Genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population

Abstract

A keloid is the process of skin healing, collagen synthesis and metabolism of the loss of normal control in a sustained hyperactive state, resulting in excessive proliferation of collagen fibers. A large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in the 3q22.3 loci that are associated with keloids in a Japanese population. However, the associations of SNPs in 3q22.3 with keloids were not confirmed in a selected Chinese population by a replication study. Thus, in the present study, the relationships between keloids and 3q22.3 were assessed in another independent Chinese Han population, including 309 keloid patients and 1080 control subjects. The results displayed that rs940187 was associated with keloids (OR=1.88, 95% CI 1.27-2.78, P=1.35E^-3) and remained significant after Bonferroni's correction for multiple testing, while rs1511412 showed only a trend association (OR=2.23, 95% CI 1.09-4.55, P=0.02) with keloids. In addition, we subsequently checked the annotation datasets for rs940187 with eQTLs and obtained two hits, trans-proteins SLC7A9 and LEMD3, with significant P values less than 1e-4. In summary, genomic risk variants at 3q22.3 are associated with keloids in a Chinese Han population and contribute to the development and deterioration of the keloids, together with environmental factors.

Keywords: Keloids; SNP; association.

Figure 1

Regional association plots showing signals in replication samples for 3q22.3. The P-values of SNPs (shown as -log₁₀ values in y-axis, from the genome-wide single-marker association analysis) were plotted against their map positions (x-axis). Gene annotations were adapted from the University of California at SantaCruz Genome Browser (http://genome.ucsc.edu/).

Figure 2

The LD pattern of the 3q22.3 region in populations of Chinese and Japanese ancestry. The LD pattern (r²) was created in the Haploview by using the genotyping data (only SNPs with MAF > 0.01) from the HapMap project. The positions of the two SNPs (rs1511412, rs940187) identified in this study are indicated by red arrows. It shows there were several independent LD blocks in the entire region, and the high r² value (0.58) indicates these two SNPs were in LD.

Figure 3

Pathway and GO enrichment analysis using ClusterProfiler method. Pathway analysis based on KEGG database (A). GO enrichment analysis based on Gene Ontology database (B). Gene Ratio corresponds to the number of genes from a specific category. Enrichment term is represented by coloured dots (red indicates high enrichment and blue indicates low enrichment).

Figure 4

Functional Annotation Clustering analysis by using DAVID online method (version 6.8). A. Functional cluster 1, enrichment score 0.45; B. Functional cluster 2, enrichment score 1.08; all show evidence of nucleus function for input gene set.