Purpose
To examine the relationship of corneal arcus with cardiovascular risk factors and inflammation in Malay adults living in Singapore.
Design
Population-based cross-sectional study.
Methods
A total of 3280 Malays aged 40-80 years (out of 4168 eligible participants; 78.7% response rate) had a standardized interview, systemic and ocular examinations, and laboratory investigations, including measurement of C-reactive protein (CRP), chronic kidney disease, and peripheral artery disease. Corneal arcus was defined from anterior segment images taken with a slit-lamp camera.
Results
Corneal arcus was seen in 2345 out of 3260 participants who had anterior segment images (73.2%). After adjustment for age, gender, total cholesterol, serum glucose, and current smoking, many cardiovascular risk factors significantly associated with corneal arcus, including male gender (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.27–2.03), older age (per 10 years, OR 4.49, 95% CI 3.91–5.15), higher body mass index (per kg/m 2 , OR 1.02, 95% CI 1.00–1.04), higher levels of CRP (per 10 mg/L, OR 1.36, 95% CI 1.13–1.64), total cholesterol (per mmol/L, OR 1.21, 95% CI 1.11–1.32), low-density lipoprotein cholesterol (per mmol/L, OR 1.94, 95% CI 1.38–2.74), presence of peripheral artery disease (OR 3.85, 95% CI 1.29–11.5), chronic kidney disease (OR 1.14, 95% CI 1.03–1.38), and current smoking (OR 1.29, 95% CI 1.02–1.69).
Conclusions
This study confirms known associations of traditional cardiovascular risk factors with corneal arcus in an Asian population. Additionally, corneal arcus may be associated with systemic inflammatory markers, peripheral artery disease, and chronic kidney disease.
Corneal arcus is a gray-white-yellowish opacity located near the periphery of the cornea and separated from the limbus margin by a clear zone. This lesion is pathogenically composed of lipids deposited within the stroma and is reported to share many pathophysiological similarities with the atherosclerotic processes. Although it is of little visual importance, studies based on Caucasian populations suggested that the presence of corneal arcus is linked to familial hypercholestrolemia and cardiovascular diseases (CVD) such as coronary heart disease, particularly in patients younger than 50 years.
Various cardiovascular risk factors were reported to be associated with corneal arcus, including hyperlipidemia, hypertension, higher body mass index (BMI), diabetes mellitus, and cigarette smoking. Studies on corneal arcus in Asian populations, however, are rare. In a multiethnic random survey (participants aged 18–69 years, mainly Chinese) in Singapore, the risk factors found to be related with corneal arcus were low-density lipoprotein (LDL) cholesterol and fasting serum glucose, while in a recent community-based study of a Chinese population in Taiwan (participants aged 30–60 years), male gender and LDL cholesterol were associated with corneal arcus.
Besides traditional risk factors, inflammation is now increasingly thought to play a key role in the pathogenesis of CVD. The major acute phase reactant of systemic inflammation, C-reactive protein (CRP), is elevated in persons with CVD and predicts major vascular events. The association of CRP with corneal arcus is unclear.
In this report, we describe relationship of cardiovascular risk factors and inflammation and corneal arcus in a Malay population in Asia.
Methods
Study Population
The Singapore Malay Eye Study (SiMES) was a cross-sectional epidemiologic study of 3280 Malay adults, aged between 40 and 80 years, living in Singapore. Details of the study design, sampling plan, methodology, and baseline characteristics have been reported elsewhere. In brief, an age-stratified random sample of all Malay adults aged 40 to 80 years residing in 15 residential districts in the southwestern part of Singapore was selected. Of the 4168 eligible individuals, 3280 participated in the study (78.7% response rate).
All examinations were conducted from August 2004 to June 2006.
Ophthalmologic Examination and Corneal Arcus Grading
At the study clinic, all participants underwent extensive and standardized ocular examination of both anterior and posterior segments of the eyes. Images of anterior segments were taken under slit-lamp microscope by a digital camera (Topcon SL-D7; Topcon Medical Systems, Tokyo, Japan). Corneal arcus was graded by the study ophthalmologist (R.W.) and was defined as absent; partial, if the arc of involved cornea was <180 degrees; or circumferential, if the arc of the involved cornea was >180 degrees.
