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

https://doi.org/10.1016/j.diabres.2007.04.010Get rights and content

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.

Introduction

C-peptide is secreted into the bloodstream by the pancreas along with insulin. Since half-life of C-peptide in plasma is longer than insulin, C-peptide concentration is 5–10 times higher than that of insulin. The main physiological role of C-peptide is to facilitate the folding of the pro-insulin molecule. However, recent studies have been demonstrated physiological effects of C-peptide involving renal and nerve function, and the stimulation of whole body glucose uptake in patients with type 1 diabetes [1], [2], [3], [4]. For example, a positive linear relationship has been observed between residual plasma C-peptide concentration and erythrocyte Na+–K+-ATPase activity in a cohort of patients with T2D [5]. Under diabetic conditions, Na+, K+-ATPase activity is decreased in different cell types and might be involved in the pathogenesis of various diabetic complications [6], [7], [8]. In contrast, similar physiologic effects of C-peptide have not been observed in health subjects or animals suggesting a saturation of the mechanisms of C-peptide action in health subjects [6]. These growing physiologic importances of C-peptide prompted us to considerate C-peptide as a phenotype in whole-genome linkage studies for T2D.

Section snippets

Subjects

Participants included in these analyses were enrolled in the AADM study as described in detail by Rotimi et al. [9], [10]. The protocol was approved by Institutional Review Board (IRB) of each institution and written informed consent was obtained from all participants. At the time of these analyses, the AADM study enrolled only affected pairs with T2D. In this regard, data on parents and other family members were not available. Participants were enrolled from three centers in Nigeria (Enugu,

Results

Clinical characteristics of the affected subjects are shown in Table 1. The study sample included 691 persons (59.3% women) with T2D. The mean age was 53 years, age at diagnosis was 48 years and mean duration of diabetes at the time of the study was 7 years. Mean value of C-peptide, insulin and glucose were 1.25 ng/ml, 21.70 μU/ml, and 201.00 mg/dl, respectively. The correlation between the log C-peptide value and covariates are shown in Table 2. The maximum likelihood heritability estimates for log

Discussion

Physiologically, C-peptide has been shown to increase forearm muscle blood flow [17], to enhance oxygen uptake and capillary diffusion capacity in the exercising forearm [2]. Under diabetic condition C-peptide has been shown to: (1) redistribute micro-vascular skin blood flow in C-peptide negative patients [18]; (2) improve micro-vascular complications, such as diabetic nephropathy and diabetic neuropathy [1], [3]; (3) attenuate Na+–K+-ATPase activity in different cell types [19], [20]; and (4)

Acknowledgements

Support for the AADM study is provided by NIH grant no. 3T37TW00041-03S2 from the National Center for Minority Health and Health Disparities. This project is also supported other NIH institutes (NGHRI, and NIDDK; DK-54001). Genotyping was done by the Center for Inherited Disease Research (CIDR). Some of the results of this paper were obtained using the program S.A.G.E. which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the National Center for Research Resources.

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