Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

Ding, Keyue; Feng, Deng; Andrade, Mariza de; Mosley, Thomas H.; Turner, Stephen T.; Boerwinkle, Eric; Kullo, Iftikhar J.

doi:10.1038/sj.jhh.1002297

Cited by 14 publications

(18 citation statements)

References 61 publications

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“…A GWAS of normotensive African Americans identified a suggestive (p=5.73×10 −6 ) association between DBP and rs2823756 on chromosome 21q21.1 (4 Mb from our marker D21S1437) 18 . Perhaps clues about potential candidate genes can be gleaned from the suggestive bivariate linkage evidence (LOD=3.03) of D21S1437 on chromosome 21q21.1 (13.05 cM) with C-reactive protein (CRP) and fibrinogen in GENOA Caucasians 30 . Both CRP and fibrinogen are inflammation indicators and predictors of cardiovascular disease 31-32 .…”

Section: Discussionmentioning

confidence: 99%

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Five Blood Pressure Loci Identified by an Updated Genome-Wide Linkage Scan: Meta-Analysis of the Family Blood Pressure Program

Simino

Kume

et al. 2011

American Journal of Hypertension

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Background A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension. Methods We performed one overall and 4 race-specific meta-analyses of genome-wide blood pressure linkage scans using data on 4,226 African American, 2,154 Asian, 4,229 Caucasian, and 2,435 Mexican American participants (total N=13,044). Variance components models were fit to measured (raw) blood pressure levels and two types of antihypertensive medication adjusted blood pressure phenotypes within each of 10 subgroups defined by race and network. A modified Fisher's method was used to combine the p-values for each linkage marker across the 10 subgroups. Results Five quantitative trait loci (QTLs) were detected on chromosomes 6p22.3, 8q23.1, 20q13.12, 21q21.1, and 21q21.3 based on significant linkage evidence (defined by logarithm of odds (LOD) score ≥3) in at least one meta-analysis and LOD scores ≥1 in at least 2 subgroups defined by network and race. The chromosome 8q23.1 locus was supported by Asian-, Caucasian-, and Mexican-American-specific meta-analyses. Conclusions The new QTLs reported justify new candidate gene studies. They may help support results from genome-wide association studies (GWAS) that fall in these QTL regions but fail to achieve the genome-wide significance.

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Section: Discussionmentioning

confidence: 99%

“…Both CRP and fibrinogen are inflammation indicators and predictors of cardiovascular disease 31-32 . CRP inhibits endothelial nitric oxide synthase expression, while fibrinogen helps determine plasma viscosity 30 and is a member of the coagulation cascade.…”

Section: Discussionmentioning

confidence: 99%

Five Blood Pressure Loci Identified by an Updated Genome-Wide Linkage Scan: Meta-Analysis of the Family Blood Pressure Program

Simino

Kume

et al. 2011

American Journal of Hypertension

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“…Heritability is likely to explain a larger portion of the variation[27], and has been recently linked to several distinct chromosomal regions[28]. The rest of the variation likely reflected a combination of measurement error, within-individual variation and unmeasured environmental factors such as diet and lifestyle that may influence CRP levels.…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein among community-dwelling hypertensives on single-agent antihypertensive treatment

Fülöp

Rule

Schmidt

et al. 2009

Journal of the American Society of Hypertension

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Background C-reactive protein is a predictor of adverse cardiovascular outcomes. The effect of antihypertensive therapy on C-reactive protein levels is largely unknown. Method We undertook a cross-sectional study of CRP levels among participants with primary hypertension on single-agent anti-hypertensive therapy in the community-based biracial Genetic Epidemiology Network of Arteriopathy cohort. Linear regression models were used to assess the association of anti-hypertensive medication class with log-transformed C-reactive protein after adjustment for age, gender, ethnicity, body mass index, smoking, diabetes, HMG-Co-A reductase inhibitor use, achieved blood pressure control (<140/90 mmHg), serum creatinine and urine albumin-to-creatinine ratios. Results There were 662 participants in the cohort taking single-agent therapy for hypertension. Median C-reactive protein levels differed across participants: 0.40 mg/dL for those on diuretics, 0.34 mg/dL on calcium channel blockers, 0.25 mg/dL on beta blockers and 0.27 mg/dL on renin-angiotensin-aldosterone system inhibitors (p<0.001). With multivariable adjustment, the group on renin-angiotensin-aldosterone system inhibitors had a 20% lower mean CRP on average than the group on diuretics (p=0.044), differences between other medication classes were not apparent. Heart rate had a strong association with C-reactive protein (p < 0.001). Conclusions Antihypertensive medication class may influence inflammation, particularly in patients on RAAS inhibitors.

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“…According to the US National Center for Biotechnology Information (NCBI) Gene database (http://www.ncbi.nlm.nih.gov/gene/), the potential candidate genes are diverse, coding for parts of the major histocompatibility complex (HLA-A and HLA-B); angiopoietin involved in vascular development and angiogenesis (ANGPT1); a zinc-finger protein (ZFPM2); a cytokine that increases production of both angiotensin II and endothelin-1 (TNFα); a voltage-gated potassium channel with a role in insulin secretion, heart regulation, and neurotransmitter release (KCNB1); an enzyme producing prostacyclin (a vasodilator and inhibitor of platelet aggregation, PTGIS); a signal transduction protein that may play a role in insulin sensitivity (YWHAZ); and a protein that may prevent oxidative damage (OXR1). The chromosome 21 QTLs had external support [60,[66][67][68][69] but lacked strong candidate genes (although this region has been moderately linked to two markers of inflammation, C-reactive protein and fibrinogen [70]). …”

Section: Genome-wide Linkage Scansmentioning

confidence: 98%

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

2011

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Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.

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Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

Cited by 14 publications

References 61 publications

Five Blood Pressure Loci Identified by an Updated Genome-Wide Linkage Scan: Meta-Analysis of the Family Blood Pressure Program

Five Blood Pressure Loci Identified by an Updated Genome-Wide Linkage Scan: Meta-Analysis of the Family Blood Pressure Program

C-reactive protein among community-dwelling hypertensives on single-agent antihypertensive treatment

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

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