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A total of 3, 237 participants fulfilled the eligibility criteria and were included in the analyses (Figure 1). The mean age of the eligible participants (48.7% male) was 53.5 ± 8.6 years, and the mean ALP level was 71.39 ± 20.35 U/L. The characteristics of the eligible participants and the excluded population are presented in Supplementary Table S1 (available in www.besjournal.com). All participants were divided into quintile groups according to their serum ALP levels, and the demographic data and cardiovascular risk factors were compared across the five quintile groups, as presented in Table 1. Participants in the higher ALP quintiles were older, had a higher BMI, and were more likely to have hypertension, diabetes mellitus, and stroke (all P < 0.05). From the lowest to the highest quintile, TC, LDL-C, and TG levels increased, while eGFR and HDL-C levels decreased (all P < 0.05).
Characteristics Included Population Excluded Population P Value Number 3, 237 1, 383 < 0.0001 Age, year 53.55 ± 8.58 51.89 ± 8.70 < 0.0001 Male, % 1, 576 (48.69) 736 (53.22) 0.0048 BMI, kg/m2 24.97 ± 3.24 25.07 ± 3.53 0.5446 Hypertension, % 760 (23.48) 289 (20.90) 0.0550 Diabetes, % 269 (8.31) 107 (7.74) 0.5139 eGFR, mL·min-1 1.73 m-2 88.18 ± 12.99 90.02 ± 13.28 < 0.0001 Myocardial infarction, % 23 (0.71) 17 (1.23) 0.0814 Stroke, % 87 (2.69) 29 (2.10) 0.2398 Current smoker, % 773 (23.88) 391 (28.27) 0.0016 Heavy alcoholism, % 26 (0.80) 15 (1.08) 0.3503 Total cholesterol, mmol/L 4.71 ± 0.90 4.67 ± 0.91 0.1162 LDL-C, mmol/L 2.65 ± 0.60 2.62 ± 0.63 0.0988 TG, mmol/L 1.73 ± 1.43 1.72 ± 1.48 0.8393 HDL-C, mmol/L 1.21 ± 0.27 1.20 ± 0.28 0.4096 Statins therapy, % 56 (1.73) 16 (1.16) 0.1498 Education level 0.0004 Illiteracy/primary/middle school 1, 035 (31.97) 377 (27.26) High school 1, 049 (32.41) 436 (31.53) College/University 1, 153 (35.62) 570 (41.21) Income, 0.0083 ≤3, 000 1, 605 (49.58) 659 (47.65) 3, 001-5, 000 1, 442 (44.55) 609 (44.03) > 5, 000 190 (5.87) 115 (8.32) ALP level, U/L 71.39 ± 20.35 70.30 ± 24.06 0.0493 Note.ALP: alkaline phosphatase; BMI: body mass index; eGFR: estimated glomerular filtration rate; LDL-C: low density lipoprotein cholesterol; TG: triglyceride; HDL-C: high density lipoprotein cholesterol. Table Supplementary Table S1. Comparison of Characteristics between Included and Excluded Participants
