Association Between Genetic Variation And Young Secondary Hypertension

Part ?:Adrenocortical monogenic hypertension in young Chinese hypertensive cohort Background and objectives:Adrenocortical monogenic hypertension is a consequence of abnormal biosynthesis,metabolism or action of steroid hormones.The adrenocortical monogenic hypertension included familial aldosteronism(FH),congenital adrenal hyperplasia(CAH),apparent mineralocorticoid excess syndrome(AME)and glucocorticoid resistance syndrome(GR).It has been reported that genetic causes play important role in the pathogenesis of these diseases,but no data were available for Chinese patients.In this study,we screened the genetic variants and linked these variants with clinic phenotype in a young hypertensive cohort.Methods:We recruited 280 hypertensives with age less than 40 years old when diagnosed as hypertension.Secondary causes of hypertension other than hyperaldosteronism were excluded.A candidate approach was explored and adrenocortical monogenic hypertension pathogenic genes were included.All exons and flanking introns of five genes-KCNJ5,CYP11B1,CYP17A1,HSD11B2 and NR3C1-were sequenced and bioinformatic analysis were used to analyse the variants.Long distance PCR was used to detect CYP11B1/CYP11B2 chimeric gene.Variants with a minor allele frequency<1%and bioinformatic analysis proved probably damaging were defined as rare variants.Pedigree analysis were performed for patients with rare variants and genotype-phenotype analysis were performed.Results:Fifteen kinds of rare variants were identified in 14 patients.One patient was compound heterozygous in the CYP17A1(C183Y and T390R)gene and proved to be atypical congenital adrenal hyperplasia.Thirteen patients with heterozygotic rare variants in KCNJ5,CYP11B1,CYP17A1,HSD11B2 and NR3C1 were compared with patients without rare variants.The ages of hypertension onset in rare variant heterozygots were younger(21.20±6.83 vs.28.61±8.31 years old,p=0.01)and the blood pressure were higher(142.17±12.43 vs.138±18.2 mm Hg,p=0.018)than those didn' t carry rare variants.Rare variant heterozygots had higher rate of early-onset hypertension and stroke family history(30.8%vs.6.4%,p=0.011).No significant differences were found in serum potassium,serum renin,aldosterone,target organ damage and cardiovascular complications between rare carriers and non-carriers.Rare variants heterozygotes of recessive traits congenital adrenal hyperplasia and glucocorticoid resistance syndrome-CYP17A1,CYP11B1 and NR3C1 rare variant carriers-didn' t have congenital adrenal hyperplasia and glucocorticoid resistance syndrome phenotypes,however,compared to the control group,the serum free corticosterone were higher(10.36(5.72,11.58)vs.1.86(0.77,6.74)ng/ml,p=0.007).Serum 11-desoxycortone of CYP17A1,CYP11B1 and NR3C1 rare variant carriers were slightly higher than non-carrier controls,but the difference didn' t reach statistically significance(0.66(0.30,1.27)vs.(0.60(0.21,0.93)ng/ml,p=0.057).Conclusions:Our findings indicate that some atypical congenital adrenal hyperplasia individuals were phenotypically indistinguishable.Next generation sequencing is a useful tool in diagnosis of monogenic hypertension patients with less obvious phenotype.Rare KCNJ5,CYP11B1,CYP17A1?HSD11B2 and NR3C1 variants may be associated with the onset of hypertension in young people and higher blood pressure.Rare variants carriers of CYP17A1,CYP11B1 and NR3C1 may have more mineralocorticoid precursor than non-carriers.Part ?:Susceptibility of Takayasu arteritis and gene polymorphisms in Chinese Han population Background and objectives:Takayasu arteritis is a rare inflammatory arteriopathy of unknown aetiology.It commonly involves the aorta and its main branches.Stenosis of renal artery,thoracic aorta or abdominal aorta can result in hypertension in young patients.The aim of this study was to investigate the relationship between several gene polymorphisms and susceptibility of Takayasu arteritis in Chinese Han population.Methods:Four single nucleotide polymorphisms locate in the IL12B region(rs56167332),the MLX region(rs665268),the FCGR2A1/FCGR3A locus(rs10919543)and the HLA-B/MICA locus(rsl2524487),which were reported recently associated with Takayasu arteritis in different populations,were genotyped in 123 Chinese Takayasu arteritis patients and 147 healthy controls.Results:Among the four SNPs,rs10919543 was found to be significantly associated with Takayasu arteritis in the studied population.The GG genotype of rs10919543 at the FCGR2A/FCGR3A locus increase the risk of Takayasu arteritis(OR=6.532,95%CI=2.402-17.763,p<0.001).Among Takayasu arteritis patients,the level of eosinophil granulocytes in the peripheral blood was higher in the GG group of rs10919543(n=23,Eos=0.11(0.08-0.17)×109/L)than in the GA+AA group(n=100,Eos=0.08(0.05-0,13)× 109/L,p=0.028).No correlation was observed between the genotypes of the other 3 SNPs and Takayasu arteritis patients.Conclusion:Our findings revealed GG genotype of rs10919543 at FCGR2A/FCGR3A locus confered high risk of Takayasu arteritis in Chinese population.FCGR2A polymorphisms have been reported to be related with hypomethylation and alteration in autoantibody clearance.FCGR2A and FCGR3A were proved to be associated with susceptibility for several autoimmune diseases.This study provides further evidence to suggest that humoral immunity could be a mechanism in the onset of Takayasu arteritis.Further work is required on this region to confirm the role of FCGR2A and FCGR3A gene in Takayasu arteritis etiology.