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. 2024 Aug 8;17(8):100949.
doi: 10.1016/j.waojou.2024.100949. eCollection 2024 Aug.

Proteomic analysis of cardiovascular disease-associated proteins in Korean patients with moderate-to-severe atopic dermatitis

Seon-Pil Jin  1   2   3 , Hosu Kim  4 , Ji Hwan Moon  5 , Seunghee Kim-Schulze  6 , Yookyung Sophie Chun  7 , Hyo Jeong Nam  7 , Yoon Ji Bang  7 , Ji Su Lee  1   2   3 , Jung Eun Kim  8 , Chung-Gyu Park  4   7   9   10 , Hyun Je Kim  4   7   9   10 , Dong Hun Lee  1   2   3
Affiliations

Proteomic analysis of cardiovascular disease-associated proteins in Korean patients with moderate-to-severe atopic dermatitis

Seon-Pil Jin et al. World Allergy Organ J. .

Abstract

Background: Cardiovascular diseases (CVDs) have been associated with atopic dermatitis (AD), including in Korean patients. Previous studies on AD have primarily focused on patients of European ancestry, while the Asian endotype exhibits distinct characteristics. This study aimed to characterize the blood proteomic signature of Korean patients with moderate-to-severe AD, with an emphasis on proteins related to CVDs.

Methods: A total of 78 participants, including 39 patients with moderate-to-severe AD and 39 age- and sex-matched healthy controls, were enrolled. Blood proteomics analysis was performed using the Olink CVD II panel, which measures the expression levels of 92 proteins associated with CVDs.

Results: Unsupervised hierarchical clustering revealed 44 upregulated and 5 downregulated proteins in AD patients compared to healthy controls. Principal component analysis (PCA) effectively distinguished AD patients from healthy subjects based on the complete set of proteins or the subset of upregulated proteins. A multiple linear regression model comprising CCL17 and FGF21 showed a strong correlation with disease severity (R = 0.619). Correlation analysis identified 25 highly correlated proteins, including STK4, ITGB1BP2, and DECR1, which were newly found to be upregulated in Korean AD patients. Pathway analysis highlighted the involvement of these proteins in vascular system, inflammation, and lipid metabolism pathways.

Conclusion: The blood proteomic profile of moderate-to-severe AD patients in Korea differed from healthy controls using the CVD II panel. This study provides potential biomarkers for the AD-CVD association and insights into the pathways contributing to this relationship in the Korean population.

Keywords: Atopic dermatitis; Cardiovascular diseases; Korean patients; Proteomics.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Protein subsets with increased and decreased expression levels are identified in AD. (A) Heatmap of AD patients with healthy controls. AD patients and healthy controls are listed at the top according to the unsupervised hierarchical clustering and denoted according to the group: red, AD patients; blue, healthy controls. The unsupervised hierarchical clustering of the proteins is shown in the right corner. Expression levels were color-coded according to normalized expression values, as indicated in the vertical legend. Light green indicates higher expression levels and dark green indicates lower expression levels. (B) The upregulated and downregulated proteins with statistically significant (adjusted P < 0.05) are listed along with their P values in scientific notation (E = exponent) and log2 fold change values. P values were adjusted using the Benjamini-Hochberg multiple testing correction methods. AD, atopic dermatitis. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article)
Fig. 2
Fig. 2
The CVD II panel and its subsets of upregulated proteins effectively distinguish AD from healthy controls. Each red and blue dot represents a patient with AD or a healthy volunteer, respectively. (A) The PCA was drawn using 92 proteins. (B) Forty-four upregulated proteins were used to compute the PCA. (C) Five downregulated proteins were used for the PCA. AD, atopic dermatitis; CVD, cardiovascular disease; PCA, principal component analysis. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article)
Fig. 3
Fig. 3
Proteins associated with CVD in AD patients highly correlate with disease severity. (A) Multiple linear regression model displays the linear relationship between the proteins and the EASI score. Out of 92 proteins in the panel, those with multicollinearity (condition index >20) were excluded before conducting analysis. (B) The scatter plot displays the relationship between CCL17 expression levels and EASI scores. AD, atopic dermatitis; CCL17, CC chemokine ligand 17; CVD, cardiovascular disease; EASI, eczema area and severity index
Fig. 4
Fig. 4
The distinct protein set exhibits a strong correlation, with STK4, ITGB1BP2, and DECR1 showing significant upregulation in AD patients in Korea. (A) Heatmap for Pearson correlations between protein expression levels. The correlations were color-coded according to the vertical color map based on their computed correlation coefficient values. Orange indicates higher correlations, and violet indicates lower correlations. The yellow box includes a cluster of 25 proteins with high correlations. The proteins were first categorized using unsupervised hierarchical clustering and had to report a correlation coefficient greater than 0.6 with proteins other than themselves. The proteins were labeled alternatively on either the vertical or horizontal axis of the heatmap. (B) Correlating proteins previously mentioned in the non-Olink studies for AD are listed in the left column. The correlating proteins previously reported to be upregulated in the AD Olink studies are listed in the center column. The correlating proteins newly identified in this study are listed in the right column. (C) Box plots were drawn to compare the expression levels of the newly identified proteins, STK4, ITGB1BP2, and DECR1, in the AD patients and the healthy volunteers. An asterisk denotes statistical significance with ∗∗P < 0.01, ∗∗∗P < 0.001. AD, atopic dermatitis; CCL17, CC chemokine ligand 17; CVD, cardiovascular disease; EASI, eczema area and severity index; STK4, Serine Threonine Kinase 4; ITGB1BP2, integrin subunit beta 1 binding protein 2; DECR1, 2, 4 dienoyl-CoA reductase (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article)
Fig. 5
Fig. 5
Pathway and GO analyses identified pathways enriched in relation to CVD within AD patients. Bubble plot of GO and various pathway enrichment analyses (Reactome Pathway Database, GO terms including GO_MF, GO_BP, KEGG, BioPlanet) of the 25 proteins from the CVD II panel. The X-axis represents the -log adjusted P value (-log 10 AdjP). Color displays -log10 adjusted P value; closer to red indicates more significant enrichment. The bubble size represents the enrichment score. GO, gene ontology; GO_MF, GO molecular function; GO_BP, GO biological process; KEGG, Kyoto Encyclopedia of Genes and Genomes; CVD, cardiovascular disease; AD, atopic dermatitis. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article)
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