November 2015
Volume 56, Issue 12
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Clinical and Epidemiologic Research  |   November 2015
Sex Differences in the Relationship Between Obesity and Choroidal Nevus in US Adults
Author Affiliations & Notes
  • Rebecca M. Sieburth
    Temple University School of Medicine Philadelphia, Pennsylvania, United States
  • Mary Qiu
    Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Carol L. Shields
    Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
  • Correspondence: Mary Qiu, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107, USA; mary.qiu@gmail.com
  • Carol L. Shields, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107, USA; carolshields@gmail.com
Investigative Ophthalmology & Visual Science November 2015, Vol.56, 7489-7495. doi:10.1167/iovs.15-17803
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      Rebecca M. Sieburth, Mary Qiu, Carol L. Shields; Sex Differences in the Relationship Between Obesity and Choroidal Nevus in US Adults. Invest. Ophthalmol. Vis. Sci. 2015;56(12):7489-7495. doi: 10.1167/iovs.15-17803.

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Abstract

Purpose: To investigate sex differences and the effect of other variables on the association between obesity and choroidal nevus in the US adult population.

Methods: The study population of this cross-sectional study included 5575 subjects aged ≥40 years from the 2005 to 2008 National Health and Nutrition Examination Survey (NHANES) who underwent retinal imaging. Primary predictor variables were body mass index (BMI) when the subject was 25 years old (“former BMI”) and BMI at time of NHANES participation (“current BMI”). Body mass index was classified “elevated” (≥25 kg/m2) versus “normal” (<25 kg/m2). The main outcome measure was choroidal nevus in either eye on retinal imaging. Subgroup analysis was stratified by sex and race.

Results: The mean age of the study population was 56.4 years, with 47.3% male and 52.7% female subjects. The prevalence of choroidal nevus was 4.7% overall. Former elevated BMI was associated with choroidal nevus in the overall population (odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.06–1.71, P = 0.01) and males (OR: 1.43, CI: 1.03–1.99, P = 0.03). Current elevated BMI was associated with choroidal nevus in the overall population (OR: 1.37, CI: 1.02–1.85, P = 0.04); females (OR: 1.72, CI: 1.11–2.68, P = 0.02), and postmenopausal females (OR: 1.94, CI: 1.23–3.06, P = 0.006).

Conclusions: Choroidal nevus is associated with former and current obesity. Sex and postmenopausal status differences in this association could provide insight into the demographics of patients at risk for developing choroidal nevus.

