n/a |
| X1030 | 553.4108 | 865 | 10.95 ± 0.12 | 10.87 ± 0.13 | 10.83 ± 0.13 | 10.73 ± 0.13 | 0.0008 | N | n/a |
| X904 | 243.1954 | 864 | 10.00 ± 0.13 | 9.92 ± 0.13 | 9.88 ± 0.13 | 9.77 ± 0.13 | 0.001 | N | n/a |
| X673 | 563.5005 | 865 | 11.29 ± 0.11 | 11.24 ± 0.11 | 11.17 ± 0.11 | 11.10 ± 0.11 | 0.001 | N | n/a |
| X1063 | 345.2784 | 863 | 9.20 ± 0.12 | 9.15 ± 0.12 | 9.10 ± 0.12 | 9.00 ± 0.12 | 0.001 | N | n/a |
| X899 | 393.3726 | 865 | 10.57 ± 0.12 | 10.49 ± 0.12 | 10.49 ± 0.12 | 10.37 ± 0.12 | 0.001 | N | n/a |
| X802 | 533.4567 | 865 | 12.66 ± 0.09 | 12.60 ± 0.09 | 12.56 ± 0.09 | 12.50 ± 0.09 | 0.001 | N | n/a |
| X1074 | 524.3946 | 865 | 10.93 ± 0.12 | 10.90 ± 0.12 | 10.85 ± 0.12 | 10.75 ± 0.12 | 0.002 | N | n/a |
| X650 | 309.2786 | 862 | 8.59 ± 0.16 | 8.54 ± 0.16 | 8.48 ± 0.16 | 8.34 ± 0.16 | 0.002 | N | n/a |
| X712 | 567.4624 | 865 | 11.22 ± 0.10 | 11.14 ± 0.10 | 11.10 ± 0.10 | 11.04 ± 0.10 | 0.002 | N | n/a |
| X698 | 255.2317 | 865 | 10.70 ± 0.09 | 10.65 ± 0.09 | 10.62 ± 0.09 | 10.56 ± 0.09 | 0.002 | N | n/a |
| X709 | 551.467 | 865 | 12.75 ± 0.10 | 12.67 ± 0.10 | 12.62 ± 0.10 | 12.58 ± 0.10 | 0.002 | N | n/a |
| X1069 | 526.4104 | 865 | 12.19 ± 0.09 | 12.14 ± 0.09 | 12.11 ± 0.09 | 12.04 ± 0.09 | 0.003 | N | n/a |
| X855 | 541.4474 | 865 | 11.74 ± 0.10 | 11.66 ± 0.10 | 11.63 ± 0.10 | 11.56 ± 0.10 | 0.003 | N | n/a |
| X477 | 680.58 | 853 | 9.73 ± 0.31 | 9.43 ± 0.31 | 9.53 ± 0.32 | 9.17 ± 0.32 | 0.003 | N | n/a |
| X1012 | 321.2786 | 865 | 9.86 ± 0.13 | 9.78 ± 0.13 | 9.74 ± 0.13 | 9.65 ± 0.13 | 0.003 | N | n/a |
| X701 | 237.2209 | 865 | 10.14 ± 0.10 | 10.11 ± 0.10 | 10.08 ± 0.10 | 10.00 ± 0.10 | 0.004 | N | n/a |
| X807 | 453.3566 | 865 | 12.00 ± 0.08 | 11.93 ± 0.08 | 11.93 ± 0.08 | 11.87 ± 0.08 | 0.004 | N | n/a |
| X3096 | 347.2214 | 830 | 9.43 ± 0.49 | 9.24 ± 0.50 | 9.61 ± 0.50 | 9.99 ± 0.51 | 0.005 | N | n/a |
| X811 | 377.3411 | 865 | 10.76 ± 0.09 | 10.71 ± 0.09 | 10.70 ± 0.09 | 10.63 ± 0.09 | 0.005 | N | n/a |
| X431 | 786.6593 | 830 | 9.90 ± 0.33 | 9.62 ± 0.34 | 9.72 ± 0.34 | 9.34 ± 0.34 | 0.005 | N | n/a |
| X516 | 654.5658 | 859 | 9.96 ± 0.29 | 9.70 ± 0.29 | 9.76 ± 0.30 | 9.50 ± 0.30 | 0.006 | N | n/a |
