Emilin1 gene and essential hypertension: a two-stage association study in northern Han Chinese population

Abstract

BackgroundElastogenesis of elastic extracellular matrix (ECM) which was recognized as a major component of blood vessels has been believed for a long time to play only a passive role in the dynamic vascular changes of typical hypertension. Emilin1 gene participated in the transcription of ECM's formation and was recognized to modulate links TGF-β maturation to blood pressure homeostasis in animal study. Recently relevant advances urge further researches to investigate the role of Emilin1 gene in regulating TGF-β signals involved in elastogenesis and vascular cell defects of essential hypertension (EH).MethodsWe designed a two-stage case-control study and selected three single nucleotide polymorphisms (SNPs), rs3754734, rs2011616 and rs2304682 from the HapMap database, which covered Emilin1 gene. Totally 2,586 subjects were recruited from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). In stage 1, all the three SNPs of the Emilin1 gene were genotyped and tested within a subsample including 503 cases and 490 controls, significant SNPs would enter into stage 2 including 814 cases with hypertension and 779 controls and analyze on the basis of testing total 2,586 subjects.ResultsIn stage 1, single locus analyses showed that SNPs rs3754734 and rs2011616 had significant association with EH (P < 0.05). In stage 2, weak association for dominant model were observed by age stratification and odds ratio (ORs) of TG+GG vs. TT of rs3754734 were 0.768 (0.584-1.009), 0.985 (0.735-1.320) and 1.346 (1.003-1.806) in < 50, 50-59 and ≥ 60 years group and ORs of GA+AA vs. GG of rs2011616 were 0.745 (0.568-0.977), 1.013 (0.758-1.353) and 1.437 (1.072-1.926) in < 50, 50-59 and ≥ 60 years group respectively. Accordingly, significant interactions were detected between genotypes of rs3754734 and rs2011616 and age for EH, and ORs were 1.758 (1.180-2.620), P = 0.006 and 1.903 (1.281-2.825), P = 0.001, respectively. Results of haplotypes analysis showed that there weren't any haplotypes associated with EH directly, but the interaction of hap2 (GA) and age-group found to be significant after being adjusted for the covariates, OR was 1.220 (1.031-1.444), P value was 0.020.ConclusionOur findings don't support positive association of Emilin1 gene with EH, but the interaction of age and genotype variation of rs3754734 and rs2011616 might increase the risk to hypertension.

Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

“…In fact, recent association studies have suggested that specific haplotypes of EMILIN1 are useful genetic markers of essential hypertension in Japanese men and that the interaction of age and genotype variation of specific single nucleotide polymorphisms might increase the risk of hypertension in a northern Han Chinese population. 6,7 Here, we have addressed the question of the cellular context of Emilin-1 activity using a phenotype rescue approach by expressing the protein in either ECs or VSMCs or in all cells of the arterial wall of Emilin1 −/− mice. Our results indicate that Emilin-1 expression in VSMCs is specifically required for BP control and further clarify that the protein regulates the arteriolar myogenic response through TGF-β.…”

Association of intronic single-nucleotide polymorphisms in the EMILIN1 gene with essential hypertension in a Chinese population

“…The present study in Singaporean Chinese subjects (mean age below 50 years) observed a similar association of EH with rs2011616 (Table 3) as found in northern Han Chinese subjects aged o50 years. 28 Similarly, the Japanese study by Shimodaira et al in hypertensive patients and controls without FHH showed a genotypic association of EH with the G allele (AG/ GG genotype) of rs2011616. 15 The present study also detected an association of the G allele of rs2011616 with hypertension.…”

“…We identified rs7424556 after screening for genetic variants. Shen et al 28 and Shimodaira et al 15 might have missed rs7424556, because they selected their SNPs from public databases, such as those of the International HapMap Project and the NCBI.…”

“…The study by Shen et al showed that northern Han Chinese aged 460 years with the A allele (AG/ AA genotype) of rs2011616 had increased risk for hypertension, but persons aged o50 years had a decreased risk. 28 This discrepant allelic effect on the BP is difficult to interpret. The present study in Singaporean Chinese subjects (mean age below 50 years) observed a similar association of EH with rs2011616 (Table 3) as found in northern Han Chinese subjects aged o50 years.…”

Association study of AGER gene polymorphism and hypertension in Han Chinese population

“…Recently, several genes were reported to be involved in blood pressure regulation and the susceptibility to hypertension modulated by age (Dao et al, 2005;Lunetta et al, 2007;Shen et al, 2009;Shi et al, 2009). Furthermore, the statistical analysis strategy of age-genetic effects can prevent potential confounding bias modified by age-varying characteristics (Lunetta et al, 2007;Lasky-Su et al, 2008;Percy et al, 2009).…”