Assessment and Definitions of Risk Factors
All participants underwent a standardized interview and examination, including collection of nonfasting venous blood samples. Lifestyle risk factors (eg, smoking and alcohol intake) and self-reported history of systemic diseases were elicited from the interview. Alcohol consumption was defined as having drinks more than once a week. Previous myocardial infarction, angina, and stroke were self-reported. Blood pressure was measured with a digital automatic blood pressure monitor (Dinamap model Pro Series DP110X-RW, 100V2; GE Medical Systems Information Technologies, Inc, Milwaukee, Wisconsin, USA) after the participants were seated for at least 5 minutes. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication. The ratio of the higher of the 2 systolic pressures at the ankle to the average of the 2 readings of brachial artery pressures was calculated as ankle brachial index (ABI). ABIs were calculated separately for each leg and the lower ABI between the 2 legs was used as the index ABI of the person. Peripheral arterial disease was defined if ABI ≤ 0.9.
Blood samples were analyzed for serum lipid levels (total cholesterol, high-density lipoprotein [HDL] cholesterol, and LDL cholesterol), hemoglobin A 1C , and glucose on the same day at the National University Hospital Reference Laboratory. Serum CRP was measured from frozen plasma stored at −80°C using an immunoturbidimetric assay (intra-assay precision 0.6%–1.3%, inter-assay precision 2.3%–3.1%) implemented on a Roche Integra 400 (Roche Diagnostics, Mannheim, Germany). The detection limit of this assay is 0.07 mg/L and the coefficient variation is 2.9% at 6.3 mg/L and 3.9% at 108 mg/L mean value. Diabetes mellitus was defined as random glucose ≥11.1 mmol/L, use of diabetic medication, or a physician diagnosis of diabetes.
Urine samples were collected to determine levels of microalbuminuria and creatinine at the Alexandra Hospital Laboratory. Glomerular filtration rate (GFR) was indirectly estimated using the 4-variable Modification of Diet in Renal Disease Study (MDRD) equation. Chronic kidney disease was defined as estimated GFR of <60 mL/minute per 1.73 m 2 , consistent with National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) > Stage 2 chronic kidney disease.
Statistical Analysis
Descriptive analyses were performed for all variables and differences between participants with and without corneal arcus were initially assessed using t test or χ 2 test, as appropriate. Characteristics associated with corneal arcus were evaluated initially by contingency tables. Binary logistic regression analysis was then performed to evaluate associations between systemic risk factors (independent variables) and prevalence of corneal arcus (the dependent variable), after adjustment of: 1) age and gender; and 2) age, gender, total serum cholesterol, glucose, and current smoking. As corneal arcus is pathologically a result of lipid deposition in the corneal stroma, stratified analysis by total cholesterol levels (<6.20 or ≥6.20 mmol/L) was performed. Because of previous reports that the associations of corneal arcus with cardiovascular risk factors may differ by gender and age, we further conducted stratified analyses by these subgroups adjusted for relevant risk factors. All reported P values were based on 2-sided tests and compared to a significance level of 5%. All analyses were performed using SPSS version 15 (SPSS Inc, Chicago, Illinois, USA).
Results
Among the 3280 participants, color photographs of the anterior segments were available in 3260 persons (99.4%). Of these, corneal arcus was seen in 2345 persons (73.2%). Although it was found to be highly symmetric between the right and left eye of a subject, grade of corneal arcus from the worse affected eye was used for analysis. The Figure shows the prevalence of partial and circumferential corneal arcus in the study population by age groups. The prevalence of circumferential corneal arcus, as well as the prevalence of any corneal arcus (combined prevalence of partial and circumferential arcus), was highly age-related (both P for trend < .001). Furthermore, in each age group, the combined prevalence of partial and circumferential corneal arcus was significantly ( P < .001) higher in men than in women.
When compared to persons without corneal arcus, participants with corneal arcus were older in age (mean difference 12.4 years, 95% CI 11.7–13.2); had higher mean BMI (mean difference 1.0 kg/m 2 , 95% CI 0.6–1.4), serum hemoglobin A 1C (mean difference 0.16%, 95% CI 0.04–0.28), CRP (mean difference 0.94 mg/L, 95% CI 0.29–1.58), systolic blood pressure (mean difference 10.6 mm Hg, 95% CI 8.8–12.4), diastolic blood pressure (mean difference 0.9 mm Hg, 95% CI 0.1–1.8), total cholesterol (mean difference 0.24 mmol/L, 95% CI 0.15–0.33), HDL cholesterol (mean difference 0.04 mmol/L, 95% CI 0.01–0.06), and LDL cholesterol (mean difference 0.23 mmol/L, 95% CI 0.15–0.30); and had a significantly higher prevalence of diabetes, hypertension, self-reported CVD, peripheral arterial disease, and chronic kidney disease but a lower prevalence of alcohol consumption ( Table 1 ).
