Novel susceptibility loci identified in a genome-wide association study of type 2 diabetes complications in population of Latvia

Abstract

Background: Type 2 diabetes complications cause a serious emotional and economical burden to patients and healthcare systems globally. Management of both acute and chronic complications of diabetes, which dramatically impair the quality of patients' life, is still an unsolved issue in diabetes care, suggesting a need for early identification of individuals with high risk for developing diabetes complications.

Methods: We performed a genome-wide association study in 601 type 2 diabetes patients after stratifying them according to the presence or absence of four types of diabetes complications: diabetic neuropathy, diabetic nephropathy, macrovascular complications, and ophthalmic complications.

Results: The analysis revealed ten novel associations showing genome-wide significance, including rs1132787 (GYPA, OR = 2.71; 95% CI = 2.02-3.64) and diabetic neuropathy, rs2477088 (PDE4DIP, OR = 2.50; 95% CI = 1.87-3.34), rs4852954 (NAT8, OR = 2.27; 95% CI = 2.71-3.01), rs6032 (F5, OR = 2.12; 95% CI = 1.63-2.77), rs6935464 (RPS6KA2, OR = 2.25; 95% CI = 6.69-3.01) and macrovascular complications, rs3095447 (CCDC146, OR = 2.18; 95% CI = 1.66-2.87) and ophthalmic complications. By applying the targeted approach of previously reported susceptibility loci we managed to replicate three associations: MAPK14 (rs3761980, rs80028505) and diabetic neuropathy, APOL1 (rs136161) and diabetic nephropathy.

Conclusions: Together these results provide further evidence for the implication of genetic factors in the development of type 2 diabetes complications and highlight several potential key loci, able to modify the risk of developing these conditions. Moreover, the candidate variant approach proves a strong and consistent effect for multiple variants across different populations.

Keywords: Diabetic complications; Genome-wide genotyping; Type 2 diabetes mellitus.

Fig. 1

Venn diagram showing the distribution and overlap of cases among the analyzed T2DM complication groups

Fig. 2

Manhattan plots for GWAS of T2DM complications. a Diabetic neuropathies, b macrovascular complications, c ophthalmic complications. X-axis shows chromosomal positions. Y-axis shows –log10 P-values. The red lines indicate a genome-wide significant threshold of P < 5 × 10⁻⁸, and the blue lines denote a suggestive significance threshold of P < 5 × 10⁻⁵. Association signals that reached genome-wide significance are denoted by reference SNP ID number