Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent received.The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic treatment.As is the case in other conditions,individual genetic variants may partially explain a higher risk of DAEs.AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.METHODS We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,respectively.The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of DAEs.Thereafter,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and AHT.The value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of DAE development.CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2(rs4762)gene variant.If validated in other anti-oncogenic treatments,it might be considered a good prognosis marker.

上海某区人群AT1R和AGT基因多态与肾功能指标的相关性

[目的]探讨血管紧张素Ⅱ1型受体（angiotensin Ⅱ type Ⅰ receptor,AT1R）、血管紧张素原（angiotensinogen,AGT）基因多态性与肾功能等临床指标的关系。[方法]多阶段随机抽取2 026例上海市浦东新区20-80岁的社区居民为研究对象,排除服用降压药、降脂药和有亲缘关系者。收集人口学资料和生活方式等信息;测量身高、体重;检测血肌酐、尿肌酐及尿微量白蛋白等指标;计算尿白蛋白/肌酐比值（albumin-to-creatinine ratio,ACR）和肾小球滤过率（estimated glomerular filtration rate,eGFR）;应用聚合酶链-高温连接酶连接检测技术（PCR-LDR）检测基因多态性。[结果]2 026例成年人群中,AT1R A1166C和AGT rs699不同基因型在性别构成、年龄均值及吸烟和饮酒的比例上差异均无统计学意义（P〉0.05）。所有研究对象按性别分层,上述位点尿肌酐、尿白蛋白、血肌酐、ACR、eGFR均值,及白蛋白尿和肾功能下降的比例两类基因型间差异均无统计学意义（P〉0.05）;按年龄分层,45岁及以上人群AT1R A1166C AA基因型的eGFR均值低于AC/CC基因型,差异有统计学意义（P〈0.05）。logistic回归分析结果未发现基因型与白蛋白尿或肾功能下降有关联。广义线性模型分析结果也未发现两种突变等位基因携带之间的交互效应（P〉0.05）;以eGFR为应变量时,AT1R A1166C C等位基因携带与年龄组间交互项有统计学意义（P=0.039）,进一步按年龄组分层,AA与AC/CC之间差异无统计学意义（P〉0.05）。[结论]对于所有对象,未发现AT1R A1166C和AGT rs699多态性与肾功能指标的统计学关联,而中老年人群AT1R A1166C C等位基因突变与eGFR增高有统计上的关联。