Publication date: 2018

DOI: 10.1093/eurheartj/ehy565.P1534

Background and purpose: Candidate-gene and genome-wide association studies have been successful in discovering new genetic loci associated with hypertension and related traits. However, identifying informative genetic predictors of essential hypertension still remains one of the most important challenges of personalized predictive medicine. Chronic low-grade systemic inflammation and endothelial dysfunction are recognized as the major pathogenic processes driving the development of hypertension. We aimed to identify inflammation-related genetic predictors of essential hypertension using multilocus approach. Methods: We performed comparative analysis of transcriptional activity of inflammatory mediator genes in patients with essential hypertension and healthy normotensive subjects using real-time PCR primer assays (SABiosciences, Qiagen, USA), and genotyped polymorphic markers in 14 differentially expressed chemokine genes (CCL2, CCL8, CCL16, CCL17, CCL18, CXCL1, CXCL8, CXCL13, CCR2, CCR5, CXCR2, CXCR4, CX3CR1, CCL23) in the group of 526 male individuals (212 cases, 314 controls) of Tatar ethnic origin from the Republic of Bashkortostan (Russian Federation). We analyzed associations of chemokine loci with essential hypertension using logistic regression with age and body mass index as covariates under additive genetic model implemented in PLINK software. Multilocus associations were tested with APSampler 3.6.0 using Markov chain Monte-Carlo-based approach. Benjamini-Hochberg procedure was applied to adjust for multiple comparisons. Results: Analyzing polymorphic loci in 14 chemokine genes, we found that CXCL13 rs355689 polymorphism was independently associated with essential hypertension (OR=0.51, PFDR=9.56x10–4 for the C allele). Using multilocus approach, we obtained 2587 patterns associated with essential hypertension. The most informative predictors were CCL17*T + CCL8*C + CX3CR1*T + CXCL13*C (OR=0.17, PFDR=4.08x10–4), CCL2*A + CCL17*T + CCL8*C + CXCL13*C (OR=0.17, PFDR = 2.85x10–4), CXCR4*T + CCL18*C + CCR2*I (OR=8.13, PFDR=0.009), CXCR4*C + CCL17*C/C + CX3CR1*T (OR=2.64, PFDR=0.007). Conclusion: Using single-marker approach, we detected an association between CXCL13 rs355689 polymorphism and essential hypertension. Applying APSampler algorithm, we revealed additional associations of the combinations of the studied loci with hypertension. Our results suggest that multilocus approach is more powerful in identifying genetic predictors of the disease.

Издатель: OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND

Тип: Article