Little is known about whether geographic factors are independently associated with the development of ES. In our sample, individuals in northern states had considerably higher hazards of ES relative to those in middle and southern states, and persons living in upper-Midwestern states had substantially higher hazards of ES relative to Missourians. Our models demonstrate that greater sunshine exposure and lower ambient temperatures, in summer and winter, increase the likelihood of ES. The increased association with altitude was found only in states with relatively few sunny days.
The prevalence of ES is known to vary worldwide, with a gradient by latitude. Reported ES prevalences in Sri Lanka (latitude=7°N),51
South India (12°N),52
and Sweden (62°N)33
are 1.1%, 3.8%, 6.5%, 11.9%, and 23%, respectively. In two clinic-based U.S. studies, which might overestimate the burden of ES because of referral bias, the prevalences were low: 3% among adults aged 60 or older in North Carolina (latitude=35°N),46
and 1.4% in Louisiana (latitude=30°N).55
In our study the crude prevalences of ES in various U.S. states were considerably lower than previously reported estimates for Europe and Asia. Mississippi (32°N) had the lowest crude prevalence (0.23%), whereas Minnesota (45°N) had the highest (2.84%). The lower prevalences in our study have many possible explanations. Nevertheless, in our study, where patients’ residences spanned a latitude range of 15°, living in the northern continental U.S. tier was associated with an increased hazard for ES; residing in North Dakota was associated with the highest risk for ES relative to living in Missouri. Considering the effect of latitude was the same in whites and nonwhites suggests that a trend toward genetically predisposed Northern Europeans’ populating northern-tier states does not explain our findings. Colder temperatures in summer and winter months increased the hazard of ES. Many of the highest reported ES prevalences are from countries with cold mean temperatures. For example, ES prevalences among Icelanders, Finns, and Lapps are greater than 20%.32,34,56,57
One explanation may be that the extracellular deposits of ES represent a nucleation reaction58
that is prone to develop at lower temperatures. While the temperature in the vascular iris may be close to the core body temperature, the temperatures in the avascular ocular segments, such the anterior chamber and lens, may be susceptible to ambient temperatures.15
One notable exception to the cold-precipitation hypothesis was a study in which ES prevalence among Eskimos in Alaska, Canada, and Greenland was 0%.59
Perhaps in Eskimos a thicker iris and more abundant periorbital fat help to keep ocular temperatures high enough to prevent extracellular deposit formation.60
Alternatively, the finding could be related to cultural practices—e.g., style of dress or housing design—that may modulate climate impact.
The hazard of ES increased in states with more sunny days, and sunshine exposure appears to modify the associations with winter temperature and elevation. Studies have reported strong associations between ES and climatic droplet keratopathy,61
a condition associated with ultraviolet-light exposure.62
Furthermore, high ES prevalences have been found in populations with considerable sun exposure, including Australian Aborigines (latitude=27°S)63
and Navajo Indians (latitude=37°N).64
The cornea transmits ultraviolet rays,65
and ultraviolet radiation may add to the impaired elastogenesis caused by abnormal LOXL1
function, although further research is needed to confirm this.
The association between elevation and ES was modified by sunshine exposure. In locales with relatively few sunny days, higher altitude was associated with increased risk of ES, whereas the opposite was true for locales with more sunshine. The reason for this finding is not entirely clear and may be confounded by other variables. To date, little is known about the potential effect of altitude on ES prevalence. At 6%, the prevalence of ES was relatively high among 50 Navajo Indians, aged 60 years or older, living on an Arizona reservation at 36°N and an altitude of 1500 meters.64
These data suggest that high altitude may contribute to ES; more studies with detailed estimation of exposure to altitude are needed to better understand its impact.
In a study of 350 Aboriginies living in different regions of Australia63
, ES was associated with lower latitudes (north of the 29th parallel south) and greater levels of total global radiation exposure. Temperature, relative humidity, evaporation rate, rainfall, sunlight, and ultraviolet radiation exposure were not significant. Direct comparisons between that study and ours are difficult because of differences in climatic factors between Australia and the U.S., the sociodemographic characteristics of the samples, and the covariates included for adjustment in the analyses. We did not have information on total global radiation levels for each US state to incorporate this factor into our analyses.
Using a large administrative database to investigate the environmental variables associated with ES has several benefits. The large number of ES cases provided ample power to study the relationship between geographic factors and ES. In addition, our sample is geographically and sociodemographically diverse. Clinic or hospital-based studies are affected by selective referral of severe cases to ophthalmic centers, but our sample was not limited to referral cases, or patients seen by specialists or at academic medical centers.
Our study also has several limitations. First, misclassification of ES likely existed in our database; however, our cases had known comorbid conditions, demographic features, and ocular characteristics consistent with ES. Second, we cannot rule out the possibility that differential detection of ES in northern tier versus southern tier states explains our results, although this seems unlikely. For example, residence in North Dakota—a state with no academic ophthalmology centers—was associated with the highest ES risk relative to Missouri, which has several such centers. Yet we still cannot rule out detection bias, whereby northern eye care providers are more prone to detect ES than practitioners in the other tiers. Third, the claims database contained no zip-code-level information on beneficiaries. Therefore, the average levels of each environmental factor for a given state used for these analyses may not precisely reflect individuals’ actual exposure. We minimized such misclassification by excluding residents of California, a state that spans 9° of latitude. Fourth, we knew neither how long beneficiaries lived in their state nor whether they generally spend most or all months of the year living there. For example, the increased hazard of ES associated with residing in Florida may reflect recent migration from a northern state, but such migratory trends would have driven the tier-related results to the null. Furthermore, considerable ancillary evidence indicates that sunshine is implicated in ES.61,63,66,67
In addition, we cannot capture the extent to which individuals residing in a given U.S. state are exposed to the environmental conditions characteristic of that state. Some enrollees spend significant time outdoors because of their occupation or hobbies, whereas others may have limited exposure to environmental conditions. This ecologic bias may affect our findings. Finally, all participants were U.S. residents with health insurance; our findings may be nongeneralizable to other populations and regions.