Table 4.
Change from baseline in plasma oxylipins (nM) after 12 months of supplementation with n-3 PUFAs equivalent to 0, 1, 2, and 4 portions of fatty fish per week.
| Oxylipin | Portion of fish oil per week equivalency | PAPOE | Pdose | PAPOE*dose | Pbaselineparent PUFA | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| APOE3 | APOE4 | Total | APOE3 | APOE4 | Total | APOE3 | APOE4 | Total | APOE3 | APOE4 | Total | |||||
| (n = 14) | (n = 5) | (n = 19) | (n = 17) | (n = 10) | (n = 27) | (n = 17) | (n = 6) | (n = 23) | (n = 17) | (n = 5/6) | (n = 22/23) | |||||
| Hydroxy-EPA | ||||||||||||||||
| 5-HEPE | −0.04 ± 0.03 | −0.08 ± 0.05 | −0.05 ± 0.03 | 0.14 ± 0.07 | 0.12 ± 0.08 | 0.14 ± 0.05 | 0.25 ± 0.06 | 0.52 ± 0.19 | 0.32 ± 0.07 | 0.67 ± 0.08 | 0.57 ± 0.17 | 0.66 ± 0.07 | 0.463 | <0.001 | 0.117 | 0.001 |
| 8-HEPE | −0.02 ± 0.02 | −0.01 ± 0.01 | −0.02 ± 0.01 | 0.09 ± 0.04 | 0.31 ± 0.20 | 0.17 ± 0.08 | 0.12 ± 0.04 | 0.28 ± 0.16 | 0.16 ± 0.05 | 0.27 ± 0.06 | 0.70 ± 0.08 | 0.33 ± 0.06 | 0.004 | 0.001 | 0.486 | 0.104 |
| 9-HEPE | 0.00 ± 0.05 | −0.07 ± 0.04 | −0.02 ± 0.04 | 0.14 ± 0.06 | 0.27 ± 0.15 | 0.19 ± 0.06 | 0.23 ± 0.05 | 0.50 ± 0.18 | 0.30 ± 0.06 | 0.55 ± 0.07 | 0.92 ± 0.14 | 0.60 ± 0.07 | 0.006 | <0.001 | 0.259 | 0.005 |
| 11-HEPE | −0.03 ± 0.02 | −0.01 ± 0.01 | −0.03 ± 0.01 | 0.11 ± 0.03 | 0.13 ± 0.07 | 0.12 ± 0.03 | 0.13 ± 0.03 | 0.29 ± 0.14 | 0.17 ± 0.04 | 0.30 ± 0.05 | 0.50 ± 0.13 | 0.33 ± 0.05 | 0.012 | <0.001 | 0.207 | 0.005 |
| 12-HEPE | −0.02 ± 0.04 | −0.06 ± 0.06 | −0.03 ± 0.03 | 0.04 ± 0.09 | 0.31 ± 0.16 | 0.14 ± 0.08 | 0.38 ± 0.13 | 0.95 ± 0.42 | 0.53 ± 0.15 | 0.52 ± 0.16 | 0.27 ± 0.22 | 0.49 ± 0.14 | 0.256 | 0.002 | 0.196 | 0.114 |
| 15-HEPE | <0.13 | <0.13 | <0.13 | <0.13 | <0.13 | <0.13 | <0.13 | <0.13 | <0.13 | 0.17 ± 0.09 | 0.33 ± 0.33 | 0.19 ± 0.09 | 0.527 | 0.022 | 0.385 | 0.356 |
| 18-HEPE | −0.01 ± 0.02 | 0.01 ± 0.04 | 0 ± 0.01 | 0.11 ± 0.04 | 0.71 ± 0.42 | 0.33 ± 0.16 | 0.2 ± 0.04 | 0.37 ± 0.17 | 0.24 ± 0.05 | 0.58 ± 0.1 | 1.32 ± 0.56 | 0.69 ± 0.12 | 0.008 | 0.001 | 0.265 | 0.767 |