Choroidal nevus is a benign intraocular lesion that is often discovered coincidentally on funduscopic examination.1,2 This lesion can be a precursor to malignant uveal melanoma, and the annual rate of transformation of nevus to melanoma is estimated to be 1/8845.3 Known factors predictive of malignant transformation include larger diameter and thickness, proximity to the optic disc, orange surface pigmentation, presence of subretinal fluid, and association with visual symptoms.46 Accordingly, it is of clinical importance to identify and monitor patients with choroidal nevus. Caucasian race is currently the only known demographic risk factor for choroidal nevus.2,79 Identifying other factors associated with choroidal nevus may facilitate an understanding of the underlying pathophysiologic development of choroidal nevus, and possibly uveal melanoma. 
A recently published analysis of data from the National Health and Nutrition Examination Survey (NHANES) focusing on reproductive factors in women reported an association between choroidal nevus and postmenopausal obesity.10 Obesity is a known risk factor for cutaneous melanoma and various systemic cancers.1115 Endocrine disturbances in obese individuals include increased estrogen, insulin, inflammatory markers, and adipokines.11,16 Basic science studies have demonstrated the tumorigenic effects of these substances on melanocytes, breast tissue, and the endometrium, offering plausible mechanisms for the association between obesity and malignancy.2,9,1722 To date, there have been no published studies exploring the possible role of obesity as a risk factor for choroidal nevus or uveal melanoma. 
The National Health and Nutrition Examination Survey is a population-based survey conducted annually in the United States by the Centers for Disease Control and Prevention (CDC) with the purpose of estimating disease prevalence in the US population.23 The survey uses a complex stratified multistage sampling design to select a nationally representative sample to participate in a series of comprehensive health-related interviews and examinations every 2 years. Recruitment and testing are performed in counties across the United States, 15 of which are visited each year. The National Health and Nutrition Examination Survey purposely oversamples Hispanics and African Americans to acquire more detailed health-related information about these racial minority groups, and data are weighted to be representative of the US population as a whole.24 
The National Health and Nutrition Examination Survey contains questionnaires including demographics and weight history as well as physical examinations including body measures and retinal imaging. The purpose of this study was to: (1) characterize the association between current and former body mass index (BMI) and choroidal nevus in a nationally representative sample of US adults using data from the NHANES; (2) explore the nuances in this relationship within subgroups stratified by sex and menopausal status; and (3) identify variables, including body measures, medical history, and laboratory markers, that could mediate or confound the association between BMI and choroidal nevus. The results of this analysis could assist in identifying populations at higher risk for choroidal nevus, and potentially uveal melanoma. 
Methods
Sample and Population
The National Health and Nutrition Examination Survey is administered annually by the CDC and consists of a cross-sectional series of interviews and examinations of the civilian, noninstitutionalized US population. A stratified multistage sampling design with a weighting scheme is used to accurately estimate disease prevalence in the US population.25 The data is deidentified and publicly available on their website, so institutional review board approval is not required to analyze the data. This research adheres to the tenets of the Declaration of Helsinki and all US federal and Pennsylvania state laws. 
This analysis includes subjects from the 2005 to 2008 NHANES aged 40 years or older (n = 6797) who successfully completed the retinal imaging examination (n = 5575). The retinal imaging examination was only administered by NHANES to this age group during this 4-year period, so data on choroidal nevus are only available on these subjects. 
Measures
Predictors.
The primary predictor variables are BMI when the subject was 25 years old (“former BMI”) and BMI at the time of NHANES participation (“current BMI”). Former BMI was calculated based upon self-reported former weight and measured current height. The weight history questionnaire asked the following questions: 
  1.  
    How much did you weigh at age 25?
  2.  
    How much did you weigh one year ago?
  3.  
    How much did you weigh 10 years ago?
  4.  
    Up to the present time, what is the most you have ever weighed?
The age cutoffs for these questions were all below 40 years, so all of the subjects in this study population were eligible to answer these questions. These self-reported weights, along with measured height at the time of NHANES participation, were used to calculate BMI in kg/m2 at age 25, 1 year ago, 10 years ago, and at lifetime maximum, respectively. All self-reported measures of former weight were recorded by NHANES in pounds, and were subsequently converted to kilograms for calculation of BMI in kg/m2. Current BMI was calculated by NHANES based upon the measured height and weight at the time of NHANES participation. For this analysis, BMI was categorized as “elevated” (≥25 kg/m2) versus “normal” (<25 kg/m2), and the normal group served as the reference group. 
Covariates.
