Genome-wide search for susceptibility genes to type 2 diabetes in West Africans: Potential role of C-peptide

Abstract

C-peptide is a substance that the pancreas releases into the circulation in equimolar amounts to insulin and has demonstrated important physiological effects which relate to the vascular field, in particular the microcirculation. For this analysis, we included 321 full and 36 half sibling pairs affected with type 2 diabetes (T2D) from West Africa. A genome-wide panel of 390 tri-nucleotide and tetra-nucleotide repeats with an average distance of 8.9 cM was performed on a total of 691 persons. Variance components based on multipoint linkage approach as implemented in SOLAR were performed for log C-peptide. Significant linkage evidences were observed on 10q23 at D10S2327 with a LOD score of 4.04 (nominal p-value = 0.000008, empirical p-value = 0.0004); and on 4p15 at D4S2632 with a LOD score of 3.48 (nominal p-value = 0.000031, empirical p-value = 0.0013). Other suggestive evidence of linkage were observed on 15q14 at D15S659 with a LOD score 2.41 (nominal p-value = 0.000435, empirical p-value = 0.0068), and on 18p11 near D18S976 with a LOD score 2.18 (nominal p-value = 0.000771 and empirical p-value = 0.0094). Interestingly, five positional candidate genes for diabetes and related complications are located in our linkage region (the pituitary adenylate cyclase activating polypeptide (PACAP in 18p11); the peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGC1 in 4p15); PTEN, PPP1R5, and IDE located in 10q23. In conclusion, we identified four major genetic loci (10q23, 4p15, 15q14, and 18p11) influencing C-peptide concentration in West Africans with T2D.