| 19-HEPE | −0.05 ± 0.12 | −0.13 ± 0.07 | −0.07 ± 0.09 | 0.21 ± 0.15 | 0.17 ± 0.09 | 0.20 ± 0.10 | 0.7 ± 0.22 | 1.68 ± 0.64 | 0.96 ± 0.24 | 1.36 ± 0.24 | 2.02 ± 0.2 | 1.45 ± 0.21 | 0.026 | <0.001 | 0.027 | 0.024 |
| 20-HEPE | −0.05 ± 0.09 | −0.29 ± 0.17 | −0.11 ± 0.08 | 0.25 ± 0.11 | 0.11 ± 0.07 | 0.20 ± 0.07 | 0.42 ± 0.11 | 0.95 ± 0.38 | 0.56 ± 0.13 | 1.10 ± 0.13 | 1.33 ± 0.09 | 1.13 ± 0.12 | 0.198 | <0.001 | 0.011 | 0.008 |
| Dihydroxy-EPA | ||||||||||||||||
| 8,9-DiHETE | −0.03 ± 0.01 | −0.00 ± 0.01 0 | −0.02 ± 0.01 | 0.02 ± 0.01 | 0.07 ± 0.03 | 0.04 ± 0.01 | 0.04 ± 0.02 | 0.10 ± 0.04 | 0.06 ± 0.02 | 0.13 ± 0.02 | 0.17 ± 0.03 | 0.14 ± 0.02 | 0.007 | <0.001 | 0.633 | 0.003 |
| 11,12-DiHETE | −0.01 ± 0.01 | 0.00 ± 0.01 | −0.01 ± 0.01 | 0.01 ± 0.01 | 0.07 ± 0.04 | 0.03 ± 0.02 | 0.04 ± 0.01 | 0.07 ± 0.02 | 0.05 ± 0.01 | 0.09 ± 0.01 | 0.18 ± 0.01 | 0.10 ± 0.01 | 0.002 | <0.001 | 0.642 | 0.07 |
| 14,15-DiHETE | −0.01 ± 0.01 | −0.01 ± 0.01 | −0.01 ± 0.01 | 0.02 ± 0.01 | 0.08 ± 0.05 | 0.04 ± 0.02 | 0.07 ± 0.02 | 0.11 ± 0.03 | 0.08 ± 0.01 | 0.13 ± 0.02 | 0.26 ± 0.03 | 0.15 ± 0.02 | 0.001 | <0.001 | 0.360 | 0.023 |
| 17,18-DiHETE | −0.04 ± 0.06 | −0.01 ± 0.07 | −0.03 ± 0.05 | 0.15 ± 0.09 | 0.39 ± 0.21 | 0.24 ± 0.10 | 0.46 ± 0.12 | 0.83 ± 0.25 | 0.55 ± 0.11 | 0.72 ± 0.1 | 1.45 ± 0.17 | 0.83 ± 0.10 | 0.001 | <0.001 | 0.236 | 0.004 |
| Epoxy-EPA | ||||||||||||||||
| 11 (12)-EpETE | <0.05 | <0.05 | <0.05 | 0.03 ± 0.01 | 0.02 ± 0.01 | 0.030 | 0.06 ± 0.01 | 0.07 ± 0.02 | 0.06 ± 0.01 | 0.13 ± 0.02 | 0.17 ± 0.04 | 0.14 ± 0.02 | 0.605 | <0.001 | 0.302 | 0.343 |
| 14 (15)-EpETE | 0 ± 0.01 | −0.01 ± 0.01 | 0 ± 0.01 | 0.02 ± 0.01 | 0.02 ± 0.02 | 0.02 ± 0.01 | 0.09 ± 0.02 | 0.11 ± 0.04 | 0.09 ± 0.02 | 0.17 ± 0.03 | 0.23 ± 0.04 | 0.18 ± 0.02 | 0.450 | <0.001 | 0.818 | 0.419 |
| 17 (18)-EpETE | <0.1 | <0.1 | <0.1 | <0.1 | <0.1 | <0.1 | 0.14 ± 0.03 | 0.21 ± 0.06 | 0.16 ± 0.03 | 0.26 ± 0.03 | 0.36 ± 0.07 | 0.28 ± 0.03 | 0.067 | <0.001 | 0.294 | 0.213 |
| Hydroxy-DHA | ||||||||||||||||
