CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

Background: Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca 2+ channel Ca V2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes. Methodology/Principal Findings: In 595 GAD-negative, drug naïve patients (mean6SD; age: 58.5610.2 yrs; BMI: 29.965 kg/m 2, HbA1c: 7.061.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering,93 % of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p,0.0520.01). Both major alleles of rs2184945 and rs3905011 were each (p,0.01 and p,0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p,0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p,0.05). Conclusions/Significance: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongl

Gene structure, location of polymorphic sites, and pairwise LD among SNPs in <i>CACNA1E</i>.

<p>The upper portion of the figure shows the gene structure and location of the polymorphisms genotyped in the VNDS population. The lower portion of the figure shows a schematic of the pairwise LD, calculated as <i>r</i>², among the SNPs in the VNDS patients. The dotted lines connect each SNP name and position with the corresponding cell in the LD matrix. Increasing level of LD is shown by darker grayscale.</p

Derivative control of beta cell function in patients of the VNDS according to genotype of <i>CACNA1E</i> variants.

<p>Data are presented as mean±SE. A non-parametric test has been performed (Kruskal-Wallis) since the variable was not normally distributed.</p><p>A = major allele; B = minor allele.</p

Effects of <i>CACNA1E</i> score on the curve relating insulin secretion rate (y axis) to glucose concentration (x axis), i.e. the proportional control of beta cell function, in patients with newly diagnosed type 2 diabetes of the VNDS.

<p>The <i>CACNA1E</i> score was computed by considering two levels for rs2184945 (<i>TT</i> and <i>AA</i>/<i>AT</i>) and 3 levels for rs3905011 (<i>AA</i>, <i>GA</i> and <i>GG</i>) and by scoring them from 0 to 1 or 2 respectively. The <i>CACNA1E</i> score could range from a minimum of 0 (double genotype rs2184945<i>TT</i>–<i>rs3905011AA</i>) to a maximum of 3 (a <i>rs2184945AA</i>/<i>AT</i>–rs3905011<i>GG</i> genotype) (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032755#pone.0032755.s001" target="_blank">Supporting Information S1</a> Table S13). The higher was the <i>CACNA1E</i> score, the lower was the beta cell insulin secretory response to glucose (p<0.005 after adjusting for age, gender and BMI). Data are presented as mean±SEM.</p

Clinical and metabolic features of the VNDS population.

<p>Data are presented as median [I.Q. range].</p