| Characteristic | Corneal Arcus Present | Corneal Arcus Absent | P a | ||
|---|---|---|---|---|---|
| Mean | SD | Mean | SD | ||
| Age (years) | 62.0 | 7.4 | 49.6 | 10.2 | <.001 |
| BMI, kg/m 2 | 27.1 | 5.0 | 26.1 | 5.2 | <.001 |
| Blood glucose, mmol/L | 6.84 | 3.64 | 6.63 | 3.78 | .148 |
| Hemoglobin A 1C , % | 6.49 | 1.56 | 6.33 | 1.52 | .010 |
| C-reactive protein, mg/L | 4.34 | 8.96 | 3.41 | 5.22 | .005 |
| Systolic blood pressure, mm Hg | 149.9 | 23.6 | 139.3 | 22.4 | <.001 |
| Diastolic blood pressure, mm Hg | 80.0 | 11.2 | 79.1 | 11.3 | .043 |
| Total cholesterol, mmol/L | 5.69 | 1.20 | 5.45 | 1.04 | <.001 |
| HDL cholesterol, mmol/L | 1.36 | 0.34 | 1.32 | 0.30 | .004 |
| LDL cholesterol, mmol/L | 3.61 | 1.04 | 3.37 | 0.89 | <.001 |
| No. | % | No. | % | ||
|---|---|---|---|---|---|
| Gender, male | 1240 | 51.9 | 333 | 38.3 | <.001 |
| Diabetes | 601 | 25.1 | 156 | 18.0 | <.001 |
| Hypertension | 1782 | 74.6 | 449 | 51.7 | <.001 |
| Self-reported CVD b | 302 | 12.7 | 61 | 7.0 | <.001 |
| Peripheral arterial disease | 74 | 10.1 | 5 | 2.4 | <.001 |
| Chronic kidney disease | 578 | 24.2 | 89 | 10.2 | <.001 |
| Current smoking | 489 | 20.5 | 172 | 19.8 | .658 |
| Alcohol consumption | 21 | 1.3 | 32 | 2.4 | .042 |
a P value for the difference in characteristics by corneal arcus, based on χ 2 test or ANOVA as appropriate.
b Including self-reported myocardial infarction, angina, and stroke.
As shown in Table 2 , older age, male gender, greater BMI, prevalence of chronic kidney disease, prevalence of peripheral arterial disease, current smoking, and high levels of CRP and total and LDL cholesterol were all associated with an increased prevalence of corneal arcus after adjustment for age and gender. These associations remained significant after further adjustment for total cholesterol, serum glucose, and current smoking, which are all known risk factors for CVD, diabetes, and hyperlipidemia. Specifically, age was the major risk factor of corneal arcus prevalence (odds ratio [OR] 4.5 per decade of increase in age). When compared with women, men had a 60% higher likelihood to have corneal arcus. For persons with higher LDL cholesterol levels, the likelihood of having corneal arcus almost doubled (OR 1.94). Patients with peripheral arterial disease had 3.85 fold of odds to have corneal arcus.
