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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Cornea. 2021 Dec 1;40(12):1567–1570. doi: 10.1097/ICO.0000000000002689

Relationship of Body Mass Index with Fuchs’ Endothelial Corneal Dystrophy Severity and TCF4 CTG18.1 Trinucleotide Repeat Expansion

Bhumi B Kinariwala 1, Timothy T Xu 2, Keith H Baratz 3, Ross A Aleff 4, Sanjay V Patel 3, Leo J Maguire 3, Michael P Fautsch 3, Eric D Wieben 4, Amy E Millen 5, Sangita P Patel 1,6
PMCID: PMC8478960  NIHMSID: NIHMS1662276  PMID: 33782268

Abstract

Purpose.

To investigate the association of body mass index (BMI) with Fuchs’ endothelial corneal dystrophy (FECD) severity and TCF4 CTG18.1 expansion.

Methods.

343 patients with FECD were enrolled from the Mayo Clinic. FECD severity was graded by slit lamp biomicroscopy. BMI values were obtained from the electronic medical records. DNA extracted from leukocytes was analyzed for CTG18.1 expansion length, with ≥40 repeats considered expanded. Wilcoxon signed rank tests were used to compare FECD grade and CTG18.1 expansion length in patients by BMI (< 25, ≥ 25 to < 30 and ≥ 30 kg/m2). FECD grade was regressed on age, sex, BMI, and CTG18.1 expansion and separately, BMI on CTG18.1 expansion. Models were investigated for effect modification by age and sex with an interaction term of p<0.05 considered statistically significant.

Results.

When examining the association between BMI and FECD, there was a significant interaction between BMI and sex (p for interaction=0.004). When controlling for age and CTG18.1 expansion, a positive association was observed between BMI and FECD grade in women, but not in men. Additionally, BMI was not associated with CTG18.1 expansion when controlling for age and sex.

Conclusion.

BMI was positively associated with FECD severity among women but not men. There was no significant association between BMI and CTG18.1 expansion. These findings suggest that increased BMI is potentially a modifiable risk factor for FECD disease progression among women.

Keywords: Fuchs’ endothelial dystrophy, cornea, body mass index, trinucleotide repeat expansion, risk factors

INTRODUCTION

Fuchs’ endothelial corneal dystrophy (FECD) is a progressive, bilateral disorder, characterized by guttae on Descemet’s membrane, dysfunction and death of corneal endothelial cells, corneal edema, and loss of vision over time. Both genetic and environmental factors play roles in the manifestation of FECD. The common late-onset form of FECD is associated with an intronic trinucleotide repeat expansion in the CTG18.1 locus in the TCF4 gene. CTG18.1 expansion with repeat length > 50 is found in 79% of Caucasians with FECD.1 Other risk factors for FECD include age, smoking and female sex.25

Anthropomorphic factors have inconsistently been associated with FECD, either showing no association2 or an inverse association5 between weight or body mass index (BMI) and presence of guttae. We have observed a significantly lower self-reported weight and BMI at age 18 in women with FECD compared to without FECD in a clinical sample.6 It is possible that BMI could be associated with FECD through an influence of CTG18.1 expansion on BMI. Among patients with the trinucleotide repeat expansion disorder spinocerebellar ataxia type 3, increased repeat length was associated with low BMI and increased disease severity.79 For the current study, we examined whether associations between BMI and FECD grade, and CTG18.1 expansion and BMI exist in our cohort of FECD patients.

MATERIALS AND METHODS

Protocols were approved by the Mayo Clinic Institutional Review Board. Study participants with FECD were recruited at Mayo Clinic (Rochester, Minnesota, USA; June 2007 through August 2019) and provided written consent. FECD severity was assessed by clinician investigators (KHB, LJM, SVP) via slit-lamp biomicroscopy and was graded using the modified Krachmer grading system: grade 1 (≤12 central guttae) through grade 6 (confluent guttae with edema) with grade ≥2 (>12 central guttae) considered diagnostic of FECD.10 Eyes with corneal transplantation for FECD were considered grade 6. DNA was extracted from peripheral blood leukocytes to determine TCF4 CTG18.1 expansion length using direct sequencing and short tandem repeat assay of PCR-amplified DNA. For samples with only one repeat length identified, Southern blotting was performed to differentiate bi-allelic CTG18.1 lengths of the same size versus the presence of a large CTG18.1 expansion. Linked electronic medical records were searched for height and weight closest to the date of study recruitment (median interval =3 months) in order to calculate BMI (kg/m2). Patients were excluded if BMI, FECD grade of both eyes and repeat length of both alleles were not available or if a family member (proband) was already included in the study.

