Intercellular adhesion molecule-1 rs5498 in North India: Genetic spark for diabetic retinopathy inflammasome, not yet a clinical beacon

Abstract

In a case-control study involving 614 individuals with type 2 diabetes from northern India published in the World Journal of Diabetes, Kaur et al first reported a 1.6-fold increase in the diabetic retinopathy (DR) among carriers of the intercellular adhesion molecule-1 rs5498 GG genotype, whereas rs1799969 demonstrated no significant association. However, the relatively low odds ratio of 1.6 (95% confidence interval: 1.01-2.53) and population-attributable risk of only approximately 11% limits the clinical utility of genotyping rs5498 as a stand-alone marker. Readers should guard against interpreting this modest effect as justification for immediate clinical adoption. A meta-analysis of nine studies (1844 DR cases, 1595 controls) revealed no overall or Asian-specific association with rs5498, although a modest effect was observed in the Caucasian subgroup. While this study addresses a key data gap in the North-Indian population, employs rigorous phenotyping with validated genotyping, and provides new insights into DR susceptibility, the cross-sectional design, absence of functional data, small effect size, and interethnic heterogeneity preclude immediate clinical translation. Future large-scale longitudinal cohort studies, gene-environment interaction analyses, and multi-omic integration are required to establish the causal relevance of intercellular adhesion molecule-1 variations and to define its potential as a therapeutic target for precise DR prevention.

Key Words: Intercellular adhesion molecule-1 rs5498; Diabetic retinopathy; Genetic association; North-Indian population; Genetic spark

Core Tip: For the first time, the intercellular adhesion molecule-1 rs5498 GG genotype has been linked to an increased risk of diabetic retinopathy in Northern Indians, highlighting the inflammatory genetic architecture of this sight-threatening complication. However, the modest effect size, uncorrected statistical significance, absence of allele-specific expression data, and pronounced inter-ethnic heterogeneity observed in meta-analysis mandate large-scale prospective cohorts, functional validation through Clustered Regularly Interspaced Short Palindromic Repeats-based cellular assays, and multi-omic integration before this variant can be considered for clinical risk stratification or precision prevention strategies.

This editorial refers to “Association of ICAM-1 Gene Polymorphisms with Diabetic Retinopathy in T2DM Patients from Northern India: Case-control and meta-analysis” by Kaur et al, 2025; https://dx.doi.org/10.4239/wjd.v16.i12.110770.

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INTRODUCTION

Diabetic retinopathy (DR) is a major microvascular complication of diabetes and the leading cause of preventable blindness among working-age adults worldwide[1-3]. According to the International Diabetes Federation Diabetes Atlas 2021, approximately 537 million adults worldwide have diabetes, and approximately one-third of them are expected to develop some form of DR during their lifetime[4]. In South Asia, particularly India, the prevalence of DR is disproportionately high, with certain regions reporting rates as high as 34%[5]. This elevated burden is likely attributable to a combination of genetic predisposition, suboptimal glycemic index control, limited access to regular eye screening, and socioeconomic factors that hinder optimal diabetes management[6,7]. Traditional risk factors fail to explain the marked inter-individual variability in DR onset, prompting searches for genetic modifiers[8]. Candidate gene studies, genome-wide association studies, and multi-omics approaches have identified several loci implicated in DR pathogenesis, particularly in the inflammatory, endothelial, and oxidative stress pathways[9-11].

Intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein that mediates leukocyte-endothelial adhesion, has emerged as a key candidate[12]. Elevated ICAM-1 levels in vitreous humor, serum, and diabetic animal models contribute to retinal leukostasis, vascular leakage, and blood-retinal barrier breakdown[12,13]. ICAM-1 inhibition reduces retinal inflammation and microvascular damage, highlighting its potential as a biomarker and therapeutic target[12].