| Characteristic | Corneal Arcus | |
|---|---|---|
| OR (95% CI) Model 1 a | OR (95% CI) Model 2 a | |
| Gender, male | 1.88 (1.56, 2.26) | 1.61 (1.27, 2.03) |
| Age, per 10 years | 4.18 (3.72, 4.68) | 4.49 (3.91, 5.15) |
| BMI, per kg/m 2 | 1.02 (1.00, 1.04) | 1.02 (1.00, 1.04) |
| Diabetes | 0.72 (0.57, 0.92) | 1.00 (0.72, 1.40) |
| Blood glucose, per mmol/L | 0.97 (0.94, 0.99) | 0.97 (0.93, 1.04) |
| Hemoglobin A 1C , % | 0.94 (0.89, 1.01) | 0.98 (0.89, 1.09) |
| C-reactive protein, per 10 mg/L | 1.84 (1.56, 2.26) | 1.36 (1.13, 1.64) |
| Hypertension | 1.00 (0.82, 1.23) | 1.19 (0.91, 1.57) |
| Systolic blood pressure, per 10 mm Hg | 1.00 (0.99, 1.01) | 1.00 (0.99, 1.01) |
| Diastolic blood pressure, per 10 mm Hg | 1.00 (0.99, 1.00) | 1.00 (0.99, 1.02) |
| Total cholesterol, per mmol/L | 1.19 (1.09, 1.29) | 1.21 (1.11, 1.32) |
| LDL cholesterol, per mmol/L | 2.41 (1.75, 3.30) | 1.94 (1.38, 2.74) |
| HDL cholesterol, per mmol/L | 1.30 (1.17, 1.43) | 1.09 (0.91, 1.51) |
| Self-reported CVD b | 1.03 (0.77, 1.44) | 1.11 (0.78, 1.57) |
| Peripheral arterial disease | 3.33 (1.14, 9.75) | 3.85 (1.29, 11.5) |
| Chronic kidney disease | 1.12 (1.01, 1,45) | 1.14 (1.03, 1,49) |
| Current smoking | 1.34 (1.03, 1.75) | 1.29 (1.02, 1.69) |
| Alcohol consumption | 1.06 (0.56, 2.00) | 0.76 (0.38, 1.52) |
a Model 1: adjusted for age and gender; Model 2: adjusted for age, gender, total cholesterol, serum glucose, and current smoking (except for models assessing total cholesterol levels or current smoking).
b Including self-reported myocardial infarction, angina, and stroke.
Significant associations of diabetes, serum glucose, hemoglobin A 1c , and HDL cholesterol with corneal arcus prevalence were evident after adjusting for age and gender. However, these associations became nonsignificant after further adjusting for total cholesterol, serum glucose, and current smoking (or further adjusting for total cholesterol and current smoking in the model assessing serum glucose). There was no association of corneal arcus with hypertension or self-reported CVD after adjustment for age and gender ( Table 2 ).
Table 3 showed the associations of cardiovascular risk factors with the severity levels of corneal arcus stratified by 2 age groups (<50 years, ≥50 years), after adjusting for co-variables. Male gender and high levels of CRP and LDL cholesterol were associated with an increased prevalence of corneal arcus in both age groups. The associations of male gender with corneal arcus prevalence were stronger in the age group ≥50 years compared to the group <50 years. High level of total cholesterol associated with an increased prevalence of corneal arcus was only observed in the age group <50 years, while presence of chronic kidney disease or peripheral arterial disease, or high level of BMI, associated with corneal arcus was only observed in the age group ≥50 years.
| Risk Factors | OR (95% CI) a | OR (95% CI) a | ||
|---|---|---|---|---|
| Age <50 Years | Age ≤50 Years | |||
| Partial Arcus | Circumferential Arcus | Partial Arcus | Circumferential Arcus | |
| Gender, male | 1.54 (1.05, 2.28) | 1.68 (0.60, 4.70) | 2.23 (1.64, 3.03) | 2.98 (2.14, 4.14) |
| BMI, per kg/m 2 | 1.02 (0.94, 1.12) | 1.03 (0.94, 1.13) | 1.06 (1.04, 1.08) | 1.09 (1.06, 1.12) |
| C-reactive protein, per 10 mg/l | 1.39 (1.06, 1.81) | 1.18 (0.57, 2.46) | 1.20 (0.94, 1.54) | 1.28 (1.02, 1.62) |
| Total cholesterol, per mmol/L | 1.08 (1.04, 1.13) | 1.35 (1.15, 1.59) | 1.10 (0.95, 1.33) | 1.25 (0.97, 1.65) |
| LDL cholesterol, per mmol/L | 1.56 (1.07, 2.28) | 1.72 (0.67, 4.42) | 1.43 (1.14, 1.79) | 1.83 (1.41, 2.36) |
| Peripheral artery disease | 1.59 (0.78, 7.96) | 3.10 (0.57, 11.1) | 3.23 (1.17, 10.4) | 4.81 (1.46, 15.8) |
| Chronic kidney disease | 1.09 (0.51, 2.32) | 1.26 (0.16, 10.1) | 1.81 (1.33, 2.48) | 2.60 (1.88, 3.62) |
| Current smoking | 1.25 (0.84, 1.86) | 1.56 (0.59, 4.07) | 1.16 (0.80, 1.71) | 1.20 (0.80, 1.80) |
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