| X732 | 153.1273 | 865 | 11.57 ± 0.09 | 11.53 ± 0.09 | 11.48 ± 0.09 | 11.44 ± 0.09 | 0.006 | N | n/a |
| X1156 | 549.377 | 864 | 11.24 ± 0.12 | 11.17 ± 0.12 | 11.12 ± 0.13 | 11.06 ± 0.13 | 0.006 | N | n/a |
| X454 | 714.6187 | 865 | 11.72 ± 0.16 | 11.85 ± 0.16 | 11.90 ± 0.16 | 11.96 ± 0.16 | 0.007 | N | n/a |
| X1005 | 363.289 | 864 | 9.82 ± 0.11 | 9.74 ± 0.11 | 9.75 ± 0.11 | 9.65 ± 0.11 | 0.008 | N | n/a |
| X1054 | 486.4156 | 865 | 10.92 ± 0.11 | 10.89 ± 0.12 | 10.80 ± 0.12 | 10.77 ± 0.12 | 0.008 | N | n/a |
| X3616 | 433.3165 | 843 | 8.43 ± 0.43 | 8.29 ± 0.43 | 8.35 ± 0.44 | 7.93 ± 0.44 | 0.009 | N | n/a |
| X1427 | 445.2948 | 766 | 7.58 ± 0.45 | 7.56 ± 0.46 | 8.01 ± 0.46 | 8.11 ± 0.46 | 0.009 | N | n/a |
| X1194 | 547.3607 | 863 | 10.80 ± 0.13 | 10.73 ± 0.13 | 10.67 ± 0.13 | 10.62 ± 0.13 | 0.01 | N | n/a |
| X1017 | 485.3844 | 865 | 11.75 ± 0.09 | 11.67 ± 0.09 | 11.64 ± 0.09 | 11.61 ± 0.09 | 0.01 | N | n/a |
| X690 | 517.4612 | 860 | 9.76 ± 0.14 | 9.71 ± 0.15 | 9.66 ± 0.15 | 9.59 ± 0.15 | 0.01 | N | n/a |
| X1028 | 479.3357 | 865 | 12.01 ± 0.08 | 11.97 ± 0.08 | 11.94 ± 0.08 | 11.90 ± 0.08 | 0.01 | N | n/a |
| X579 | 584.5247 | 862 | 10.51 ± 0.22 | 10.47 ± 0.23 | 10.36 ± 0.23 | 10.24 ± 0.23 | 0.01 | N | n/a |
| X956 | 517.461 | 856 | 9.24 ± 0.18 | 9.24 ± 0.18 | 9.18 ± 0.18 | 9.06 ± 0.18 | 0.01 | N | n/a |
| X1137 | 551.3942 | 865 | 10.84 ± 0.14 | 10.76 ± 0.14 | 10.72 ± 0.14 | 10.65 ± 0.14 | 0.01 | N | n/a |
| X1135 | 263.1641 | 864 | 9.89 ± 0.11 | 9.89 ± 0.12 | 9.81 ± 0.12 | 9.77 ± 0.12 | 0.02 | N | n/a |
| X573 | 589.4816 | 864 | 10.36 ± 0.18 | 10.33 ± 0.18 | 10.35 ± 0.18 | 10.17 ± 0.18 | 0.02 | N | n/a |
| X1146 | 267.1953 | 865 | 11.16 ± 0.08 | 11.10 ± 0.08 | 11.07 ± 0.08 | 11.05 ± 0.08 | 0.02 | N | n/a |
| X1174 | 545.3449 | 861 | 10.08 ± 0.13 | 9.99 ± 0.13 | 9.99 ± 0.14 | 9.91 ± 0.14 | 0.02 | N | n/a |
| X414 | 760.6424 | 797 | 10.04 ± 0.37 | 9.75 ± 0.37 | 9.85 ± 0.38 | 9.54 ± 0.38 | 0.03 | N | n/a |
| X1181 | 517.3137 | 792 | 8.29 ± 0.22 | 8.24 ± 0.23 | 8.08 ± 0.23 | 8.07 ± 0.23 | 0.03 | N | n/a |
| X1255 | 521.345 | 864 | 10.80 ± 0.12 | 10.74 ± 0.12 | 10.71 ± 0.13 | 10.66 ± 0.13 | 0.03 | N | n/a |
| X886 | 498.3789 | 865 | 12.07 ± 0.09 | 12.01 ± 0.09 | 11.98 ± 0.09 | 11.96 ± 0.09 | 0.04 | N | n/a |