Despite two decades of investigation, the genetic architecture of ICAM-1 in DR remains one of the most contentious areas in diabetes pharmacogenetics. While early candidate gene studies identified rs5498 and rs1799969 as relevant loci, subsequent research has revealed striking ethnic disparities: East Asian cohorts consistently report increased DR risk associated with the rs5498 AA genotype[12,13], whereas studies in Southern India found no significant association, and a recent meta-analysis suggested a weak signal confined to Caucasian populations. These discordant findings raise fundamental questions about population-specific linkage disequilibrium patterns, gene-environment interactions, and phenotypic heterogeneity that remain unresolved. In this context, the study published in the World Journal of Diabetes by Kaur et al[14] documenting a 1.6-fold increased risk associated with the GG genotype in North Indians adds a critical fourth piece to this puzzle, while simultaneously intensifying the controversy regarding the clinical translatability of ICAM-1 genotyping.

Two common ICAM-1 coding variants, rs5498 (exon 6, p.Lys469Glu) and rs1799969 (exon 4, p.Gly241Arg), have been extensively studied. The rs5498 variant affects integrin binding and leukocyte adhesion, while the functional impact of rs1799969 remains unclear[12]. Epidemiological findings are inconsistent. East Asian cohorts display increased DR risk with the rs5498 AA genotype, whereas a Southern Indian study found no association. Such ethnicity-specific discrepancies necessitate population-specific investigations[12,13].

No prior study has examined ICAM-1 polymorphisms in North Indians, a population with a distinct genetic architecture and high DR burden. This gap impedes population-specific risk prediction and global understanding of DR genetics. Kaur et al[14], in this issue, address this lacuna by investigating ICAM-1 rs5498 and rs1799969 in 614 North Indian patients with type 2 diabetes (Figure 1). Their case-control study, combined with a meta-analysis of nine studies, revealed a modest but significant association between the rs5498 GG genotype and DR risk in this population. Nevertheless, the clinical implications require cautious interpretation, and larger longitudinal and functional studies are needed.

Figure 1 Schematic summary of the editorial scope and key findings. The graphic outlines the research background (intercellular adhesion molecule-1 gene polymorphism and type 2 diabetic retinopathy), the methods employed (North-Indian case-control cohort plus meta-analysis), and the principal results: A population-specific 1.6-fold increase in diabetic retinopathy risk associated with the rs5498 GG genotype in northern Indians, contrasted with the absence of a consistent signal in broader Asian or Caucasian populations. The figure underscores the need for population-tailored genetic risk assessment before clinical translation. ICAM-1: Intercellular adhesion molecule-1.

CURRENT ADVANCES AND ETHNIC CONTROVERSIES: THE EAST-WEST PARADOX

Recent advances in high-throughput genotyping and multi-ethnic meta-analyses have clarified the population-specific behavior of ICAM-1 variants. The landmark meta-analysis by Kaur et al[14], incorporating 1844 DR cases across nine studies, formally quantified inter-ethnic heterogeneity (I² = 88%), revealing that the “caucasian signal” rests exclusively within a single Slovenian cohort (n = 262). East Asian studies consistently implicate the A allele[12,13], while South Asian data remain equivocal: Southern Indians show no association, and Northern Indians now implicate the G allele. These advances underscore that ICAM-1-DR associations are context-dependent rather than universal.

We argue that the East-West paradox reflects three unresolved methodological controversies. First, the allele-risk discrepancy (AA risk in East Asia vs GG risk in North India) challenges the biological plausibility of a single causal variant, suggesting that rs5498 may be a population-specific tag single nucleotide polymorphisms in linkage disequilibrium with distinct causal variants across haplotype blocks. Second, the clinical significance threshold remains hotly debated; while Kaur et al[14] have reported an odds ratio of 1.6, the population-attributable risk of merely 11% falls well below the 20% threshold typically required for clinical utility. From our perspective, the field has prioritized statistical significance over biological meaningfulness, conflating “detectable association” with “actionable biomarker”.

