Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial

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Abstract
Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61–0.99); 0.67 (0.51–0.86) and 0.75 (0.59–0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14–1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.
Funding Information
  • National Institutes of Health (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Instituto de Salud Carlos III (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBEROBN] (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Centro Nacional de Investigaciones Cardiovasculares (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Ministerio de Ciencia e Innovación (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Fundación Mapfre 2010 (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Consejería de Salud de la Junta de Andalucía (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Public Health Division of the Department of Health of the Autonomous Government of Catalonia (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Fundació La Marató-TV3 (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • Regional Government of Navarra (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • American Diabetes Association (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • icrea (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)
  • SciLifeLab & Wallenberg Data Driven Life Science Program (R01HL118264, 1R01HL118264-01, 2R01HL118264-05, 2R01HL118264-09, RTIC G03/140, RTIC RD 06/0045, CNIC 06/2007, PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022, AGL-2009–13906-C02, AGL2010–22319-C03, SAF2016–80532-R, PI0105/2007, ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042, 294/C/2015, 538/U/2016, P27/2011, #1-18-PMF-029, KAW 2020.0239)

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