| X1131 | 695.5724 | 791 | 9.17 ± 0.30 | 9.49 ± 0.30 | 9.47 ± 0.30 | 9.55 ± 0.30 | 0.04 | N | n/a |
| X3995 | 605.55 | 772 | 9.86 ± 0.27 | 9.82 ± 0.27 | 9.82 ± 0.27 | 9.62 ± 0.27 | 0.046 | N | n/a |
| X1222 | 523.3613 | 860 | 10.46 ± 0.14 | 10.40 ± 0.14 | 10.38 ± 0.14 | 10.32 ± 0.14 | 0.05 | N | n/a |
| X1133 | 249.1848 | 865 | 12.67 ± 0.09 | 12.62 ± 0.09 | 12.56 ± 0.09 | 12.56 ± 0.09 | 0.05 | N | n/a |
| X440 | 734.6276 | 828 | 10.05 ± 0.42 | 9.76 ± 0.42 | 9.93 ± 0.42 | 9.57 ± 0.43 | 0.05 | N | n/a |
| X1158 | 475.3034 | 864 | 10.37 ± 0.13 | 10.32 ± 0.13 | 10.26 ± 0.13 | 10.24 ± 0.14 | 0.07 | N | n/a |
| X1271 | 519.3294 | 852 | 9.86 ± 0.16 | 9.75 ± 0.16 | 9.74 ± 0.16 | 9.68 ± 0.16 | 0.08 | N | n/a |
| X423 | 774.6596 | 799 | 9.04 ± 0.41 | 8.69 ± 0.42 | 8.64 ± 0.42 | 8.58 ± 0.42 | 0.21 | N | n/a |
| X1272 | 231.1741 | 858 | 8.87 ± 0.16 | 8.81 ± 0.16 | 8.69 ± 0.16 | 8.75 ± 0.16 | 0.26 | N | n/a |
Metabolite values are log-transformed. Model adjusted for age, sex, BMI, smoking status, history of diabetes, history of cardiovascular disease, intake of other dairy (except in total dairy; i.e., for milk, the model included cheese, cream/butter, and yogurt), and intake of fish, fruit, vegetables, meat, and nuts, as well as batch or plate (as applicable). Conversion of standard serving sizes to grams for dairy is as follows: skim milk, 245 g; whole milk, 245 g; cream, 15 g; sour cream, 12 g; sherbet/ice milk, 96 g; ice cream, 66 g; yogurt, 227 g; cottage/ricotta cheese, 105 g; cream cheese, 28 g; other cheese, 28 g; butter, 5 g. Gen3, Framingham Heart Study Third Generation cohort; n/a, not available; Q, quartile.
Unannotated/unknown metabolites were searched by m/z ratio in the Human Metabolome Database and/or METLIN (41). The m/z ratio and putative identities are provided in Supplemental Table 8. Identities have not been verified.
Significant after Bonferroni correction: P < 0.05/14 (0.004) for total dairy; <0.05/8 (0.006) for milk; <0.05/14 (0.004) for cream/butter; <0.05/69 (0.0007) for yogurt.
Tested in identical models in the Offspring total sample, where metabolite value was measured and annotated.
Association in the Offspring was directionally consistent with that in Gen3.