Covariates include age, sex, race, waist circumference, hypertension, hyperlipidemia, diabetes, smoking, and serologic measures of hyperlipidemia, glucose intolerance, and inflammation. The National Health and Nutrition Examination Survey organizes race into five categories: Mexican American, other Hispanic, non-Hispanic White, non-Hispanic black, and non-Hispanic other/multiracial. For this analysis, the Mexican American and other Hispanic groups were combined into a single Hispanic group and the non-Hispanic other/multiracial group was called “non-Hispanic other.” Menopausal status was assessed by self-report. Women were asked if they had experienced regular periods over the past year, and those who answered no were classified as being postmenopausal. Women who reported having a history of hysterectomy or oophorectomy were also classified as postmenopausal. Ever smokers were subjects who reported having smoked at least 100 cigarettes in their entire lives. Subjects who reported that a doctor has told them that they are overweight were classified as having a medical history of being overweight. A medical history of having been diagnosed with hypertension, diabetes, and hyperlipidemia was also assessed by self-report. 
Serologic variables were categorized as normal or abnormal, and the normal group served as the reference group. Normal cutoffs were based upon existing criteria for the diagnosis of metabolic syndrome,26 normal values described in the NHANES database, and reference values present in the literature. Normal value cutoffs were as follows: low density lipoproteins (LDL) < 130 mg/dL,27,28 high density lipoproteins (HDL) > 40 mg/dL,26 total cholesterol < 200 mg/dL,26 triglycerides < 150 mg/dL,26 insulin < 14 μU/mL,29 fasting plasma glucose < 100 mg/dL,30 plasma glucose following 2-hour oral glucose tolerance test < 140 mg/dL,30 C-reactive protein (CRP) < 3 mg/L,31 hemoglobin A1c < 6.0%.32 Fasting plasma glucose, fasting plasma insulin, 2-hour oral glucose tolerance test (2-hour OGTT), LDL, and triglycerides were only measured in subjects who were fasting and in the morning session. Waist circumference was considered normal if <88 cm in women, and if <102 cm in men.26 
Outcomes
The primary outcome variable for this study was the presence of choroidal nevus on retinal imaging in one or both eyes. All subjects 40 years and older were offered retinal imaging unless they had an eye infection or were unable to see light with both eyes open. Two 45° nonmydriatic digital images were obtained from each eye using a nonmydriatic retinal camera (Canon CR6-45NM; Canon, Tokyo, Japan). The first image was centered on the macula and the second was centered on the optic nerve. The images were graded using standardized methods at the University of Wisconsin retinal reading center, a center which has produced results for several previous studies including NHANES studies of diabetic retinopathy and macular degeneration, as well as an analysis of the Multi-Ethnic Study of Atherosclerosis cohort (MESA-EYE).6,33 The standard definition of choroidal nevus used in population-based studies1,6,7,34 is a variably pigmented to amelanotic choroidal lesion of brown, slate blue, green-gray, or yellow color at least 500 μm in diameter. Images graded as “questionable choroidal nevus” were categorized as “no choroidal nevus” for this analysis. 
Data Analysis
Demographic, body measures, medical history, and laboratory tests were compared between subjects with and without choroidal nevus using design-adjusted Rao-Scott Pearson-type χ2 and Wald tests for categorical and continuous variables, respectively. Multivariate logistic regression models were created to investigate whether elevated BMI, components of the medical history, or laboratory values were associated with choroidal nevus, while adjusting for age, sex, and race. Odds ratios (OR), 95% confidence intervals (CI), and adjusted P values were calculated. The analysis was repeated in sub-groups stratified by sex and menopausal status among women. Furthermore, a series of multivariate logistic regressions were performed in the overall population and in subgroups to identify variables, including body measures, components of the medical history, and laboratory values that could mediate or confound the relationship between BMI and choroidal nevus. These multivariate logistic regressions each included age, sex, race, BMI, choroidal nevus, as well as each possible confounding factor individually. To most accurately calculate confidence intervals around estimates representative of the US national population, we performed all data analyses (Stata 12.0; Stata Statistical Software, College Station, TX, USA) using weighted data, and standard errors of population estimates were calculated by Taylor linearization methods. Taylor linearization methods are the methods recommended by the National Center for Health Statistics to approximate sampling errors in complex sample surveys such as the NHANES, and help to determine the statistical reliability of the data.35 
Results
The 2005 to 2008 NHANES yielded 5575 subjects aged 40 years and older who completed the retinal imaging examination. The mean age of the study population was 56.4 years, and 47.3% subjects were male and 52.7% were female. Of female subjects, 32.1% were premenopausal and 67.9% were postmenopausal. The distribution of choroidal nevus by race was 77.3% non-Hispanic white, 9.5% Hispanic, 8.5% non-Hispanic black, and 4.7% non-Hispanic other. Overall, 4.7% subjects had choroidal nevus on retinal imaging. 
The distribution of demographic, medical, body measure, and serologic variables was compared between subjects with and without choroidal nevus (Table 1). Compared with subjects without choroidal nevus, those with choroidal nevus were older (58.6 vs. 56.3 years, P = 0.02); had higher prevalence of Caucasian race (92.0% vs. 76.6%, P < 0.0001); higher prevalence of hypertension (50.0% vs. 41.0%, P = 0.03); lower serum HDL (51.8 vs. 54.1 mg/dL, P = 0.02); lower serum fasting glucose (104.0 vs. 110.3 mg/dL, P = 0.002); and there were no statistically significant differences in sex, other medical conditions, body measures, or other laboratory tests between subjects with and without choroidal nevus. 
Table 1
 
