Polygenetic-Risk Scores Related to Crystallin Metabolism Are Associated with Age-Related Cataract Formation and Interact with Hyperglycemia, Hypertension, Western-Style Diet, and Na Intake

Abstract

Age-related cataract (ARC) development is associated with loss of crystalline lens transparency related to interactions between genetic and environmental factors. We hypothesized that polygenetic risk scores (PRS) of the selected genetic variants among the ARC-related genes might reveal significant genetic impacts on ARC risk, and the PRS might have gene-gene and gene-lifestyle interactions. We examined the hypothesis in 1972 and 39,095 subjects aged ≥50 years with and without ARC, respectively, in a large-scale hospital-based cohort study conducted from 2004 to 2013. Single nucleotide polymorphisms (SNPs) of the genes related to ARC risk were identified, and polygenetic risk scores (PRS) were generated based on the results of a generalized multifactor dimensionality reduction analysis. Lifestyle interactions with PRS were evaluated. The PRS derived from the best model included the following six SNPs related to crystallin metabolism: ULK4_rs1417380362, CRYAB_rs2070894, ACCN1_rs55785344, SSTR2_rs879419608, PTN_rs322348, and ICA1_rs200053781. The risk of ARC in the high-PRS group was 2.47-fold higher than in the low-PRS group after adjusting for confounders. Age, blood pressure, and glycemia interacted with PRS to influence the risk of ARC: the incidence of ARC was much higher in the elderly (≥65 years) and individuals with hypertension or hyperglycemia. The impact of PRS on ARC risk was greatest in middle-aged individuals with hypertension or hyperglycemia. Na, coffee, and a Western-style diet intake also interacted with PRS to influence ARC risk. ARC risk was higher in the high-PRS group than in the low-PRS group, and high Na intake, Western-style diet, and low coffee intake elevated its risk. In conclusion, ARC risk had a positive association with PRS related to crystallin metabolism. The genetic impact was greatest among those with high Na intake or hypertension. These results can be applied to precision nutrition interventions to prevent ARC.

Keywords: Age-related cataract; coffee intake; crystalline; genetic impact; hyperglycemia; hypertension.

Figure 1

Adjusted odds ratios and 95% confidence intervals for age-related cataract (ARC) risk by polygenetic risk scores (PRS) using the 5 SNPs and 6 SNPs. PRS was calculated by the summation of polygenetic-risk scores of the best PRS model with 5 and 6 SNPs and categorized into three groups (0–6, 7–9, and ≥10) by the tertiles (low-PRS, medium-PRS, and high-PRS). They were adjusted with covariates for model 1, including age, gender, residence area, survey year, education, job, and income, for model 1 and covariates in model 2 containing for model 1 plus smoking, alcohol intake, physical activity, hypertension, serum glucose concentrations, HbA1c contents, energy intake, fat, protein and carbohydrate percent intake, and arthritis and dermatitis medicine intake for model 2.

Figure 2

Age-related cataract (ARC) incidence among participants in the low-, medium- and high-PRS groups (defined using the 6 SNP genetic variant–genetic variant interaction model) for metabolic parameters. (A) In the participants, according to age (cutoff point: 65 years old). (B) In the participants, according to the blood pressure (cutoff point: 130 mmHg for SBP and 90 mmHg for DBP). (C) In the participants, according to serum glucose concentrations (cutoff point: 126 mg/dL serum glucose concentrations). PRS was calculated by the summation of polygenetic-risk scores of the best model with 6 SNPs and categorized into three groups (0–6, 7–9, and ≥ 10) by the tertiles (low-PRS, medium-PRS, and high-PRS). p-values represent the significance of differences among the PRS groups by χ2 test in each category.

Figure 3

Prevalence of age-related cataracts (ARC) in participants in the low-, medium- and high-PRS groups (defined using the 6 SNP genetic variant–genetic variant interaction model): (A) In the participants according to the Na intake (cutoff point: 1600 mg/1000 kcal; (B) In the participants according to the coffee intake (cutoff point: ≥ 3 g/day); (C) In the participants according to the consumption of a Western-style diet pattern (WD; cutoff point: 70th percentile). PRS was calculated by the summation of polygenetic-risk scores of the best model with 6 SNPs and categorized into three groups (0–6, 7–9, and ≥ 10) by the tertiles (low-PRS, medium-PRS, and high-PRS). p-value represented the significant differences among the PRS groups by χ2 test in each category.