A total of 14,700 articles were identified, of which 76 with 27 factors met the inclusion criteria. Finally, eleven factors had data eligible for the meta-analysis and all relevant studies were cross-sectional (Figure 2). The general characteristics of the articles included in the meta-analysis were presented in Table 1. A total of 48,847 subjects were included in the meta-analysis. 92.6% studies were published from 2005 onwards and 72.8% samples were recruited from Asia and North America. The age range of all recruited subjects was from 35 to 100. Where reported, the proportion of females in the samples ranged from 18% to 67.2%.
Cigarette smokers and people with metabolic syndrome (including its components of hypertension, dyslipidemia, and diabetes mellitus), hyperuricemia, hyperhomocysteinemia, negative emotion, socioeconomic strain, obstructive sleep apnea syndrome (OSAS), alcohol, air pollution, and childhood sexual abuse are more likely to have carotid atherosclerosis. Furthermore, interventions against risk factors may prevent atherosclerosis.
Modifiable risk factors
Blood pressure
Data from eight studies[14-21] including 12,474 individuals were pooled in the meta-analysis (Figure 2), which showed that hypertension could increase the risk of carotid plaque by 81% (OR=1.81, 95% CI: 1.55-2.13, I2=19%, P=0.28) (Supplementary Figure 1). Three studies[15, 17, 21] with 2,732 subjects exhibited hypertension has higher risk of increased CIMT (OR=2.60, 95% CI: 1.33-5.08, I2=84%, P<0.01) (Supplementary Figure 2). Additionally, it was indicated that the risk of plaque was significantly greater in people with increased systolic blood pressure (SBP) variability (every 10mmHg increase) and diastolic blood pressure (DBP) variability[1, 22, 23]. Pulse pressure (PP) variability (every 10mmHg increase) raises the risk of carotid plaque for both community-based subjects and stroke patients[24, 25].
Diabetes mellitus
Seven studies[14, 19-22, 26, 27] with 16,752 patients were included in the meta-analysis (Figure 2). The results showed that the risk of carotid plaque in people with diabetes was 1.31 times the risk among those without diabetes (OR=1.31, 95% CI: 1.13-1.53, I2 =0%, P=0.74) (Supplementary Figure 3).
Dyslipidemia
The meta-analysis of ten studies[14, 19-22, 26, 28-31] including 12,568 patients showed that hyperlipidemia (OR=1.92, 95% CI: 1.39-2.65, I2=0, P=0.56), hypertriglyceridemia (triglyceride≥1.7mmol/L) (OR=1.33, 95% CI: 1.14-1.55, I2 =0%, P=0.85), and higher low density lipoprotein (low density lipoprotein≥3.4mmol/L) (OR=1.11, 95% CI: 1.08-1.13, I2 =0%, P=0.46) could significantly increase the risk of carotid plaque (Supplementary Figure 4-6). Moreover, there was strong likelihood of positive relationship between lower high density lipoprotein (high density lipoprotein≤1.0mmol/L) (OR=1.28, 95% CI: 0.99-1.67, I2 =32%, P=0.22) or hypercholesterolemia (total cholesterol≥5.2mmol/L) (OR=1.20, 95% CI: 0.80-1.82, I2 =6%, P=0.34) with carotid plaque (Supplementary Figure 7-8). One cohort study[32] indicated that hypercholesterolemia, hypertriglyceridemia, and higher low density lipoprotein were risk factors for CIMT. Nevertheless, one cross-sectional study[31] failed to prove the relationship of total cholesterol (every 1 mmol/L increase) or triglyceride (every 1 mmol/L increase) with carotid plaque.