Unpaired t-tests and the Wilcoxon signed rank test (when variables were highly skewed) were performed to compare the mean age, BMI, and FECD grade (grade of the worse eye), by CTG18.1 defined as <40 repeats and CTG18.1 expansions ≥40 repeats based upon the longer allele. Unpaired ANOVAs and the Wilcoxon signed rank test were performed to compare mean age, BMI, FECD grade, and mean CTG18.1 length by BMI category defined as BMI < 25, ≥25 to <30 (overweight) and ≥ 30 (obese) kg/m2. The BMI category of underweight (<18.5) was not analyzed independently as only one participant in this dataset had an underweight BMI. We assessed the association between FECD grade and the following risk factors: age, sex, BMI, and CTG18.1 expansion, using linear regression. We also examined the association between BMI and CTG18.1 expansion, adjusted for age and sex, using linear regression. Models were investigated for effect modification by age and sex with an interaction term of p<0.05 considered statistically significant.

RESULTS

There were no statistically significant differences in percent of participants with CTG18.1 expansions, CTG18.1 expansion length, or FECD grade by BMI category in all participants or in women when used as an independent cohort. In men, there was a greater proportion of those with CTG18.1 expansion and higher BMIs (Table 1). There was a significant difference observed between FECD grade and CTG18.1 expansion with a lower median grade in those with no expansion compared to those with an expansion (Table 2). There were no statistically significant differences in BMI by CTG18.1 expansion group.

Table 1:

Relationship between BMI and variables including age, FECD grade, and CTG18.1 length

Body Mass Index (BMI) (kg/m2)
< 25 ≥25 to <30 ≥ 30 P*
Total Sample size 90 121 132
Age (years), mean (SD) 69.5 (11.6) 69.9 (10.6) 69.0 (8.3) 0.75
BMI (kg/m2), mean (SD) 22.9 (1.7) 27.4 (1.5) 35.7 (5.4) <0.001
CTG18.1 expansion (% ≥ 40 repeats) 71% 83% 80% 0.12
CTG18.1 length, median (25th–75th percentile) 46.7 (25.7–53.5) 49.0 (42.0–57.2) 49.0 (37.8–55.0) 0.13
FECD (grade, worse eye), median (25th–75th percentile) 6.0 (4.0–6.0) 6.0 (5.0–6.0) 6.0 (5.0–6.0) 0.52
Men Sample size 32 39 43
Age (years), mean (SD) 67.8 (11.3) 71.9 (9.3) 68.5 (7.8) 0.13
BMI (kg/m2), mean (SD) 23.4 (1.2) 27.3 (1.5) 35.2 (5.5) <0.001
CTG18.1 expansion (% ≥ 40 repeats) 69% 92% 84% 0.03
CTG18.1 length, median (25th–75th percentile) 44.6 (24.7–55.0) 51.0 (45.5–57.3) 50.5 (40.0–57.7) 0.24
FECD (grade, worse eye), median (25th–75th percentile) 6.0 (4.5–6.0) 6.0 (4.0–6.0) 6.0 (4.0–6.0) 0.79
Women Sample size 58 82 89
Age (years), mean (SD) 70.4 (11.7) 68.9 (11.0) 69.2 (8.6) 0.68
BMI (kg/m2), mean (SD) 22.5 (1.8) 27.5 (1.5) 35.9 (5.4) <0.001
CTG18.1 expansion (% ≥ 40 repeats) 72% 78% 78% 0.71
CTG18.1 length, median (25th–75th percentile) 46.9 (25.7–53.5) 48.8 (38.0–56.5) 48.5 (35.3–53.7) 0.44
FECD (grade, worse eye), median (25th–75th percentile) 6.0 (4.0–6.0) 6.0 (5.0–6.0) 6.0 (5.0–6.0) 0.17
*

P-values are reported from t-tests for age and BMI, for the Wilcoxon rank sum test for CTG18.1 length and FECD grade, and for chi-squares for CTG18.1 (% ≥ 40).