ALP Quintiles Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value Number of subjects, n 646 628 690 643 630 / ALP level, U/L 47.28 ± 5.59 59.17 ± 2.50 68.62 ± 2.95 79.76 ± 3.79 102.78 ± 15.94 / Age, year 49.49 ± 7.84 52.84 ± 8.27 53.81 ± 8.19 55.15 ± 8.70 56.50 ± 8.22 < 0.0001 Male, % 230 (35.60) 329 (52.39) 377 (54.64) 333 (51.79) 307 (48.73) < 0.0001 BMI, kg/m2 23.94 ± 3.19 24.87 ± 3.24 25.17 ± 3.05 25.27 ± 3.10 25.61 ± 3.36 < 0.0001 Hypertension, % 96 (14.86) 119 (18.95) 161 (23.33) 171 (26.59) 213 (33.81) < 0.0001 Diabetes, % 31 (4.80) 47 (7.48) 47 (6.81) 64 (9.95) 80 (12.70) < 0.0001 eGFR, mL·min-1 1.73 m-2 90.91 ± 12.75 89.13 ± 11.99 87.86 ± 12.73 87.00 ± 13.34 85.92 ± 13.54 < 0.0001 Myocardial infarction, % 1 (0.15) 7 (1.11) 9 (1.30) 0 (0.00) 6 (0.95) 0.0014 Stroke, % 6 (0.93) 17 (2.71) 24 (3.48) 18 (2.80) 22 (3.49) 0.0279 Current smoker, % 97 (15.02) 146 (23.25) 185 (26.81) 163 (25.35) 182 (28.89) < 0.0001 Heavy alcoholism, % 3 (0.46) 6 (0.96) 9 (1.30) 4 (0.62) 4 (0.63) 0.4370 Total cholesterol, mmol/L 4.52 ± 0.80 4.62 ± 0.85 4.71 ± 0.90 4.85 ± 0.85 4.84 ± 1.03 < 0.0001 LDL-C, mmol/L 2.49 ± 0.56 2.58 ± 0.60 2.67 ± 0.62 2.75 ± 0.58 2.74 ± 0.61 < 0.0001 TG, mmol/L 1.35 ± 0.98 1.65 ± 1.42 1.70 ± 1.16 1.89 ± 1.60 2.06 ± 1.77 < 0.0001 HDL-C, mmol/L 1.28 ± 0.29 1.21 ± 0.26 1.20 ± 0.28 1.19 ± 0.27 1.16 ± 0.25 < 0.0001 Statin therapy, % 10 (1.55) 7 (1.11) 12 (1.74) 9 (1.40) 18 (2.86) 0.1558 Education level < 0.0001 Illiteracy/primary/middle school 122 (18.89) 183 (29.14) 214 (31.01) 255 (39.66) 261 (41.43) High school 221 (34.21) 191 (30.41) 222 (32.17) 206 (32.04) 209 (33.17) College/University 303 (46.90) 254 (40.45) 254 (36.81) 182 (28.30) 160 (25.40) Income, CNY < 0.0001 ≤ 3, 000 267 (41.33) 297 (47.29) 350 (50.72) 356 (55.37) 335 (53.17) 3, 001-5, 000 336 (52.01) 286 (45.54) 301 (43.62) 265 (41.21) 254 (40.32) > 5, 000 43 (6.66) 45 (7.17) 39 (5.65) 22 (3.42) 41 (6.51) Note. ALP: alkaline phosphatase; BMI: body mass index; eGFR: estimated glomerular filtration rate; LDL-C: low-density lipoprotein cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol. Table 1. Demographic and Baseline Clinical Characteristics of the Study Population According to ALP Quintiles
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The mean common carotid IMT values across the ALP quintiles are presented in Table 2. Both sides of the common carotid IMT increased gradually from the lowest to the highest quintiles. Compared with the first quartile (the reference category), the ORs (95% CIs) for abnormal common carotid IMT were 2.14 (1.38-3.32), 2.34 (1.52-3.59), 3.24 (2.14-4.93), and 3.45 (2.27-5.23) for the second, third, fourth, and fifth quintile, respectively (all P < 0.0001). After adjusting for confounders, the ORs for abnormal common carotid IMT in the fourth and fifth quintile were 1.78 (95% CI 1.13-2.82, P = 0.0135) and 1.82 (95% CI: 1.15-2.87, P = 0.0110), respectively (Table 3). In the subgroup analysis, the risk of abnormal IMT per ALP quintile did not differ with respect to sex, age, eGFR, NAFLD, and metabolic syndrome (Supplementary Table S2 available in www.besjournal.com).
