Table 2.
Risk of CVD and Stroke by Baseline Plasma Concentrations of Choline Metabolites in the PREDIMED Study
| Variable | HR (95% CI) for Quartiles of Plasma Metabolite Concentration | P Trend Value | HR (95% CI) per 1‐SD Increment | |||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |||
| CVD | ||||||
| TMAO | ||||||
| No. of cases | 43 | 69 | 58 | 59 | … | … |
| Multivariable model 1 | Ref. | 1.44 (0.90–2.28) | 1.13 (0.70–1.80) | 1.25 (0.78–1.99) | 0.60 | 1.04 (0.89–1.21) |
| Multivariable model 2 | Ref. | 1.37 (0.85–2.22) | 1.08 (0.66–1.76) | 1.09 (0.67–1.77) | 0.94 | 1.01 (0.85–1.18) |
| Betaine | ||||||
| No. of cases | 51 | 57 | 60 | 61 | … | … |
| Multivariable model 1 | Ref. | 0.94 (0.59–1.48) | 1.03 (0.66–1.61) | 0.77 (0.49–1.21) | 0.30 | 0.89 (0.77–1.03) |
| Multivariable model 2 | Ref. | 1.00 (0.63–1.60) | 1.23 (0.77–1.97) | 0.91 (0.77–1.49) | 0.87 | 0.95 (0.82–1.12) |
| Choline | ||||||
| No. of cases | 34 | 43 | 68 | 84 | … | … |
| Multivariable model 1 | Ref. | 1.03 (0.62–1.71) | 1.30 (0.78–2.14) | 1.55 (0.96–2.52) | 0.03 | 1.21 (1.02–1.43) |
| Multivariable model 2 | Ref. | 1.08 (0.64–1.81) | 1.48 (0.89–2.46) | 1.72 (1.05–2.81) | 0.01 | 1.24 (1.05–1.46) |
| Phosphocholine | ||||||
| No. of cases | 46 | 58 | 57 | 68 | … | … |
| Multivariable model 1 | Ref. | 1.16 (0.73–1.85) | 1.29 (0.81–2.05) | 1.40 (0.89–2.24) | 0.12 | 1.09 (0.92–1.28) |
| Multivariable model 2 | Ref. | 1.18 (0.73–1.93) | 1.27 (0.77–2.08) | 1.41 (0.87–2.28) | 0.15 | 1.09 (0.92–1.30) |
| α‐Glycerophosphocholine | ||||||
| No. of cases | 51 | 56 | 47 | 75 | … | … |
| Multivariable model 1 | Ref. | 0.89 (0.56–1.42) | 0.79 (0.50–1.26) | 1.26 (0.81–1.97) | 0.30 | 1.20 (1.00–1.44) |
| Multivariable model 2 | Ref. | 0.99 (0.62–1.57) | 0.92 (0.57–1.51) | 1.42 (0.89–2.28) | 0.14 | 1.24 (1.03–1.50) |
| Choline metabolite score | ||||||
| No. of cases | 39 | 64 | 57 | 106 | … | … |
| Multivariable model 1 | Ref. | 1.26 (0.77–2.05) | 1.09 (0.64–1.81) | 1.91 (1.20–3.04) | <0.001 | 2.07 (1.25–3.41) |
| Multivariable model 2 | Ref. | 1.33 (0.81–2.19) | 1.25 (0.74–2.11) | 2.21 (1.36–3.59) | <0.001 | 2.27 (1.36–3.80) |
| Betaine/choline ratio | ||||||
| No. of cases | 74 | 52 | 63 | 40 | … | … |
| Multivariable model 1 | Ref. | 0.70 (0.46–1.08) | 0.86 (0.56–1.30) | 0.50 (0.32–0.78) | <0.001 | 0.77 (0.66–0.90) |
| Multivariable model 2 | Ref. | 0.73 (0.47–1.14) | 0.86 (0.55–1.34) | 0.57 (0.35–0.92) | 0.04 | 0.80 (0.68–0.94) |
| Stroke | ||||||
| TMAO | ||||||
| No. of cases | 24 | 38 | 31 | 25 | … | … |
| Multivariable model 1 | Ref. | 1.32 (0.74–2.35) | 1.06 (0.58–1.94) | 0.91 (0.49–1.69) | 0.55 | 0.93 (0.77–1.12) |
| Multivariable model 2 | Ref. | 1.19 (0.65–2.17) | 0.98 (0.53–1.84) | 0.78 (0.41–1.49) | 0.31 | 0.89 (0.73–1.10) |