Compounding these epidemiological controversies is the absence of functional consensus. While the rs5498 p.Lys469Glu substitution purportedly alters integrin-binding affinity, allele-specific expression data and cellular adhesion assays under hyperglycemic conditions remain conspicuously absent from the literature. We contend that the lack of mechanistic validation renders the current associations statistically intriguing but therapeutically inert.

CRITICAL APPRAISAL: WHY RS5498 IS NOT YET READY FOR PRECISION MEDICINE

Beyond ethnic heterogeneity, we identified four fundamental limitations that should temper enthusiasm for immediate clinical translation. First, the modest effect size (odds ratio: 1.6, 95% confidence interval: 1.01-2.53) with a lower boundary approaching unity suggests that the association may be biologically trivial or confounded by unmeasured covariates. Second, the uncorrected P value of 0.044, while nominally significant, did not survive Bonferroni correction for multiple comparisons across the two single nucleotide polymorphisms and multiple genetic models tested, raising the possibility of false-positive findings in underpowered subgroup analyses. Third, the cross-sectional design precludes causal inference. It remains equally plausible that chronic retinal inflammation elevates ICAM-1 expression, which in turn influences genotype-phenotype correlations through reverse causation. Finally, the absence of soluble ICAM-1 protein quantification or allele-specific expression in retinal endothelium leaves a critical gap between genetic variation and pathophysiological mechanisms. These limitations collectively indicate that rs5498 functions statistically as a marker of inflammation rather than a causal driver of retinopathy.

FUTURE DIRECTIONS: A ROADMAP FOR RESOLVING THE ICAM-1 CONTROVERSY

To resolve the East-West paradox and advance clinical utility, we propose a prioritized research agenda: (1) Immediate: Prospective validation in multiethnic cohorts. North Indian biobanks should adopt Early Treatment Diabetic Retinopathy Study-standardized phenotyping to confirm temporal directionality and quantify predictive value beyond classic risk factors, while parallel East Asian cohorts should test for GG-versus-AA risk interactions to clarify haplotype structure; (2) High priority: Functional dissection of ethnic differences. Dense regional genotyping and retinal endothelial single-cell expression quantitative trait locus mapping across Indian, East Asian, and Caucasian populations are essential to determine whether rs5498 tags are distinct causal variants in different ethnicities; (3) Mechanistic causality. CRISPR editing of the G allele in human induced pluripotent stem cell-derived endothelial cells, coupled with leukocyte adhesion assays under hyperglycemic conditions, could provide the first experimental evidence of allelic functional impact, which is currently the achilles heel of the field; (4) Protein-phenotype integration. Parallel measurements of circulating and vitreous soluble ICAM-1 with allele-specific quantification in retinal microvessels would enable Mendelian randomization to distinguish between correlation and causation; (5) Gene-environment deconvolution. High-resolution longitudinal datasets should assess whether stringent metabolic control abrogates GG genotype risk, thereby defining whether ICAM-1 acts as a genetic sentinel requiring pharmacological intervention or merely as a biochemical bystander responsive to glycemic management; and (6) Long-term: Polygenic integration. ICAM-1 variants should be integrated into polygenic risk scores encompassing the vascular endothelial growth factor, receptor for advanced glycation end products, complement, and oxidative stress pathways, with machine learning quantifying incremental contributions beyond clinical variables. Only through this rigorous multiomics validation can the field determine whether ICAM-1 rs5498 represents a genuine precision medicine target or an inflammatory red herring in the complex pathogenesis of DR.

CONCLUSION

Kaur et al[14] provided the initial evidence linking ICAM-1 rs5498 to DR in North Indians. Although the modest effect size and absence of functional data temper immediate clinical enthusiasm, this finding illuminates population-specific inflammatory pathways. Future priorities include: (1) Prospective cohort validation; (2) Allele-specific mechanistic studies; and (3) Integration into polygenic risk scores. Only through such rigorous follow-up studies can this genetic association be translated into precision medicine tools for the prevention of DR in South Asian populations.