Table 2:

Relationship between CTG18.1 expansion and Variables Including Age, BMI, FECD Grade, and CTG18.1 Length

CTG18.1 (< 40) CTG18.1exp (≥40) P*
Total Sample size 74 269
Age (years), mean (SD) 70.1 (11.0) 69.3 (9.8) 0.55
BMI (kg/m2), mean (SD) 29.1 (6.8) 29.5 (6.2) 0.67
CTG18.1 length, median (25th–75th percentile) 16.4 (15.0–20.0) 51.0 (46.3–57.5) <0.001
FECD (grade, worse eye), median (25th–75th percentile) 5.0 (3.0–6.0) 6.0 (5.0–6.0) <0.001
Men Sample size 20 94
Age (years), mean (SD) 71.6 (9.7) 69.0 (9.4) 0.28
BMI (kg/m2), mean (SD) 27.9 (6.0) 29.4 (6.1) 0.32
CTG18.1 length, median (25th–75th percentile) 16.9 (14.5–19.2) 51.8 (47.0–58.0) <0.001
FECD (grade, worse eye), median (25th–75th percentile) 3.5 (2.75–6.0) 6.0 (5.0–6.0) 0.002
Women Sample size 54 175
Age (years), mean (SD) 69.5 (11.5) 69.4 (10.0) 0.94
BMI (kg/m2), mean (SD) 29.6 (7.1) 29.5 (6.3) 0.96
CTG18.1 length, median (25th–75th percentile) 15.8 (15.0–21.0) 50.7 (46.0–57.0) <0.001
FECD (grade, worse eye), median (25th–75th percentile) 6.0 (3.0–6.0) 6.0 (5.0–6.0) 0.001
*

P-values are reported from t-tests for age and BMI, and the Wilcoxon rank sum test for CTG18.1 length and FECD grade.

In a multivariable model predicting FECD grade with all participants, only CTG18.1 expansion, when controlling for age, sex, and BMI, was significantly associated with FECD grade (Table 3). The adjusted mean FECD grade was higher in those with CTG18.1 expansion compared to those without the expansion.

Table 3:

Multivariable regression analyses for associations of risk factors with worse eye FECD grade and Body Mass Index

Model for predictors of worse eye FECD grade
Predictor Beta-coefficient (SE) P
 Age (years)* 0.008 (0.007) 0.23
 Sex 0.23 (0.15) 0.12
 BMI (kg/m2)* 0.01 (0.01) 0.26
 CTG18.1 0.87 (0.17) <0.001
Analysis in <69 years
 Sex 0.37 (0.20) 0.07
 BMI (kg/m2)* −0.002 (0.01) 0.88
 CTG18.1 1.51 (0.24) <0.001
Analysis in ≥69 years
 Sex 0.14 (0.21) 0.51
 BMI (kg/m2)* 0.02 (0.02) 0.22
 CTG18.1 0.45 (0.23) 0.05
Analysis in Women
 Age (years)* 0.004 (0.008) 0.61
 BMI (kg/m2)* 0.03 (0.01) 0.01
 CTG18.1 0.72 (0.20) <0.001
Analysis in Men
 Age (years)* 0.02 (0.02) 0.13
 BMI (kg/m2)* −0.04 (0.02) 0.06
 CTG18.1 1.33 (0.31) <0.001
Model for predictors of BMI
Predictor Beta-coefficient (SE) P
 Age (years)* −0.05 (0.03) 0.18
 Sex 0.38 (0.73) 0.60
 CTG18.1 0.35 (0.84) 0.68
*

