Alpha2A adrenergic receptor genetic variation contributes to hyperglycemia after myocardial infarction

Abstract

Background Acute myocardial infarction (AMI) is frequently associated with transient hyperglycemia even in patients without pre-existing diabetes. Acute stress can lead to increased blood glucose through the effect of catecholamines on alpha2A-adrenergic receptors (α2A-ARs) present in pancreatic islet β-cells. Variation in the gene (ADRA2A) that encodes the α2A-AR affects insulin release and glucose control and may play a particularly important role during times of stress. Methods We performed a retrospective cohort study using de-identified electronic medical records linked to a DNA repository in 521 Caucasians and 55 African-American non-diabetic patients with AMI. We examined the association between admission blood glucose concentrations and ten selected ADRA2A SNPs in Caucasians. Results Three ADRA2A SNPS were associated with stress-induced hyperglycemia in Caucasians. Individuals homozygous for the rs10885122 variant (n=9) had a 23% lower admission glucose (geometric mean [95% CI], 99 [83 – 118] mg/dl) compared with non-carriers (121 [118–125] mg/dl; n=401; P = 0.001). Admission glucose was 14% higher in rs1800544 variant homozygotes (134 [119–150] mg/dl; n=36) compared to non-carriers (118 [115–121] mg/dl; n=290, P=0.046). Furthermore, homozygotes of the rs553668 variant (n = 13) had a 13% higher glucose (133 [110–160] mg/dl) compared to non-carriers (118 [115–122] mg/dl; n=366; P = 0.056). Haplotypes including these ADRA2A SNPs were associated with higher admission glucose levels. Conclusions Three ADRA2A genetic variants are associated with blood glucose and stress-induced hyperglycemia after AMI in Caucasians.

Identification and Interaction Analysis of Molecular Markers in Myocardial Infarction by Integrated Bioinformatics Analysis

“…PLA2G2A [61], CCL23 [62], CD53 [63], TREML4 [64], TREM2 [65], CD180 [66], HPSE (heparanase) [67], CELA2A [68], TNFRSF4 [69], AMBP (alpha-1-microglobulin/bikunin precursor) [70], SOX18 [71], PANX2 [72], RSPO2 [73], COMP (cartilage oligomeric matrix protein) [74], ASGR1 [75] and NOXA1 [76] are involved in progression of atherosclerosis. A previous study reported that S100A9 [77], ADORA3 [78], IL1R2 [79], FPR1 [80], CCL20 [81], CD163 [82], S100A8 [83], TLR2 [84], HAS2 [85], PTX3 [86], TIMP4 [87], AREG (amphiregulin) [88], LBP (lipopolysaccharide binding protein) [89], IL18R1 [90], ALOX5AP [91], RETN (resistin) [92], F13A1 [93], FPR2 [94], SAA1 [95], FLT3 [96], AQP4 [97], FCER1G [98], CCL18 [99], HP (haptoglobin) [100], CDK1 [101], SLC7A11 [102], CFTR (CF transmembrane conductance regulator) [103], F8 [104], STC1[44], IL18RAP [90], TIMP3 [105], PDE4D [106], CYP4A11 [107], SCN10A [108], APOB (apolipoprotein B) [109], ACE (angiotensin I converting enzyme) [110], PENK (proenkephalin) [111], HSPB6 [112], TLR9 [113], EGR1 [114], CACNG8 [115], FOXD3 [116], DBH (dopamine beta-hydroxylase) [117], FOXP3 [118], GLP1R [119], IL34 [120], CCN1 [121], ADRA2A [122], BGN (biglycan) [123], NOS2 [124], AGRN (agrin) [125], DRD1 [126], GNB3 [127], EGR2 [128], MDK (midkine) [129], NOTCH3 [130], AZIN2 [131], NOTCH1 [132], LOX...…”

Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective α-adrenoceptor antagonist

“…The α 2A -adrenoceptors are widely distributed in the body, and are also present in the pancreatic islet β-cells [ 24 ]. During physiological conditions, catecholamines that act on the postsynaptic α 2A -adrenoceptors located on the pancreatic islet β-cells, inhibit the insulin secretion and consequently increase the blood glucose levels [ 25 ]. Thus, the reduction of the α 2A -adrenoceptor activity may facilitate the insulin secretion from the pancreatic islets and, as a result, reduce elevated glucose levels [ 26 ].…”

Variation in the α 2A -Adrenergic Receptor Gene and Risk of Gestational Diabetes

“…Although carriers of rs10885122 showed a consistent but modest decrease in insulin release after OGTT in nondiabetic Danish subjects [6] and the variant was associated with a small increase in fasting glucose levels in the MAGIC study [15], it was not associated with T2DM, HOMA-B and response to glucose challenge at genome-wide significance in large studies [14,15], which is compatible with our findings. It is also possible that the clinical effects of rs10885122 and rs553668 manifest during conditions of extreme sympathetic activation since we have previously reported that in patients with acute myocardial infarction, both variants are associated with stress-induced hyperglycemia [8].…”

“…In the general population, hyperfunctional genetic variants in the ADRA2A gene have been associated with reduced insulin secretion and increased the risk of Type 2 diabetes mellitus (T2DM) [6,7]. Recently, our group found that ADRA2A variants rs553668 and rs10885122 were significantly associated with stress-induced hyperglycemia in patients with an acute myocardial infarction [8], a condition that is accompanied by increased sympathetic drive [9,10].…”