Metabolic syndrome (MetS)
MetS was defined according to the criteria of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III)[33]. Six studies[19, 20, 34-37] including 18,058 individuals explored the association between MetS and carotid atherosclerosis, which showed that MetS could elevate the risk of carotid plaque by 39% (OR=1.39, 95% CI: 1.23-1.57, I2 =8%, P=0.36) (Supplementary Figure 9). Notably, there was a dose-response relationship between the elevated risk of carotid plaque and an increasing number of components of MetS (OR=1.71, 95% CI: 1.10-2.66, I2 =0%, P=0.64 for MetS-1; OR=2.17, 95% CI: 1.39-3.37, I2 =0%, P=0.48 for MetS-2; OR=2.21, 95% CI: 1.42-3.46, I2 =0%, P=0.56 for MetS-3; OR=2.65, 95% CI: 1.57-4.47, I2 =8%, P=0.30 for MetS-4; OR=4.78, 95% CI: 2.60-8.81, I2 =0%, P=0.36 for MetS-5) (Supplementary Figure 10-14). Consistently, the association was confirmed by one cohort study[38] showing that individuals with MetS had higher risk of carotid plaque (HR=1.92, 95% CI: 1.06-3.47).
Hyperuricemia
The association between hyperuricemia (uric acid≥420μmol/L in man or uric acid≥360μmol/L in woman) and carotid plaque was reported in four studies[23, 37, 39, 40] including 17,113 participants. Pooled results indicated that hyperuricemia was a risk factor for the presence of plaque (OR=1.57, 95% CI: 1.11-2.22, I2 =84%, P<0.01) (Supplementary Figure 15). Similarly, the risk of increased CIMT was elevated in those with higher uric acid level (OR=1.24, 95% CI: 1.04-1.47)[41]. Further, people with carotid plaque or stenosis were reported to have higher uric acid level. But another cross-sectional study [42] failed to find the relationship between uric acid and plaque.
Hyperhomocysteinemia
Four studies[15, 43-45] with 5,623 individuals were included and a significant positive relationship between hyperhomocysteinemia (homocysteine≥15μmol/L) and carotid plaque was found (OR=1.88, 95% CI: 1.19-2.95, I2 =78%, P<0.01) (Supplementary Figure 16). Additionally, one cross-sectional study[46] found CIMT increased 0.06mm as the level of homocysteine elevated per 1μmol/L.
Smoking
A pooled analysis of six studies[14, 21, 22, 28, 47, 48] including 7,995 participants indicated that smoking had a significant association with the risk of carotid plaque. Subgroup analyses showed that current smoking (OR=1.52, 95% CI: 1.14-2.03, I2 =59%, P=0.03) conferred greater risk than former smoking (OR=1.42, 95% CI: 1.08-1.87, I2 =9%, P=0.33) for the presence of carotid plaque (Supplementary Figure 17-18). Similarly, tobacco smoking is associated with increased CIMT, especially current smokers[49].
Sensitivity analyses
In sensitivity analyses (Supplementary Table 4), the results were robust for hypertension, hyperhomocysteinemia, MetS, and hypercholesterolemia. For current smoking, the heterogeneity was reduced after omitting one study[28] without changing the significance of the results. For hyperuricemia, the pooled effect became non-significant (OR=1.50, 95% CI: 0.95-2.38) after omitting one study[39] with different races.
Assessment of publication bias
For studies reporting the association between hypertension, diabetes mellitus, MetS, current smoking and the presence of carotid plaque, there was evidence of publication bias. After using the trim and fill method, the result barely changed for hypertension, diabetes mellitus, and MetS, but not for current smoking (Supplementary Figure 19-26).
Others
Some modifiable factors could not be included in the meta-analysis due to insufficient data, consisting of sexual abuse in early life[50], air pollution[51, 52], socioeconomic strain[53-55], negative emotion[56-58], lifestyles (drinking, physical activity, and sleep duration)[5, 59-62], diet (vitamin supplementation, egg consumption, vegetable intake and fish consumption)[63-70], medications (antihypertensive drugs, lipid-lowering drugs, and glucose-lowering drugs)[71-80], and pre-existing disease (OSAS) (apnea-hypopnea index>15 events/h)[81, 82] in mid-to-late life (Figure 3 and Supplementary Table 3).