| 4-HDHA | −0.08 ± 0.07 | 0.01 ± 0.14 | −0.05 ± 0.06 | 0.06 ± 0.07 | 0.14 ± 0.09 | 0.09 ± 0.06 | 0.26 ± 0.08 | 0.36 ± 0.12 | 0.29 ± 0.07 | 0.48 ± 0.06 | 0.45 ± 0.17 | 0.47 ± 0.05 | 0.458 | <0.001 | 0.994 | 0.688 |
| 7-HDHA | <0.1 | <0.1 | <0.1 | 0.13 ± 0.02 | 0.11 ± 0.02 | 0.12 ± 0.02 | 0.16 ± 0.02 | 0.23 ± 0.09 | 0.18 ± 0.03 | 0.25 ± 0.03 | 0.31 ± 0.06 | 0.26 ± 0.03 | 0.301 | <0.001 | 0.54 | 0.605 |
| 8-HDHA | −0.08 ± 0.09 | −0.15 ± 0.12 | −0.1 ± 0.07 | 0.21 ± 0.09 | 0.28 ± 0.11 | 0.24 ± 0.07 | 0.37 ± 0.09 | 0.68 ± 0.31 | 0.45 ± 0.10 | 0.82 ± 0.12 | 1.34 ± 0.21 | 0.90 ± 0.11 | 0.062 | <0.001 | 0.458 | 0.514 |
| 10-HDHA | −0.02 ± 0.01 | −0.01 ± 0.03 | −0.02 ± 0.01 | 0.03 ± 0.02 | 0.11 ± 0.04 | 0.06 ± 0.02 | 0.1 ± 0.02 | 0.19 ± 0.10 | 0.12 ± 0.03 | 0.19 ± 0.02 | 0.35 ± 0.02 | 0.21 ± 0.02 | 0.008 | <0.001 | 0.577 | 1.000 |
| 11-HDHA | −0.03 ± 0.02 | −0.02 ± 0.05 | −0.03 ± 0.02 | 0.01 ± 0.03 | 0.14 ± 0.04 | 0.06 ± 0.03 | 0.15 ± 0.04 | 0.27 ± 0.10 | 0.18 ± 0.04 | 0.21 ± 0.04 | 0.34 ± 0.01 | 0.23 ± 0.03 | 0.016 | <0.001 | 0.658 | 0.717 |
| 13-HDHA | −0.01 ± 0.01 | 0.01 ± 0.03 | −0.01 ± 0.01 | 0.04 ± 0.02 | 0.05 ± 0.02 | 0.05 ± 0.02 | 0.08 ± 0.02 | 0.14 ± 0.09 | 0.10 ± 0.03 | 0.15 ± 0.02 | 0.31 ± 0.09 | 0.17 ± 0.03 | 0.024 | <0.001 | 0.352 | 0.369 |
| 14-HDHA | 0.09 ± 0.16 | −0.42 ± 0.43 | −0.04 ± 0.16 | −0.38 ± 0.32 | 1.45 ± 0.91 | 0.3 ± 0.42 | 1.04 ± 0.45 | 2.7 ± 1.35 | 1.47 ± 0.49 | 0.61 ± 0.34 | 0.32 ± 0.82 | 0.57 ± 0.31 | 0.21 | 0.015 | 0.096 | 0.106 |
| 16-HDHA | −0.02 ± 0.01 | −0.01 ± 0.04 | −0.02 ± 0.01 | 0.05 ± 0.02 | 0.14 ± 0.06 | 0.08 ± 0.03 | 0.10 ± 0.03 | 0.17 ± 0.09 | 0.12 ± 0.03 | 0.18 ± 0.03 | 0.41 ± 0.04 | 0.22 ± 0.03 | 0.003 | <0.001 | 0.312 | 0.412 |
| 17-HDHA | −0.11 ± 0.07 | −0.06 ± 0.17 | −0.1 ± 0.06 | 0.06 ± 0.15 | 0.03 ± 0.18 | 0.05 ± 0.11 | 0.28 ± 0.11 | 0.67 ± 0.22 | 0.38 ± 0.10 | 0.63 ± 0.11 | 1.36 ± 0.08 | 0.73 ± 0.11 | 0.033 | <0.001 | 0.155 | 0.455 |
| 20-HDHA | −0.06 ± 0.04 | 0.02 ± 0.13 | −0.04 ± 0.04 | 0.09 ± 0.06 | 0.35 ± 0.17 | 0.18 ± 0.08 | 0.24 ± 0.05 | 0.38 ± 0.22 | 0.28 ± 0.07 | 0.43 ± 0.06 | 0.93 ± 0.10 | 0.50 ± 0.07 | 0.004 | <0.001 | 0.429 | 0.666 |
