Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

Abstract

Abstract-Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3′-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10 -5 , odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10 -5 , odds ratio [95% confidence interval]=1. 75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. Results Characteristics of PopulationsTwo thousand six hundred thirty patients with EH and 3171 controls of Han Chinese were recruited from 3 geographically independent medical centers in total. The characteristics of these populations are shown in Table 1. In addition to the prevalence of coronary artery disease and diabetes mellitus, the biochemical parameters were significantly different between case and control groups at each center. Although most of the hypertensive patients were treated with antihypertensive drugs, the SBP and diastolic blood pressure remained higher compared with their counterparts (Table 1). Single-Nucleotide Polymorphism Association TestTwenty-nine single-nucleotide polymorphisms (SNPs) from the LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 genes and their flanking sequences were first genotyped in population 1 by multiplex ligation-dependent probe amplification. Twenty-eight SNPs were genotyped successfully. The 28 SNPs are shown in Table S5. The primers used for multiplex ligation-dependent probe amplification and sequencing are listed in Tables S2 and S3. The consistency between 2 genotyping methods was generally >99%. All SNPs passed the Hardy-Weinberg equilibrium test (Table S5). In allelic association analysis, 2 SNPs in the LPAR1 gene, rs2766997 (P=0.037) and rs531003 (P=0.006), exhibited positive signals (P<0.05) associated with EH in population 1 in the regression test adjusted risk factors, including sex, age, body mass index, and diabetes mellitus (Tabl...

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice

“…Both in vitro and in vivo data suggested that LPA We found that the expression of ATX and LPAR1 in the renal cortex of db/db mice was increased compared with wildtype mice, and that ki16425 treatment reduced glomerular injury, which suggested that LPAR1 signaling was involved in the pathogenesis of diabetic nephropathy. It was previously reported that the expression of LPAR1 was increased in white blood cells of patients with essential hypertension, 37 which is a major factor for kidney injury during diabetes progression. 1,3,4 These results indicated that LPAR1 expression was correlated with kidney injury.…”

maLPA1-null mice as an endophenotype of anxious depression

“…In humans, polymorphism in the LPA1 receptor has been related to augmented risk of essential hypertension. Given that stress, the main environmental cause of depression, increases the susceptibility of patients with risk alleles, 69 genetic variants in this receptor may participate in the aetiology of depression. Here, we have identified for we believe the first time the possible relationship of the LPA1 receptor with a mixed depressive-anxiety phenotype, shedding light on the unknown neurobiological basis of this subtype of depression 5 and generating the opportunity to explore a new therapeutic target for the treatment of mood disorders, namely the anxious-depression subtype.…”

Alterations of the Gut Microbiome in Hypertension

“…Moreover, it is believed to be one of the most common comorbidities associated with chronic renal disease (Lash et al, 2009 ), obesity and type 2 diabetes (Landsberg and Molitch, 2004 ; Kotchen, 2010 ). Presently, genome-wide association studies (GWAS) have identified a series of genetic loci and pathways associated with blood pressure (Xu et al, 2015 ; Liu et al, 2016 ). The environmental factors, such as, dietary salt intake, alcohol consumption and lack of exercise, are also linked to the occurrence of hypertension (Fuchs et al, 2001 ; Karppanen and Mervaala, 2006 ).…”