Characteristics of US Adults With and Without Choroidal Nevus
Table 1
 
Characteristics of US Adults With and Without Choroidal Nevus
A series of multivariate logistic regressions were performed to explore the relationship between choroidal nevus and obesity, body measures, medical history, and laboratory values, adjusting for age, sex, and race (Table 2). Overall, subjects with elevated former BMI had 35% higher odds of choroidal nevus than subjects with normal former BMI (OR: 1.35, CI: 1.06–1.71, P = 0.01), and subjects with elevated current BMI had 37% higher odds of choroidal nevus than those with normal current BMI (OR: 1.37, CI: 1.02–1.85, P = 0.04). Individuals with high waist circumference had 41% higher odds of choroidal nevus than those with normal waist circumference (OR: 1.41, CI: 1.09–1.82), P = 0.01). High fasting insulin was inversely associated, with 46% lower odds of choroidal nevus (OR: 0.54, CI: 0.29–0.99, P = 0.05). Hypertension was associated with 40% higher odds of choroidal nevus, but did not reach statistical significance (OR: 1.40, CI: 0.99–1.98, P = 0.06). Smoking history was not significantly associated with odds of choroidal nevus (P = 0.3). 
Table 2
 
Multivariate Logistic Regressions Identifying Independent Predictors for Choroidal Nevus, Adjusting for Age, Race, and BMI
Table 2
 
Multivariate Logistic Regressions Identifying Independent Predictors for Choroidal Nevus, Adjusting for Age, Race, and BMI
Additional multivariate logistic regressions were performed to explore the relationship between choroidal nevus and former and current obesity in subgroups stratified by sex and postmenopausal status among females; these regressions adjusted for age and race (Table 3). In males, elevated former BMI was associated with 43% higher odds of choroidal nevus (OR: 1.43, CI: 1.03–1.99, P = 0.03). In females, elevated current BMI was associated with 72% higher odds of choroidal nevus (OR: 1.72, CI: 1.11–2.68, P = 0.02). In postmenopausal females, elevated current BMI was associated with 94% higher odds of choroidal nevus (OR: 1.94, CI: 1.23–3.06, P = 0.006). Neither former nor current elevated BMI was associated with choroidal nevus in premenopausal females. 
Table 3
 
Association of Elevated BMI (≥25 kg/m2) With Choroidal Nevus by Sex and Menopausal Status
Table 3
 