| 21-HDHA | −0.10 ± 0.48 | −1.08 ± 0.37 | −0.36 ± 0.38 | 0.18 ± 0.33 | 0.26 ± 0.34 | 0.21 ± 0.24 | 1.62 ± 0.38 | 2.40 ± 1.13 | 1.82 ± 0.40 | 3.21 ± 0.47 | 4.68 ± 0.63 | 3.42 ± 0.42 | 0.357 | <0.001 | 0.434 | 0.093 |
| 22-HDHA | −0.10 ± 0.41 | 0.03 ± 1.14 | −0.07 ± 0.41 | 0.08 ± 0.35 | 0.12 ± 0.41 | 0.1 ± 0.26 | 1.29 ± 0.32 | 1.99 ± 0.97 | 1.47 ± 0.34 | 3.08 ± 0.48 | 4.08 ± 0.47 | 3.23 ± 0.42 | 0.209 | <0.001 | 0.786 | 0.225 |
| Dihydroxy-DHA | ||||||||||||||||
| 4,5-DiHDPE | −0.23 ± 0.15 | −0.19 ± 0.22 | −0.22 ± 0.12 | 0.05 ± 0.16 | 0.10 ± 0.1 | 0.06 ± 0.11 | 0.92 ± 0.34 | 1.15 ± 0.27 | 0.98 ± 0.26 | 0.80 ± 0.19 | 1.81 ± 0.57 | 0.95 ± 0.19 | 0.144 | <0.001 | 0.523 | 0.316 |
| 10,11-DiHDPE | −0.04 ± 0.02 | −0.03 ± 0.04 | −0.04 ± 0.02 | 0.00 ± 0.03 | 0.03 ± 0.02 | 0.01 ± 0.02 | 0.09 ± 0.03 | 0.18 ± 0.10 | 0.11 ± 0.03 | 0.12 ± 0.03 | 0.33 ± 0.07 | 0.15 ± 0.03 | 0.005 | <0.001 | 0.228 | 0.089 |
| 13,14-DiHDPE | −0.04 ± 0.02 | −0.04 ± 0.03 | −0.04 ± 0.02 | 0.01 ± 0.02 | 0.16 ± 0.12 | 0.06 ± 0.05 | 0.11 ± 0.03 | 0.14 ± 0.05 | 0.12 ± 0.03 | 0.14 ± 0.03 | 0.41 ± 0.05 | 0.18 ± 0.03 | 0.004 | <0.001 | 0.182 | 0.145 |
| 16,17-DiHDPE | −0.02 ± 0.02 | −0.03 ± 0.03 | −0.02 ± 0.02 | −0.01 ± 0.02 | 0.16 ± 0.11 | 0.05 ± 0.04 | 0.16 ± 0.04 | 0.16 ± 0.07 | 0.16 ± 0.03 | 0.15 ± 0.03 | 0.42 ± 0.07 | 0.19 ± 0.04 | 0.008 | <0.001 | 0.100 | 0.095 |
| 19,20-DiHDPE | −0.44 ± 0.29 | −0.25 ± 0.32 | −0.39 ± 0.22 | 0.02 ± 0.21 | 1.33 ± 1.10 | 0.51 ± 0.43 | 1.45 ± 0.37 | 1.72 ± 0.68 | 1.52 ± 0.32 | 1.39 ± 0.28 | 3.85 ± 0.77 | 1.74 ± 0.32 | 0.006 | <0.001 | 0.349 | 0.054 |
| Epoxy-DHA | ||||||||||||||||
| 10 (11)-EpDPE | 0.00 ± 0.04 | −0.05 ± 0.03 | −0.01 ± 0.03 | 0.00 ± 0.04 | 0.03 ± 0.05 | 0.02 ± 0.03 | 0.16 ± 0.06 | 0.24 ± 0.10 | 0.18 ± 0.05 | 0.31 ± 0.09 | 0.43 ± 0.09 | 0.32 ± 0.07 | 0.496 | <0.001 | 0.931 | 0.37 |
| 13 (14)-EpDPE | −0.01 ± 0.03 | −0.06 ± 0.02 | −0.03 ± 0.02 | 0.00 ± 0.03 | 0.06 ± 0.05 | 0.03 ± 0.03 | 0.15 ± 0.05 | 0.15 ± 0.10 | 0.15 ± 0.04 | 0.27 ± 0.07 | 0.46 ± 0.12 | 0.29 ± 0.06 | 0.394 | <0.001 | 0.452 | 0.387 |
