The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility.Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression.We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus.Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility.

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The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease

Clinical Science ◽

10.1042/cs20160084 ◽

2016 ◽

Vol 130 (12) ◽

pp. 987-1003 ◽

Cited By ~ 37

Author(s):

Sri N. Batchu ◽

Angela S. Brijmohan ◽

Andrew Advani

Keyword(s):

Cardiovascular Disease ◽

Chronic Disease ◽

Kidney Disease ◽

Neurodegenerative Diseases ◽

Histone Deacetylase ◽

Cellular Function ◽

Histone Deacetylase 6

Despite its name, histone deacetylase 6 (HDAC6) resides primarily in the cytosol and exerts both enzymatic and non-enzymatic effects on cellular function. HDAC6 inhibitors are being investigated for their effects in cancer, neurodegenerative diseases, cardiovascular disease, inflammation and kidney disease.

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Common variants associated with OSMR expression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans

10.1101/576793 ◽

2019 ◽

Author(s):

D. van Keulen ◽

I.D. van Koeverden ◽

A. Boltjes ◽

H.M.G. Princen ◽

A.J. van Gool ◽

...

Keyword(s):

Cardiovascular Disease ◽

Coronary Artery ◽

Coronary Artery Calcification ◽

Carotid Plaque ◽

Multiple Testing ◽

Disease Susceptibility ◽

Oncostatin M ◽

Plaque Vulnerability ◽

Common Genetic Variants ◽

The Impact

Background and aimsOncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility.Methods and resultsWe queried Genotype-Tissue Expression data and found rs13168867 (C allele) and rs10491509 (A allele) to be associated with decreased OSMR and increased LIFR expression in arterial tissue respectively. No variant was significantly associated with OSM expression.We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. rs13168867 was associated with an increased overall plaque vulnerability (β=0.118 ± s.e.=0.040, p=3.00×10−3, C allele) and although not significant after correction for multiple testing, it showed strongest associations with intraplaque fat (β=0.248 ± s.e.=0.088, C allele) and collagen content (β=−0.259 ± s.e.=0.095, C allele). rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus.ConclusionsOur study suggests that genetically decreased arterial OSMR expression contributes to increased carotid plaque vulnerability. However, the OSM signaling pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility as none of the investigated variants associated with cardiovascular diseases.

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