Age and BMI entered in model as a continuous variable

Beta coefficient is for women with men as the referent group; Beta-coefficient is for CTG18.1 expansion ≥40 with the referent group as CTG18.1 length <40

Next, we examined whether the associations between BMI and FECD and between CTG18.1 expansion and BMI varied by age or sex. We found a significant interaction between age (continuous) and CTG18.1 expansion (p for interaction=0.04) in the model examining FECD grade as an outcome, suggesting a stronger association with genetic risk in those with younger ages (Table 3). A significant interaction was also observed between sex and BMI (continuous) in the model examining FECD grade as an outcome (p for interaction=0.004). BMI was positively associated with FECD grade in women but not men.

In a multivariable model, analysis of the association between CTG18.1 expansion and BMI (continuous) controlling for age and sex (Table 3) found no association. The association between CTG18.1 length and BMI in those with CTG18.1 expansion (≥40) and without (<40) was also null (data not shown).

DISCUSSION

Our study objective was to investigate the association of BMI with both FECD severity and CTG18.1 expansion. We did not find an association between CTG18.1 expansion and BMI. We did, however, find a significant positive association between BMI and FECD grade in women, but not men where a negative association did not reach statistical significance. This suggests that BMI in FECD is not dictated by TCF4 genetics but could be a potential modifiable risk factor for severe FECD, particularly for women, although our study does not determine causation. Differences in risk factors between men and women may be partly responsible for the known differences in FECD prevalence between men and women.

Research in spinocerebellar ataxia type 3, a trinucleotide repeat disorder in the ATXN3 gene, shows an association between low BMI, severe disease, and increased repeat length.79 The trinucleotide repeat in spinocerebellar ataxia type 3 differs from that of FECD because it falls within a coding region (compared to the intronic repeat of FECD) and results in translation of polyglutamine expansions with toxic properties. Several polyglutamine diseases have shown an association with BMI.11 However, from our data, it is likely that a relationship between BMI and FECD is independent of TCF4 CTG18.1 expansion.

In this study, we observed more severe FECD in those with higher compared to lower BMIs in women but not men. In a separate study involving a different FECD cohort containing participants with and without guttae, we found lower self-reported BMI at age 18 in women but not men with guttae, similar to data from other reports.6 The differences in these associations may be due to the different populations studied, and the lack of a control population without guttae in the current study. Fully elucidating these differences in associations between BMI and FECD will require further investigation into additional study cohorts. Based on the current data, higher BMI may have adverse physiologic effects on FECD pathophysiology in women similar to the systemic effects of obesity in many diseases. Another possibility is the role of estrogen metabolism. Higher endogenous estrogen levels seen with higher BMI, may promote toxicity of estrogen metabolites in the corneal endothelium.12

There are several limitations to this study. First, as mentioned above, the FECD grade of study participants was skewed towards higher grades, thus these data may not accurately reflect the spectrum of FECD disease severity. FECD grade may also appear higher due to analysis of the worse-eye grade from each participant, although analysis by better-eye grade did not change the significant data trends. Second, smoking is a known risk factor for FECD, but we did not have smoking history data for adjustment. Third, we only had BMI data close to the time of enrollment which may not accurately reflect the potential effect of fluctuating BMI throughout adulthood.

In summary, TCF4 CTG18.1 expansion status is not related to BMI. BMI is associated with FECD grade independent of genetic risk in women, making it a potential sex-related modifiable risk factor for FECD, with causation yet to be determined.

Acknowledgments

Conflicts of Interest and Source of Funding: This work was funded by Office of the Director and National Eye Institute, National Institutes of Health to SPP (K08EY029007), MPF (EY26490) and KHB (EY25071) and the Robert R. Waller Career Development Award, Mayo Clinic (KHB). This material is the result of work supported with resources and the use of facilities at the VA Western New York Healthcare System. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. SPP, BBK, TTX, KHB, RAA, LJM, MPF, EDW and AEM report no commercial relationships disclosures. SVP is a consultant to GlaxoSmithKline, Senju Pharmaceuticals, and Santen Inc.

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