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. 2024 Nov 8;27(12):111344.
doi: 10.1016/j.isci.2024.111344. eCollection 2024 Dec 20.

Lipid-lowering drug and complement factor H genotyping-personalized treatment strategy for age-related macular degeneration

Can Can Xue  1 , Kelvin Y C Teo  1   2 , Yih Chung Tham  1   2   3   4 , Hengtong Li  3   4 , Sahil Thakur  1 , Charumathi Sabanayagam  1   2 , Qiao Fan  2   5 , David L Silver  6 , Xiaomeng Wang  1   2   7 , Chui Ming Gemmy Cheung  1   2 , Tien Yin Wong  1   2   8 , Usha Chakravarthy  9 , Ching-Yu Cheng  1   2   3   4 , Simon Nusinovici  1   2
Affiliations

Lipid-lowering drug and complement factor H genotyping-personalized treatment strategy for age-related macular degeneration

Can Can Xue et al. iScience. .

Abstract

We investigated whether the effect of lipid-lowering drugs (LLDs) on age-related macular degeneration (AMD) differs according to the main complement genetic variants in Singapore Epidemiology of Eye Diseases (SEED) (n = 5,579) and UK Biobank studies (n = 445,727). The effect of LLD was determined for each stratum of 20 complement genetic variants. In SEED, 484 individuals developed AMD and 216 showed progression over 6 years. In the UK Biobank, 913 participants developed AMD over 11 years. rs1061170 variant (complement factor H gene) was the only variant for which we found a protective effect in both populations. This effect was found in individuals carrying at least one C allele in SEED (odds ratio [OR] = 0.41; 95% confidence interval [CI], 0.19-0.87) and in individuals carrying two C alleles in UK Biobank (hazard ratio [HR] = 0.65; 95% CI, 0.45-0.93). These effects corresponded to a 50% and 35% decrease in AMD risk, respectively. Our study highlights the potential for personalized therapy for AMD based on complement genotyping.

Keywords: Cardiovascular medicine; Health sciences; Internal medicine; Medical specialty; Medicine; Pharmacology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Effect of lipid-lowering drug on the risk of AMD in Singapore Epidemiology of Eye Diseases and UK Biobank according to the rs1061170 genetic variant The squares represent the odds ratios (Singapore Epidemiology of Eye Diseases [SEED]) or hazard ratios (UK Biobank [UKBB]), with the horizontal bars indicating the 95% confidence intervals. The outcome is AMD progression in SEED study and AMD incidence in UKBB study. ITPW, inverse treatment probability weighting; OW, overlap weights.
Figure 2
Figure 2
Predicted AMD progression and incidence according to the lipid-lowering drug and the CFH rs1061170 genotype (A) Predicted AMD progression in Singapore Epidemiology of Eye Diseases (SEED) study according to the lipid-lowering drug (LLD) and the CFH rs1061170 genotype. (B) Predicted AMD incidence in UK Biobank populations according to the LLD and the CFH rs1061170 genotype. The points represent the mean predicted progression rate (SEED) or incidence rate (UKBB), with the vertical bars indicating their 95% confidence intervals. Predictions from the UK Biobank were multiplied by 100 to facilitate the reading. These predictions were calculated using the LLD effects estimated from the multivariable models (as shown in Figure 1) using the inverse treatment probability weighting approach, and applied to the untreated population (see STAR Methods for details).
Figure 3
Figure 3
Effect of lipoprotein sub-fractions and lipid-lowering drug according to CFH rs1061170 genotype (A) Estimates corresponding to the interactions between 49 low-density lipoprotein and high-density lipoprotein (HDL) sub-fractions and CFH genetic variant (rs1061170) on AMD. The gray dotted and red dashed lines corresponded to 5% significance threshold before and after FDR correction, respectively. The two HDL sub-fractions with FDR corrected p values < 5% (above the red dashed line) were considered for the analyses (B), (C), and (D). (B) Effect of lipid-lowering drug on triglycerides sub-fractions in large and very large HDL according to rs1061170 genetic variant. (C) Effects of triglycerides in large HDL (L_HDL_TG) on AMD according to rs1061170 genetic variant. The shaded areas around the solid and dotted lines corresponded to the 95% confidence intervals. (D) Effects of triglycerides in very large HDL (XL_HDL_TG) on AMD according to rs1061170 genetic variant. The shaded areas around the solid and dotted lines corresponded to the 95% confidence intervals.
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