FormalPara Key Summary Points

Certain fibroproliferative diseases have been reported to be more common among white persons, including idiopathic pulmonary fibrosis (IPF).

On the basis of prior clinical observation of an association between light eye color and IPF, we explored this association further in a database containing medical records of a population with a high prevalence of IPF and for whom facial photos were taken as part of their electronic medical record.

Comparing the frequency of light (blue, green, hazel) and dark (brown) eye color between white persons diagnosed with IPF and lung granuloma only, the prevalence of light eye color was statistically higher in patients with IPF (77.6%) than in those with lung granuloma (49.0%).

This observation concurs with genetically related lysosomal organelle dysfunction apparent in white persons for eye and skin diseases, as well as premature gray hair.

Light eye color is predominant among white persons diagnosed with IPF.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease in elderly individuals driven by a combination of host genetics and environmental factors that causes progressive lung fibrosis resulting in respiratory failure and mortality. Certain clinical and demographic factors clearly associate with increased IPF incidence and prevalence. A large USA Medicare claims study found IPF to be more commonly observed in white persons, accounting for 90% of cases [1]. This was confirmed by other studies demonstrating that Black, Asian, and Hispanic cohorts had lower rates of IPF than white persons [2]. The reasons for these observed racial/ethnic differences in IPF prevalence are unclear but might implicate differences in genetics among these groups. Specific host genetics have previously been observed as factors contributing to IPF incidence [3].

Distinct genetic susceptibility factors have been reported in IPF. In a study of kindred cohorts with familial pulmonary fibrosis, telomerase (TERT) mutation carriers, compared with noncarriers, were found to have shorter telomeres, impaired lung function, and increased frequency of radiographic interstitial abnormalities [4]. Notably, the TERT mutation carriers were also found to have higher rates of premature gray hair [4]. This raises the question of whether other clinical features are associated with IPF. Clinically, over a period of several years at our academic medical center, we observed that light eye color was a common phenotypical feature among white persons diagnosed with IPF. Interestingly, light eye color, in addition to albinism, occurs in individuals with Hermansky–Pudlak syndrome (HPS) [5, 6], which can lead to the development of progressive pulmonary fibrosis (HPSPF) at an early age. This suggests a potential premise for an association between light eye color and IPF. Another fibroproliferative disease, Dupuytren’s disease, causes hand contracture and originated in Northern Europe, an area also associated with high rates of blue eyes [7].

To our knowledge, beyond HPS, we are not aware of published reports associating fibrotic lung diseases with eye color. Given this, and our prior observation that most white patients with IPF in the clinical setting had light-colored eyes, we evaluated the possible association of eye color and IPF as part of a large epidemiologic study of interstitial lung disease (ILD).

Methods

To address the question of light eye color association with increased IPF incidence, we utilized data in a retrospective cohort study of ILD from six Veterans Affairs (VA) Health Systems in North Carolina and Virginia [8]. This retrospective study was approved by the Durham VA Medical Center institutional review board in accordance with the Helsinki Declaration of 1964 and its amendments. This study identified 3293 patients of all races through billing records from 2009 and 2015 based on ILD International Classification of Diseases-9 codes, 2604 of whom were identified as white persons and 703 of whom had no evidence of ILD. Following identification, collection of electronic health record (EHR) data was supplemented with an in-depth manual chart review of outpatient encounters that included procedures, radiography reports, and physical examinations. A unique feature of the VA EHR is the availability of facial photos of sufficient quality to judge eye color. One reviewer recorded eye color as light (blue, green, hazel) or dark (brown or light brown) from the EHR when available and discernible. Among these 2604 patients with facial photos of discernible eye color, those with IPF (ICD 9 516.3) or lung granuloma only (control) were selected for this analysis. Lung granuloma was coded under post-inflammatory fibrosis (ICD 9 515.0) and included in this analysis if the radiologic report demonstrated only granuloma and no other evidence of ILD.

Results

Among the 248 white patients in the EHR with IPF (based on the ICD-9 code 516.31), 147 (59% of total) had facial photos of adequate quality to judge eye color as light or dark. For the control group, we identified 397 white patients with lung granuloma only. The median age among patients with lung granuloma was 66 years, and 69 years for those with IPF. Eye color was available in 263 (66%) of the control patients. A small segment of patients who had both retinal photos and facial photos was used to judge the reviewer’s accuracy at determining eye color. Among 48 white patients with any ILD with both retinal and facial photos, the reviewer matched colors in 31/33 (93.9%) cases for light eyes and 14/15 (93.3%) cases for dark eyes. Among 147 white patients with IPF, the prevalence of light-colored eyes was 77.6% (114/147) (Fig. 1). In the 263 white patients with lung granuloma only, 49.0% (129/263) had light-colored eyes, a difference that was statistically significantly different (p < 0.001).

Fig. 1
figure 1

Frequency of light and dark eye color among white patients in a Veteran’s Administration population with idiopathic pulmonary fibrosis and lung granuloma. Light eye color (blue, green, hazel) compared with dark eye color (light brown, brown). Difference between light and dark eye color between two cohorts was statistically significant p < 0.001 (chi-square with Yates correction, two-tailed test)

Full size image

Discussion

Human genes associated with protection from the external environment include those for eye color, skin color, and lung epithelium. Most of the genes associated with eye color are involved in the production, transport, or storage of a pigment called melanin [9]. Gene mutations in lysosomal organelle function in the eyes and skin can alter melanin production by melanosomes [5], thereby increasing the risk of skin damage and macular degeneration [10]. Premature gray hair is also related to melanocyte function in hair follicles, where downregulation of pigmentation genes is present [11]. Similarly, lysosomal organelle function is involved in melanosomes and melanin production in hair follicles [12].

The evidence that individuals with HPS, a rare genetic disease, exhibit hypopigmentation of the skin and eyes, associated with an ILD clinically and pathologically similar to IPF, suggests a potential genetic link between eye color and IPF [5]. Interestingly, the genetic defects leading to the light eye colors in mutated HPS  mice (HPS1 and HPS4) are also highly associated with HPS-associated pulmonary fibrosis [13]. Also supporting this, injury to type II alveolar epithelial cells is a common feature of both IPF [3] and HPSPF [5] disease pathogenesis. In individuals with an HPS1 mutation, it is reported that the incidence of pulmonary fibrosis is 100%, the highest penetrance of any ILD mutation [6]. Furthermore, a study of mice with 15 different HPS mutations found that the mice with the lightest coat, ears, and eyes (red versus ruby or black) exhibited lamellar body accumulation of surfactant, a feature observed in dysfunctional alveolar type 2 cells [13]. Supporting this link in humans, patients with HPS who have brown hair and eyes associated with the HPS 3, 5, and 6 mutations do not exhibit the same prevalence of HPSPF [6]. This suggests a potential link between eye and skin color and development of pulmonary fibrosis that could underlie our association between light eye color and IPF prevalence.

There are some limitations to the study that should be acknowledged. Although this study is consistent with our initial clinical observation, it should be considered early evidence warranting further study with additional cohorts. Not all patients had facial photos or were of adequate quality to enable us to clearly define eye color in individuals. In addition, only 79% of patients diagnosed with IPF in the EHR had accessible high-resolution computed tomography imaging to confirm usual interstitial pneumonia. Finally, we do not report whether the group of individuals with light eye color and IPF diagnosis had a more aggressive clinical disease course.

Conclusion

We present preliminary evidence indicating that light eye color is associated with increased prevalence of IPF among white persons. Whether there is a direct connection between lighter eyes and development of IPF or it is simply a phenotypic representation of underlying genetic traits is uncertain and requires further investigation.