Implication of RAGE Polymorphic Variants in COPD Complication and Anti-COPD Therapeutic Potential of sRAGE

Figures & data

Figure 1. Ligand signaling and inflammation mediated RAGE involvement in COPD pathogenesis.

Figure 2. Summary of -374 T/A, -429 T/C and G82S RAGE gene SNPs possible involvement in inflammation and COPD manifestation. The representations pinpoint the findings of 2014 study by Li Y and colleagues, wherein the depicted RAGE gene SNPs feature in top five of most noted ones.

Table 1. Noted polymorphisms of RAGE gene (AGER) with their implicit SNP prospects, molecular significance and characteristic involvement in COPD pathogenesis.

Polymorphism	Key molecular aspects and pathological complications	Specific role in COPD pathogenesis
rs2070600 NM_001136.4:c.-244G > A p.Gly82Ser	Most prevalent SNP within AGER gene, missensed variation inducing glycine substitution by serine at codon 82 within RAGE protein, exon 3 is a putative ligand binding site, located in the second N-glycosylation motif and promotes RAGE glycosylation that modifies the RAGE ligand binding structure with an increased affinity for ligand AGEs, aggravates RAGE stimulation by its ligands, implicated in microangiopathy in type 2 diabetes, reported significant in diabetic retinopathy and type 2 diabetes, worsens chemotherapeutic response to gastric, epithelial ovarian and non-small cell lung cancer (in Chinese population), aggravates the risk of developing acute respiratory distress syndrome (ARDS) with higher plasma sRAGE levels, despite 50% reduced sRAGE expressions no significant association with rs2070600 has been noticed	Associated with related pulmonary functioning characterized by exacerbated lung inflammatory response, specifically involved with enhanced COPD occurrence (a study on Caucasian smokers from Poland), has a strong association with Forced Expiratory Volume (FEV) per second and Forced vital Capacity (FVC), aggravates emphysema among European and African Americans
rs1800624 NM_001136.4:c.-388T > A	Located in promoter region of AGER gene, one amongst five most described AGER SNPs, 85% T and 15% A allele frequency in general population, enhances in vitro AGER transcription by modulating binding affinity of transcription factor site, influences the pathogenesis of inflammatory and diabetes related vascular complications, occurrence frequency positively correlated with lung and breast cancer risk, decreases Crohn’s disease risk in Chinese and German population but not in Americans, associated with reduced risk of heart disease, cancer, Crohn’s disease and type I diabetes criticalities, ethnicity based involvement in diabetic neuropathy, major allele confers disease severity in lupus nephritis patients	Although not specifically implicated in COPD but associations with related pulmonary complications are ethnicity driven, such as severity of lung disease in European population, association with higher levels of circulating RAGE (sRAGE and esRAGE) signify a positive factor for COPD aggravation
rs1800625 NM_001136.4:c.443T > C	Increases AGER transcription in vitro, often referred as −429 T > C, T and C allele frequency in general population are 86.3 and 13.7.	Aggravates lung inflammation via enhanced RAGE expression, no significant association prevails for enhanced risk of type 2 diabetes, diabetic retinopathy or diabetic neuropathy, inconclusive observations pertaining to cardiovascular risk
rs184003 NM_001136.4:c.822 + 49 G > T	Commonly known as 1704 G/T, 84.4% G allele and 15.6% T allele frequency in general population, aggravates coronary artery disease (Chinese citizens study), breast cancer and diabetes (Asian residents study)	Associated with coronary artery diseases (in Chinese population but not with idiopathic pulmonary fibrosis, no clear involvement in COPD has been noticed.
63 bp deletion NM_001136.4:c.- -421_-359del	Located in AGER gene promoter, overlaps with rs1800624 and is downstream from rs1800625, ethnicity based involvement in cardiovascular complications (decreased survival of type 2 diabetic neuropathy Chinese patients while low frequency was noticed in African Brazilian patients without any survival impact) increases AGER transcription, reduces survival from cardiac complications during diabetic nephropathy	No significant association with COPD has been noted till date
rs2071288 NM_001136.4:c.992-6G > A	With 94.6% and 5.4%, G and A allele frequency in general population, this polymorphism is located at a splice site in intron 9 and has an association with varying sRAGE and esRAGE expressions, a GWA study revealed its association with 43% reduced sRAGE expressions	Associated with significant reductions in sRAGE expression and CO diffusing capacity in emphysema in COPD

GWA: Genome-Wide Association, CO: Carbon monoxide. The associations between AER polymorphisms and the development of disease exhibit conflicting outcomes, vis-à-vis explored pathological aspects of AGER SNPs, the dissimilarities are accountable to varying AGER SNP frequencies based on ethnicity.

Figure 3. Implication of RAGE in COPD pathogenesis pinpointed distinctly in young smokers, adult mice and mitigated via neutrophilic inflammation.

Figure 4. Alveolar type I (AT-I) epithelial cells are predominant RAGE expressing in the lungs. The interaction of RAGE with AGE/other ligands generates reactive oxygen species from oxidoreductases and mitochondria which accumulates the troubling oxidative and inflammatory stress. Enhanced oxidative and inflammatory stress causes tissue injury (AT-I cells) and COPD complications.