Association of Elevated BMI (≥25 kg/m2) With Choroidal Nevus by Sex and Menopausal Status
Further individual adjustment for waist circumference, medical history, and laboratory values associated with hypertension, dyslipidemia, and glucose intolerance (data not shown), rendered the association between elevated BMI and choroidal nevus no longer significant in certain subgroups. In males, the association between former elevated BMI and choroidal nevus was no longer statistically significant after adjusting for dyslipidemia (LDL, HDL, triglycerides) or glucose intolerance (fasting insulin, fasting glucose, and 2-hour OGTT). In females, the association between current elevated BMI and choroidal nevus was no longer statistically significant after adjusting for waist circumference, medical history of being overweight, hypertension, dyslipidemia (LDL, HDL, triglycerides), or glucose intolerance (fasting insulin, fasting glucose, 2-hour OGTT). In postmenopausal females, the association between current elevated BMI and choroidal nevus was no longer statistically significant after adjusting for waist circumference or dyslipidemia (HDL). 
Discussion
The prevalence of choroidal nevus in the overall population was 4.7%, similar to previous studies. The study MESA-EYE, which examined a US population using similar retinal photography methods, found an overall choroidal nevus prevalence of 2.1%, with a 4.1% prevalence among whites.7 Prior studies of predominantly white US populations have estimated the prevalence of choroidal nevus to be between 4.6% to 7.9%.3 The Blue Mountains Eye Study, which studied a 99% white Australian population using six standard retinal photographs, yielded a 6.5% prevalence of choroidal nevus.3,9 
This large cross-sectional analysis of US adults identified an association between elevated BMI and choroidal nevus, which varied by sex, menopausal status, and the temporality of the elevated BMI. Certain laboratory results and aspects of medical history that may represent metabolic, endocrine, and inflammatory derangements could mediate the complex relationship between elevated BMI and choroidal nevus. This analysis identifies former, irrespective of current, elevated BMI as a predictor for choroidal nevus in males, and current, irrespective of former, elevated BMI as a predictor for choroidal nevus in postmenopausal females. 
There are no studies in the literature describing any relationship between obesity and uveal melanoma. A recent analysis focusing on reproductive factors in a female cohort from the 2005 to 2008 NHANES identified an association between current obesity and choroidal nevus in postmenopausal females.10 This study further explores the implications of that finding by including males in the analysis, examining both current and former elevated BMI, and investigating whether there are any other variables that could mediate the relationship between elevated BMI and choroidal nevus. The results of this NHANES analysis assist in characterizing the demographic risk factors for choroidal nevus, a precursor of uveal melanoma. The association between former elevated BMI and choroidal nevus in males is similar to previously reported associations between former obesity and systemic cancer risk in males, including cutaneous melanoma as well as pancreatic, esophageal, renal, and colorectal cancers.14,3639 The Agricultural Health Study found an association between obesity at age 20 years and higher rates of cutaneous melanoma, but no association between current obesity and cutaneous melanoma.14 It is possible that early or long-term exposure to a tumorigenic microenvironment characteristic of obesity contributes to male risk of developing cutaneous melanoma. A similar mechanism may underlie the association between former elevated BMI in males and higher odds of choroidal nevus. 
The associations between current elevated BMI and choroidal nevus among females and postmenopausal females reflect established trends in the literature about the relationship between current obesity and breast, ovarian, and endometrial cancers.21,4042 The lack of a clear association between elevated BMI and choroidal nevus in premenopausal females could be due to the small population of premenopausal females with choroidal nevus in this analysis, and is reflected in the literature—current obesity has been shown to have both positive and inverse relationships with breast cancer in premenopausal females.43 
Sex-related differences in the association between obesity and choroidal nevus may be due to sex-related bias in self-reported weight at age 25. Follow-up of the NHANES I cohort demonstrated that females tend to underestimate former BMI, males tend to overestimate former BMI, and heavier subjects tend to underestimate former BMI regardless of sex.44 Furthermore, the prevalence of obesity is most greatly underreported in older age groups.4547 While the actual error in self-reported weight and BMI is small, self-reported BMI and weight estimates do significantly underrepresent the burden of obesity in a population.44 These trends could mask a real correlation between former BMI and choroidal nevus in postmenopausal women, and could inflate the significance of the association between former BMI and choroidal nevus in men. Alternatively, the association of choroidal nevus with former obesity in males and current obesity in postmenopausal females may be due to sex differences in the type, duration, and intensity of estrogen exposure over time. 
