Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang

Abstract

Essential hypertension is a common cardiovascular disease with complex etiology, closely related to genetic and environmental factors. The pathogenesis of hypertension involves alteration in vascular resistance caused by sympathetic nervous system (SNS) and renin angiotensin system (RAS). Susceptibility factors of hypertension vary with regions and ethnicities. In this study, we conducted target capture sequencing on 54 genes related to SNS and RAS derived from a collection of Han nationality, consisting of 151 hypertension patients and 65 normal subjects in Xinjiang, China. Six non-synonymous mutations related to hypertension were identified, including GRK4 rs1644731 and RDH8 rs1801058, Mutations are predicted to affect 3D conformation, force field, transmembrane domain and RNA secondary structure of corresponding genes. Based on protein interaction network and pathway enrichment, GRK4 is predicted to participate in hypertension by acting on dopaminergic synapse, together with interacting components. RDH8 is involved in vitamin A (retinol) metabolism and consequent biological processes related to hypertension. Thus, GRK4 and RDH8 may serve as susceptibility genes for hypertension. This finding provides new genetic evidence for elucidating risk factors of hypertension in Han nationality in Xinjiang, which in turn, enriches genetic resource bank of hypertension susceptibility genes.

Identification of Key Genes and Biological Pathways in Bipolar Disorder by Bioinformatics and Next Generation Sequencing Data Analysis

“…Altered expression of SLC6A9 [56] and RHD (Rh blood group D antigen) [57], CHRFAM7A [58], ANXA3 [59], SLC1A5 [60], KCNH2 [61], HP (haptoglobin) [62], SELENBP1 [63], SNCA (synuclein alpha) [64], TGM2 [65], PINK1 [66], B2M [67], QPCT (glutaminyl-peptide cyclotransferase) [68], CBS (cystathionine beta-synthase) [69], NQO2 [70], GLRX5 [71], BASP1 [72], GAS7 [73], GPX1 [74], OLIG2 [75], RPTN (repetin) [76], IL33 [77], SOX10 [78], GRIK1 [79], ZFPM2 [80], SHANK3 [81], ERBB3 [82], ARC (activity regulated cytoskeleton associated protein) [83], GFAP (glial fibrillary acidic protein) [84], PLAT (plasminogen activator, tissue type) [85], GRIK5 [86], CACNB2 [87], NRXN2 [88], TERT (telomerase reverse transcriptase) [89], GNB3 [90], L1CAM [91], EGR3 [92], CAV1 [93], CACNA1B [94], MAGI1 [95], KIR2DL1 [96], PAH (phenylalanine hydroxylase) [97] and CYP3A5 [98] have been shown in schizophrenia. Recent studies showed that SLC6A9 [99], FKBP1B [100], S100A12 [101], SLC6A19 [102], TXN (thioredoxin) [103], TLR9 [104], HP (haptoglobin) [105], ARG1 [106], PINK1 [107], B2M [108], C5AR1 [109], MYADM (myeloid associated differentiation marker) [110], CBS (cystathionine beta-synthase) [111], GPX1 [112], SIAH2 [113], PRDX2 [114], RDH8 [115], CYP11B2 [116], RARRES2 [117], NOX1 [118], IL33 [119], OTC (ornithine transcarbamylase) [120], CYP1A1 [121], NFATC4 [122], TSLP (thymic stromal lymphopoietin) [123], WNT4 [124], MGP (matrix Gla protein) [125], FGFBP1 […”

“…[97] and CYP3A5 [98] have been shown in schizophrenia. Recent studies showed that SLC6A9 [99], FKBP1B [100], S100A12 [101], SLC6A19 [102], TXN (thioredoxin) [103], TLR9 [104], HP (haptoglobin) [105], ARG1 [106], PINK1 [107], B2M [108], C5AR1 [109], MYADM (myeloid associated differentiation marker) [110], CBS (cystathionine beta-synthase) [111], GPX1 [112], SIAH2 [113], PRDX2 [114], RDH8 [115], CYP11B2 [116], RARRES2 [117], NOX1 [118], IL33 [119], OTC (ornithine transcarbamylase) [120], CYP1A1 [121], NFATC4 [122], TSLP (thymic stromal lymphopoietin) [123], WNT4 [124], MGP (matrix Gla protein) [125], FGFBP1 [126], GHR (growth hormone receptor) [127], ERBB3 [128], GFAP (glial fibrillary acidic protein) [129], CCDC40 [130], CACNB2 [131], CD34 [132], NOTCH3 [133], TERT (telomerase reverse transcriptase) [134], GNB3 [135], TP73 [136], RYR2 [137], ENPEP (glutamyl aminopeptidase) [138], SCN7A [139], WNK4 [140], SFRP5 [141], GDF15 [142], CAV1 [143], KCNA5 [144], FOXC1 [145], ASIC1 [146], VASH2 [147], CXCL8 [148], PAPPA2…”

Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension

“…However, increased GRK4 activity per se may impair D 1 R [140] and D 3 R function [137]. The GRK4 locus 4p16.3 is linked to hypertension [141] and GRK4 polymorphisms (rs2960306, rs1024323, rs1801058, rs1644731, and rs1557213) are associated with hypertension and the response to anti-hypertensive medications in several ethnic groups [141][142][143][144][145][146][147][148][149][150]. The positive association of GRK4 polymorphisms and hypertension is not found in all reports, which may be related to not testing for all the aforementioned GRK4 polymorphisms or their interactions with other genes, eg, NOS3 and GRK4 rs2960306 [151,152], GNB3, AGT, and GRK4 rs1801058 [152], and GRK4 rs1801058 and ADD1 rs4961 [142].…”