| 16 (17)-EpDPE | −0.02 ± 0.03 | −0.02 ± 0.05 | −0.02 ± 0.03 | 0.00 ± 0.04 | 0.04 ± 0.05 | 0.02 ± 0.03 | 0.15 ± 0.05 | 0.16 ± 0.08 | 0.15 ± 0.04 | 0.30 ± 0.07 | 0.41 ± 0.10 | 0.32 ± 0.06 | 0.566 | <0.001 | 0.886 | 0.681 |
| 19 (20)-EpDPE | −0.01 ± 0.05 | −0.10 ± 0.04 | −0.03 ± 0.04 | 0.02 ± 0.06 | 0.07 ± 0.06 | 0.04 ± 0.04 | 0.25 ± 0.08 | 0.37 ± 0.19 | 0.29 ± 0.08 | 0.47 ± 0.11 | 0.69 ± 0.10 | 0.50 ± 0.10 | 0.405 | <0.001 | 0.862 | 0.301 |
| Hydroxy-ARA | ||||||||||||||||
| 5-HETE | −0.28 ± 0.23 | −0.26 ± 0.10 | −0.27 ± 0.17 | −0.14 ± 0.08 | −0.21 ± 0.16 | −0.16 ± 0.08 | −0.06 ± 0.24 | −0.29 ± 0.07 | −0.12 ± 0.18 | −0.24 ± 0.10 | −0.32 ± 0.36 | −0.25 ± 0.10 | 0.187 | 0.928 | 0.924 | 0.349 |
| 8-HETE | −0.02 ± 0.02 | −0.02 ± 0.02 | −0.02 ± 0.01 | −0.02 ± 0.02 | 0.01 ± 0.03 | −0.01 ± 0.02 | −0.03 ± 0.02 | −0.01 ± 0.03 | −0.03 ± 0.02 | −0.04 ± 0.01 | −0.02 ± 0.01 | −0.04 ± 0.01 | 0.600 | 0.684 | 0.971 | 0.674 |
| 11-HETE | −0.03 ± 0.01 | −0.07 ± 0.02 | −0.04 ± 0.01 | 0.00 ± 0.02 | 0.00 ± 0.05 | 0.00 ± 0.02 | −0.04 ± 0.03 | −0.02 ± 0.02 | −0.04 ± 0.02 | −0.06 ± 0.01 | −0.05 ± 0.03 | −0.06 ± 0.01 | 0.545 | 0.181 | 0.784 | 0.357 |
| 12-HETE | 0.09 ± 0.39 | −0.65 ± 0.54 | −0.11 ± 0.33 | 0.07 ± 0.45 | 0.21 ± 0.66 | 0.12 ± 0.37 | −0.26 ± 0.49 | −0.54 ± 1.26 | −0.33 ± 0.47 | −0.61 ± 0.27 | −0.05 ± 0.06 | −0.53 ± 0.23 | 0.332 | 0.790 | 0.997 | 0.239 |
| 15-HETE | −0.09 ± 0.06 | −0.23 ± 0.09 | −0.13 ± 0.05 | −0.10 ± 0.07 | −0.13 ± 0.06 | −0.11 ± 0.05 | −0.17 ± 0.06 | −0.14 ± 0.05 | −0.16 ± 0.05 | −0.28 ± 0.05 | −0.12 ± 0.11 | −0.25 ± 0.05 | 0.634 | 0.546 | 0.391 | 0.131 |
| 20-HETE | 0.04 ± 0.09 | −0.08 ± 0.14 | 0.01 ± 0.08 | −0.10 ± 0.08 | −0.25 ± 0.08 | −0.16 ± 0.06 | −0.18 ± 0.05 | 0.10 ± 0.18 | −0.10 ± 0.06 | −0.22 ± 0.08 | 0.15 ± 0.22 | −0.17 ± 0.08 | 0.827 | 0.517 | 0.051 | 0.791 |
| Dihydroxy-ARA | ||||||||||||||||
