Introduction

Intraocular pressure (IOP) is the only treatable risk factor of glaucoma, which is one of the world’s leading causes of irreversible blindness [1]. IOP is maintained primarily by the balance between the rates of aqueous humor production by the ciliary body and aqueous outflow via Schlemm’s canal and uveoscleral tissues that drain into the veins; thus, the episcleral vein and intraorbital tissue pressures are involved in the maintenance of IOP [2]. Previous studies have suggested that some local factors, such as resistance of the trabecular meshwork and juxtacanalicular connective tissues, are the major determinants of IOP [3,4]. However, the exogenous effects on the glaucoma [5,6] or IOP [7] by various systemic factors, lifestyle, and diet also have been suggested recently to be contributors.

The current cross-sectional study evaluated the possible effects of the various systemic factors on the IOP using a dataset from a health examination program in Japan.

Methods

Results

The characteristics of the 1569 study subjects (819 men, 52%; 750 women, 48%; mean age, 62.2±8.7 years; range, 27–92 years) are summarized in Table 1. The mean IOP was 12.8±3.0 mmHg (range, 7–33.1 mmHg) in the right eye and 12.8±3.0 mmHg (range, 7–33.8 mmHg) in the left eye.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Subjects’ demographic data (N = 1569).

https://doi.org/10.1371/journal.pone.0234042.t001

During screening analyses, the associations between various systemic parameters and the IOP were analyzed by univariate analyses (Table 2). Among the parameters, possible associations with the IOP (p<0.1) were found in age, height, BMI, percent body fat, waist circumference, sBP, dBP, mean BP, pulse rate, TP, albumin, alanine aminotransferase, guanosine triphosphate, triglycerides, HbA1c, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, creatinine, calcium, and amylase in both the right and left eyes. The BNP, albumin/globulin ratio, total cholesterol, LDL cholesterol, and both the right and left IMTs were possible correlations only for the right eyes. The waist circumference, BUN, and chlorine were possible correlations only for the left eyes. Of these parameters, the age, height, BNP, BUN, creatinine, chlorine, amylase, and both the right and left IMTs were correlated negatively with the IOP, while others were correlated positively with the IOP. Both the right and left IOPs of women (mean, 13.0±2.8 mmHg for the right eyes; mean, 13.0±2.8 mmHg for left eyes) were slightly higher than those of the men (mean, 12.6±3.1 mmHg for the right eyes; mean, 12.6±3.1 mmHg for the left eyes) (p = 0.0048 for the right eyes and p = 0.0304 for the left eyes, Student t-test). Possible associations between each pair of parameters other than IOPs are shown in S2 Table.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Univariate analyses for possible correlations between IOP and various systemic parameters.

https://doi.org/10.1371/journal.pone.0234042.t002

To determine the significant parameters associated with IOP, stepwise multivariate analyses that included all parameters obtained from the univariate analyses (p<0.1) and sex were performed. From the independently performed analyses for the right and left IOPs, the same six parameters, i.e., age, percent body fat, sBP, pulse rate, albumin, and HbA1c, were detected as significant parameters for both the right and left IOP models (Table 3). Among them, age was associated negatively with both the right and left IOPs, while the other five parameters were associated positively with the right and left IOPs.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Multivariate analyses for possible correlations between IOP levels and various systemic parameters.

https://doi.org/10.1371/journal.pone.0234042.t003

Discussion

The current study found that percent body fat, sBP, pulse rate, albumin, and HbA1c were correlated positively with IOP, while age was correlated negatively with IOP. These associations have been detected in multivariate models for IOPs of both eyes; thus, the detection of the same six parameters in independent models strengthened our results.

Cross-sectional studies in Italy [23] and in the United States [10, 11] reported the positive association between age and IOP in general populations, while in Korea [12–15] reported a negative association, as did in Taiwan [16, 17], in China [18], and in Japan [19–21]. A longitudinal family-based cohort study also reported a negative association in Koreans and Mongolians [22]. A negative association was significant only in men from community-based studies in Korea [15] and Taiwan [17] while only in women from healthy participants of a health examination system in Korea [13]. We found a slight but significant difference in IOP between men and women (higher IOP in women), although we did not find a significant association between sex and IOP by multivariate analysis. In other studies, the distributions of the IOPs did not differ significantly between the sexes [14, 15, 19, 21], while other studies have reported a significant association between sex and IOP (higher IOP in men) [16, 23, 24]. Previously, a significant association between sex and IOP seen in univariate regression analysis was explained by the interaction of other variables such as the sex difference in insulin resistance indices, sBP, total cholesterol, and HDL cholesterol [13, 14]. Thus, relationships between IOP and age may vary according to race and sex. The IOP is determined by the balance between aqueous humor inflow and outflow. Aging may cause a decrease in aqueous humor production [25–27] and increased trabecular meshwork resistance [28]; dominance of former change than later change with aging may explain our observation. A large difference in the myopia prevalence, lifestyle, diet, and systemic factors such as obesity can explain the different trends between Western and Asian populations [22, 29].