| Betaine | ||||||
| No. of cases | 27 | 32 | 32 | 27 | … | … |
| Multivariable model 1 | Ref. | 1.08 (0.61–1.91) | 1.06 (0.60–1.86) | 0.73 (0.39–1.34) | 0.29 | 0.91 (0.75–1.11) |
| Multivariable model 2 | Ref. | 1.15 (0.64–2.04) | 1.32 (0.74–2.36) | 0.89 (0.46–1.71) | 0.85 | 1.00 (0.81–1.23) |
| Choline | ||||||
| No. of cases | 19 | 24 | 31 | 44 | … | … |
| Multivariable model 1 | Ref. | 1.04 (0.54–2.00) | 1.18 (0.59–2.33) | 1.58 (0.84–2.99) | 0.10 | 1.24 (0.98–1.56) |
| Multivariable model 2 | Ref. | 1.08 (0.56–2.09) | 1.33 (0.67–2.62) | 1.73 (0.91–3.29) | 0.06 | 1.27 (1.02–1.59) |
| Phosphocholine | ||||||
| No. of cases | 23 | 26 | 29 | 40 | … | … |
| Multivariable model 1 | Ref. | 0.95 (0.51–1.79) | 1.33 (0.72–2.44) | 1.67 (0.94–2.98) | 0.04 | 1.23 (0.99–1.53) |
| Multivariable model 2 | Ref. | 0.96 (0.50–1.84) | 1.28 (0.66–2.46) | 1.70 (0.93–3.11) | 0.05 | 1.25 (1.00–1.57) |
| α‐Glycerophosphocholine | ||||||
| No. of cases | 31 | 23 | 23 | 41 | … | … |
| Multivariable model 1 | Ref. | 0.63 (0.34–1.18) | 0.63 (0.35–1.15) | 1.15 (0.67–1.98) | 0.52 | 1.17 (0.91–1.50) |
| Multivariable model 2 | Ref. | 0.68 (0.36–1.26) | 0.71 (0.38–1.35) | 1.29 (0.74–2.25) | 0.31 | 1.22 (0.96–1.55) |
| Choline metabolite score | ||||||
| No. of cases | 21 | 25 | 22 | 50 | … | … |
| Multivariable model 1 | Ref. | 1.10 (0.58–2.09) | 0.78 (0.40–1.53) | 1.94 (1.07–3.50) | 0.03 | 1.83 (1.13–2.97) |
| Multivariable model 2 | Ref. | 1.21 (0.63–2.33) | 0.88 (0.44–1.76) | 2.27 (1.24–4.16) | 0.01 | 2.07 (1.25–3.44) |
| Betaine/choline ratio | ||||||
| No. of cases | 38 | 26 | 33 | 21 | … | … |
| Multivariable model 1 | Ref. | 0.68 (0.39–1.20) | 0.88 (0.52–1.52) | 0.54 (0.30–0.97) | 0.08 | 0.78 (0.64–0.95) |
| Multivariable model 2 | Ref. | 0.73 (0.41–1.30) | 0.91 (0.52–1.61) | 0.66 (0.35–1.26) | 0.31 | 0.83 (0.66–1.03) |
Inverse normal transformation was applied to raw values of metabolites. To build the score, we applied a weighted sum of concentrations of 5 metabolites in the choline pathway (TMAO, betaine, choline, phosphocholine, and α‐glycerophosphocholine). The betaine/choline ratio was calculated by dividing the raw values and then applying inverse normal transformations. Model 1 was adjusted for age, sex, body mass index, family history of premature heart disease, and smoking and was stratified by intervention group (only in the overall analyses). Model 2 was adjusted as for model 1 and for physical activity (metabolic equivalent task units in min/d), hypertension, dyslipidemia, and diabetes mellitus. CI indicates confidence interval; CVD, cardiovascular disease; HR, hazard ratio; PREDIMED, Prevention With Mediterranean Diet; Ref., reference; and TMAO, trimethylamine N‐oxide.