ALP Quintiles Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value Left Mean common carotid IMT, mm 0.69 ± 0.13 0.73 ± 0.16 0.74 ± 0.20 0.76 ± 0.16 0.78 ± 0.18 < 0.0001 Carotid plaque, % 40 (6.19) 67 (10.67) 70 (10.14) 83 (12.91) 102 (16.19) < 0.0001 Right Mean common carotid IMT, mm 0.68 ± 0.13 0.72 ± 0.16 0.73 ± 0.18 0.76 ± 0.20 0.76 ± 0.16 < 0.0001 Carotid plaque, % 29 (4.49) 60 (9.55) 69 (10.00) 78 (12.13) 86 (13.65) < 0.0001 Note.IMT: Intima media thickness; ALP: alkaline phosphatase. Table 2. Comparison of Common Carotid IMT and Carotid Plaque Across different ALP Levels
Adjusted Odd Ratios 95% Confidence Interval P for Interaction Sex 0.1644 Male 1.09 0.97-1.21 Female 1.26 1.05-1.51 Age 0.3846 < 65 years 1.14 1.03-1.26 ≥ 65 years 1.23 1.00-1.51 Estimated glomerular filtration rate (eGFR) 0.8495 < 50th 1.08 0.96-1.22 ≥ 50th 1.19 1.03-1.38 Nonalcoholic fatty liver disease (NAFLD) 0.8362 Yes 1.13 1.00-1.27 No 1.14 0.98-1.33 Metabolic syndrome 0.2544 Yes 1.10 0.97-1.25 No 1.14 0.99-1.32 Table Supplementary Table 2. Adjusted risks of abnormal common carotid IMT per ALP quintile across different subgroup
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We examined the correlation of serum ALP levels with carotid plaque and ECAS. As shown in Table 2, the prevalence of carotid plaques increased gradually from the lowest to the highest quintile (from 6.19% to 16.19% on the left side and from 4.49% to 13.65% on the right side, all P < 0.0001). The unadjusted risks of carotid plaques were significantly elevated in the higher quintiles, compared to the reference (the lowest quintile). However, after adjusting for confounding covariates, the association between carotid plaques and ALP quintiles was no longer significant (Table 3). Therefore, our data indicate that there is no significant link between ALP levels and carotid plaques.
ALP Unadjusted Adjusted OR 95% CI P value OR 95% CI P value Mean common carotid IMT > 0.9 mm Quintile 1 reference - - - - - Quintile 2 2.14 1.38-3.32 0.0007 1.53 0.95-2.47 0.0812 Quintile 3 2.34 1.52-3.59 0.0001 1.47 0.92-2.34 0.1085 Quintile 4 3.24 2.14-4.93 < 0.0001 1.78 1.13-2.82 0.0135 Quintile 5 3.45 2.27-5.23 < 0.0001 1.82 1.15-2.87 0.0110 Carotid plaques Quintile 1 reference - - - - - Quintile 2 1.90 1.34-2.68 0.0003 1.28 0.87-1.88 0.2072 Quintile 3 1.92 1.37-2.70 0.0002 1.12 0.77-1.64 0.5438 Quintile 4 2.45 1.75-3.41 < 0.0001 1.23 0.84-1.78 0.2895 Quintile 5 2.77 1.99-3.85 < 0.0001 1.27 0.88-1.85 0.2071 Note.The lowest quintile (quintile 5) was used as the reference. IMT: Intima media thickness; ALP: alkaline phosphatase; OR: odds ratio; CI: confidence interval. Table 3. Risk of Abnormal Common Carotid IMT or Carotid Plaque Across ALP Quintiles
Using the first ALP quintile as the reference, we found that the ORs for ECAS in the second, third, fourth, and fifth quintile were 1.77 (95% CI: 1.34-2.33), 1.65 (95% CI: 1.25-2.18), 1.880 (95% CI: 1.43-2.48), and 2.47 (95% CI: 1.88-3.23), respectively. In addition, the OR for ECAS in the fifth quintile was 1.47 (95% CI: 1.09-1.97, P = 0.0106) after adjusting for age, sex, BMI, hypertension, diabetes mellitus, eGFR, myocardial infarction, stroke, smoking, alcohol drinking, lipid profile, education level, family income, and statin therapy (Table 4).
ALP Unadjusted Adjusted OR 95% CI P value OR 95% CI P value Quintile 1 reference - - reference - - Quintile 2 1.77 1.34-2.33 < 0.0001 1.30 0.96-1.74 0.0864 Quintile 3 1.65 1.25-2.18 0.0004 1.11 0.83-1.49 0.4896 Quintile 4 1.88 1.43-2.48 < 0.0001 1.20 0.90-1.62 0.2180 Quintile 5 2.47 1.88-3.23 < 0.0001 1.47 1.09-1.97 0.0106 Note. ALP: alkaline phosphatase; OR: odds ratio; CI: confidence interval; ECAS: extracranial carotid artery stenosis. Table 4. Risk of ECAS Across different ALP Quintiles