In both Western and Asian populations, obesity or high BMI was associated with high IOP [11–13, 15–17, 19–21, 30, 31]. In the current analysis, although several obesity-related parameters such as BMI, percent body fat, waist circumference, total cholesterol, triglycerides, LDL cholesterol, and IMT possibly were associated with IOP in univariate analysis, only the percent body fat remained significant in multivariate analysis. In a Korean population-based studies, in non-glaucomatous participants, increased body fat was associated with high IOP in both men and women, while greater lean body mass was associated with lower IOP in women [32]; and in both glaucomatous and non-glaucomatous participants, increased body fat was associated with a low prevalence of primary open-angle glaucoma (POAG) (including normal tension glaucoma) in women, while increased body muscle volume was associated with high POAG prevalence in men [33]. Thus, the roles of body fat on glaucoma may differ between sexes when the fat and skeletal muscle masses were separately evaluated. Collectively, the percent body fat may be a good indicator for exploring the effects of obesity on ocular status. Obesity has been suspected to be associated with increasing IOP by sympathetic hyperactivation, increased corticosteroid, excessive intraorbital adipose tissue, increases in blood viscosity with high hemoglobin and hematocrit values, increased episcleral venous pressure, and a consequent decrease in the facility of aqueous outflow [29, 30, 34, 35]. It is well established that sympathetic hyperactivation is a common feature of obesity, whereas topical beta-adrenergic antagonist reduces IOP. Beta-adrenergic receptor polymorphism is associated with obesity, insulin resistance, IOP, and POAG [36–38]. Another study has suggested that increased IOP may be due to transitory elevations in IOP resulting from breath-holding and thorax compression while tonometry is performed during slit-lamp examinations in obese patients [39].

Previous studies have reported a significant association with IOP elevation and high sBP [17, 19, 21, 22, 31, 40, 41] or both high sBP and dBP [11, 13, 15, 16, 42]. The proposed mechanisms for the roles of BP in IOP elevation have postulated that increased BP leads to an increased filtration fraction of the aqueous humor through elevated ciliary artery pressure, and increased serum corticoids and sympathetic tone result in elevated IOP [30, 43]. Increased sympathetic tone may explain the positive association between heart rate and IOP observed in the current study. Previous studies have reported a relationship between elevated IOP and high HbA1c [11, 44, 45] or high fasting blood sugar [13, 16, 17]. Meta analyses have reported an increased glaucoma risk in diabetic patients (relative risk, 1.48) [46], while Tan et al. (2009) reported that diabetes was associated with higher IOP but persons with diabetes were not more likely to have glaucomatous optic neuropathy or POAG. The autonomic dysfunction in diabetes and the osmotic gradient induced by elevated blood glucose with a consequent fluid shift into the intraocular space may explain the association between glucose and IOP [47, 48]. The positive correlation between blood albumin and IOP that we observed was unique in the literature, although the mechanism of the association requires elucidation.

The current study had several limitations, the first of which was its cross-sectional design, which provided only epidemiologic data and did not address mechanistic analysis. Therefore, the causal relationship could not be determined. This study was based on a self-paid health examination program; and probably has selection bias. Since the participants did not undergo detailed ocular evaluations, such as slit-lamp and fundus examinations, we could not determine the prevalence of ocular diseases in the current subjects. Use of non-contact tonometry, which is generally believed to be less reliable than Goldmann applanation tonometry, and the absence of central corneal thickness measurements that were related to measurement errors during tonometry [49, 50] were other limitations. Absent of information regarding oral medications that possibly affect the IOP is another limitation of this study.

In conclusion, in a Japanese population, the members of which were enrolled in a health examination program, we determined the systemic factors associated with IOP. Other than age, the factors reflecting metabolic syndrome were found to be associated with a risk of high IOP in our population.

Supporting information

Acknowledgments

The authors have no financial interests in any aspect of this study.