| 5,6-DiHETrE | −0.18 ± 0.15 | −0.02 ± 0.01 | −0.14 ± 0.11 | −0.02 ± 0.03 | −0.01 ± 0.03 | −0.02 ± 0.02 | 0.02 ± 0.15 | 0 ± 0.04 | 0.02 ± 0.11 | −0.08 ± 0.04 | −0.08 ± 0.1 | −0.08 ± 0.04 | 0.544 | 0.717 | 0.991 | 0.765 |
| 8,9-DiHETrE | −0.03 ± 0.03 | 0 ± 0.02 | −0.02 ± 0.02 | −0.03 ± 0.01 | −0.04 ± 0.02 | −0.03 ± 0.01 | −0.02 ± 0.03 | 0.01 ± 0.04 | −0.02 ± 0.03 | −0.08 ± 0.02 | −0.02 ± 0.03 | −0.07 ± 0.02 | 0.613 | 0.224 | 0.735 | 0.657 |
| 11,12-DiHETrE | −0.04 ± 0.03 | −0.03 ± 0.04 | −0.04 ± 0.03 | −0.06 ± 0.02 | −0.16 ± 0.03 | −0.1 ± 0.02 | −0.08 ± 0.03 | −0.04 ± 0.04 | −0.07 ± 0.02 | −0.19 ± 0.03 | −0.01 ± 0.08 | −0.17 ± 0.03 | 0.369 | 0.164 | 0.02 | 0.459 |
| 14,15-DiHETrE | −0.02 ± 0.04 | −0.03 ± 0.06 | −0.02 ± 0.03 | −0.07 ± 0.02 | −0.14 ± 0.02 | −0.09 ± 0.02 | −0.06 ± 0.03 | −0.05 ± 0.04 | −0.06 ± 0.02 | −0.18 ± 0.04 | −0.02 ± 0.09 | −0.16 ± 0.04 | 0.648 | 0.132 | 0.193 | 0.38 |
| Epoxy-ARA | ||||||||||||||||
| 5 (6)-EpETrE | 0.08 ± 0.12 | −0.11 ± 0.16 | 0.03 ± 0.1 | −0.13 ± 0.12 | −0.06 ± 0.15 | −0.1 ± 0.1 | −0.09 ± 0.12 | 0.05 ± 0.14 | −0.05 ± 0.1 | −0.13 ± 0.13 | −0.06 ± 0.25 | −0.12 ± 0.12 | 0.673 | 0.636 | 0.903 | 0.998 |
| 8 (9)-EpETrE | 0 ± 0.02 | 0 ± 0.04 | 0 ± 0.02 | −0.02 ± 0.02 | 0 ± 0.03 | −0.01 ± 0.02 | −0.01 ± 0.03 | 0.01 ± 0.04 | 0 ± 0.02 | 0 ± 0.02 | 0 ± 0.03 | 0 ± 0.02 | 0.736 | 0.928 | 0.916 | 0.635 |
| 11 (12)-EpETrE | −0.01 ± 0.02 | −0.01 ± 0.02 | −0.01 ± 0.01 | −0.03 ± 0.02 | −0.02 ± 0.03 | −0.03 ± 0.02 | 0 ± 0.02 | 0 ± 0.05 | 0 ± 0.02 | −0.01 ± 0.02 | 0.03 ± 0.01 | 0 ± 0.02 | 0.861 | 0.538 | 0.878 | 0.766 |
| 14 (15)-EpETrE | −0.01 ± 0.05 | −0.01 ± 0.07 | −0.01 ± 0.04 | −0.11 ± 0.04 | −0.07 ± 0.07 | −0.09 ± 0.03 | −0.03 ± 0.05 | −0.02 ± 0.1 | −0.03 ± 0.04 | −0.03 ± 0.04 | 0.09 ± 0.05 | −0.02 ± 0.04 | 0.393 | 0.223 | 0.639 | 0.582 |
Mean ± SEM(n) absolute change in individual hydroxy-, dihydroxy- and epoxy-EPAs, -DHAs and -ARAs. P values are shown for genotype, dose PUFA and genotype*dose interaction using univariate GLM. P value for baseline parent PUFA was calculated in the same univariate GLM as a covariate. Other covariates used are age, gender and BMI.