This study's finding of an association between obesity and choroidal nevus mirrors previously published reports of associations between obesity and cutaneous melanoma, as well as breast, endometrial, ovarian, and visceral cancers.11,18,20,21,40,43,48 These similarities suggest that there could be a common mechanism linking obesity to tumors. The relationship between obesity and choroidal nevus could be mediated via estrogen, as explored in a recent analysis.10 Elevated body fat mass can lead to elevated levels of circulating estrogens.49 In general, greater duration and intensity of exposure to high levels of endogenous or synthetic estrogen have been linked to higher risk of cancers in estrogen-sensitive tissues such as breast, endometrium, and ovary.5052 Obese individuals have also been shown to have higher levels of insulin, inflammation, and adipokines, which are associated with a higher risk of cancer in animal and in vitro studies.53 Often dysregulated and potentially carcinogenic in obese individuals, these endocrine substances include insulin-like growth factor 1 (IGF-1), leptin, VEGF, and tumor necrosis factor.11,16 
High levels of IGF-1, leptin, and possibly insulin have been associated with cutaneous melanoma.20,5456 After adjusting for lipid panels and fasting glucose-tolerance parameters, the association between elevated BMI and choroidal nevus was no longer significant in certain groups, suggesting that dyslipidemia and impaired glucose tolerance may mediate the association between elevated BMI and choroidal nevus. 
In our analysis, hypertension was independently associated with choroidal nevus in females. However, hypertension was negatively associated with choroidal nevus in the MESA-EYE study.7 The causality of this association could not be established in this analysis and further studies are needed to better characterize the association between hypertension and choroidal nevus. In addition, MESA-EYE reported an association between choroidal nevus and elevated levels of the inflammatory marker CRP.7 In this analysis, the association between choroidal nevus and obesity remained significant even after adjusting for CRP, suggesting that the mechanism for this association is not mediated via inflammation. 
A key strength of the NHANES database is its broad inclusion criteria, multistage sampling, and complex weighing system that permits an accurate assessment of disease prevalence in a subject population representative of the whole United States. Limitations of our study include the NHANES cross-sectional design, which precludes identification of causality in the nuanced association between obesity and choroidal nevus, as well as among covariates. The subjective assessment via questionnaire of past weights and presence of medical conditions allows the possibility of inaccurate recollection and recall bias. Sex and BMI associated differences in self-reported weight history may impact the associations between choroidal nevus and former BMI identified in this study. Additionally, our study population is limited to the subjects who underwent retinal imaging, all of whom are age 40 years and older. The majority of the 1222 participants that could not complete retinal imaging were African American or Hispanic, possibly leading to overrepresentation of non-Hispanic whites in our study. Furthermore, NHANES does not contain data about levels of hormones such as estradiol, adipokines such as leptin and adiponectin, or cytokines such as IGF-1 and VEGF. The retinal imaging protocol of NHANES only captures two 45° fields, one centered on the macula and one centered on the optic disc, and it is expected that this methodology greatly underestimates the true prevalence of choroidal nevi within the entire fundus.24 Additionally, retinal image graders did not describe details that would have helped to characterize choroidal nevi as low or high risk.6 In addition, long-term follow-up of NHANES participants would be valuable to characterize change over time, if any, in observed choroidal nevi, and potentially assist in further characterizing the demographics of groups at higher risk for uveal melanoma. Unfortunately, long-term follow-up is impractical and not part of the NHANES methodology. 
In conclusion, this large cross-sectional study of 5575 US adults aged ≥40 years identified associations between choroidal nevus and former elevated BMI in males, and current elevated BMI in females and postmenopausal females. The association between elevated BMI and choroidal nevus could speculatively be mediated by estrogen, dyslipidemia, hyperinsulinemia, glucose intolerance, or cardiovascular disease. This analysis suggests that this association is not mediated by inflammation or smoking, but these findings need to be confirmed by other studies. Overall, the results of this analysis support the hypothesis that obesity, defined by BMI ≥ 25 kg/m2, could be a factor in the pathogenesis of choroidal nevus. 
Acknowledgments
Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania, United States (CLS). Rebecca Sieburth, BA, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. The authors alone are responsible for the content and writing of the paper. 
Disclosure: R.M. Sieburth, None; M. Qiu, None; C.L. Shields, None 
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Table 1
 
Characteristics of US Adults With and Without Choroidal Nevus
Table 1
 
Characteristics of US Adults With and Without Choroidal Nevus
Table 2
 
Multivariate Logistic Regressions Identifying Independent Predictors for Choroidal Nevus, Adjusting for Age, Race, and BMI
Table 2
 
Multivariate Logistic Regressions Identifying Independent Predictors for Choroidal Nevus, Adjusting for Age, Race, and BMI
Table 3
 
Association of Elevated BMI (≥25 kg/m2) With Choroidal Nevus by Sex and Menopausal Status
Table 3
 
Association of Elevated BMI (≥25 kg/m2) With Choroidal Nevus by Sex and Menopausal Status
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