Analysis of Glucocorticoid-Related Genes Reveal CCHCR1 as a New Candidate Gene for Type 2 Diabetes

Abstract

Glucocorticoids have multiple therapeutic benefits and are used both for immunosuppression and treatment purposes. Notwithstanding their benefits, glucocorticoid use often leads to hyperglycemia. Owing to the pathophysiologic overlap in glucocorticoid-induced hyperglycemia (GIH) and type 2 diabetes (T2D), we hypothesized that genetic variation in glucocorticoid pathways contributes to T2D risk. To determine the genetic contribution of glucocorticoid action on T2D risk, we conducted multiple genetic studies. First, we performed gene-set enrichment analyses on 3 collated glucocorticoid-related gene sets using publicly available genome-wide association and whole-exome data and demonstrated that genetic variants in glucocorticoid-related genes are associated with T2D and related glycemic traits. To identify which genes are driving this association, we performed gene burden tests using whole-exome sequence data. We identified 20 genes within the glucocorticoid-related gene sets that are nominally enriched for T2D-associated protein-coding variants. The most significant association was found in coding variants in coiled-coil α-helical rod protein 1 (CCHCR1) in the HLA region (P = .001). Further analyses revealed that noncoding variants near CCHCR1 are also associated with T2D at genome-wide significance (P = 7.70 × 10^-14), independent of type 1 diabetes HLA risk. Finally, gene expression and colocalization analyses demonstrate that variants associated with increased T2D risk are also associated with decreased expression of CCHCR1 in multiple tissues, implicating this gene as a potential effector transcript at this locus. Our discovery of a genetic link between glucocorticoids and T2D findings support the hypothesis that T2D and GIH may have shared underlying mechanisms.

Keywords: corticosteroid; diabetes; genetics.

Figure 1.

Regional association plot of the type 2 diabetes association at chromosome 6p21.33 (location of coiled-coil α-helical rod protein 1 [CCHCR1]). Single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms [SNPs]) are plotted by position on chromosome 6 (x-axis) against association with type 2 diabetes from DIAMANTE (–log10 P value). The strongest signal at SNV rs3131012 is denoted by the purple diamond. Other SNVs are color-coded to reflect their linkage disequilibrium with the top SNV. The location and the direction of transcription for genes in the region are shown below the x-axis.

Figure 2.

Phenotype-wide association study (PheWAS) of rs3131012 in the AMP-T2D Knowledge Portal. We submitted a query for the top single-nucleotide variation (SNV, formerly single-nucleotide polymorphism [SNP]) rs3131012 to the multiple genome-wide association study (GWAS) databases contained in the AMP-T2D Knowledge Portal (www.type2diabetesgenetics.org). Phenotypes are listed along the x-axis including anthropometric, cardiovascular, glycemic, lipid, metabolite, renal, and other, plotted against association (–log10 P value). Multiple phenotypes are associated with this locus as revealed by the height GIANT GWAS and the type 2 diabetes DIAMANTE GWAS.

Figure 3.

Tissue-specific expression of coiled-coil α-helical rod protein 1 (CCHCR1) [43, 44].

Figure 4.

A, The type 2 diabetes risk variants rs3131012, rs3130453, and rs 2073721 act as expression quantitative trait loci (eQTLs) for coiled-coil α-helical rod protein 1 (CCHCR1) gene expression in skeletal muscle, with additive allelic effects at each variant [43, 44]. Additionally, these variants, specifically rs2073721, colocalize in skeletal muscle tissue for CCHCR1 expression. Other genes, including B, HCG27, C, PSORS1C1, and D, PSORS1C2, act as eQTLs. However, they do not colocalize in diabetes-related tissues with their gene expression as illustrated by subcutaneous adipose tissue. Violin plots were created using GTEx v8. Colocalization plots were created using Scott et al (2017) [45] for genome-wide association study analysis and plotted against v7 GTEx expression data.