Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

Beecham, Ashley; Wang, Liyong; Blanton, Susan H.; Guo, Shengru; Rundek, Tatjana; Sacco, Ralph L.

doi:10.1371/journal.pone.0167202

Cited by 4 publications

(6 citation statements)

References 47 publications

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“…Therefore, care must be taken to translate results from experimental mouse studies on atherosclerosis to patients. However, a genome-wide association study has already shown that a rare variant of NOD1 is associated with intima-media thickness in patients [11] suggesting a potential role for the NOD pathway in cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis

et al. 2020

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Atherosclerosis is crucially fueled by inflammatory pathways including pattern recognition receptor (PRR)-related signaling of the innate immune system. Currently, the impact of the cytoplasmic PRRs nucleotide-binding oligomerization domaincontaining protein (NOD) 1 and 2 is incompletely characterized. We, therefore, generated Nod1/Nod2 double knockout mice on a low-density lipoprotein receptor (Ldlr)-deficient background (= Ldlr −/− Nod1/2 −/−) which were subsequently analyzed regarding experimental atherosclerosis, lipid metabolism, insulin resistance and gut microbiota composition. Compared to Ldlr −/− mice, Ldlr −/− Nod1/2 −/− mice showed reduced plasma lipids and increased hepatic expression of the scavenger receptor LDL receptor-related protein 1 after feeding a high-fat diet for 12 weeks. Furthermore, intestinal cholesterol and its bacterial degradation product coprostanol were elevated in Ldlr −/− Nod1/2 −/− mice, correlating with the increased abundance of Eubacterium coprostanoligenes as assessed by 3rd generation sequencing of the gut microbiota. Atherosclerotic plaques of Ldlr −/− Nod1/2 −/− mice exhibited less lipid deposition and macrophage accumulation. Moreover, macrophages from Ldlr −/− Nod1/2 −/− mice showed higher expression of the cholesterol efflux transporters Abca1 and Abcg1 and accordingly reduced foam cell formation. Deficiency of Nod1 and Nod2 led to reduced plaque lipid deposition and inflammatory cell infiltration in atherosclerotic plaques. This might be explained by diminished plasma lipid levels and foam cell formation due to altered expression of key regulators of the hepatic cholesterol pathway as well as differential intestinal cholesterol metabolism and microbiota composition.

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Section: Discussionmentioning

confidence: 99%

Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis

et al. 2020

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“…98 Some studies report the association between oligomerization domain-containing protein 1 genotypes and susceptibility to cerebrovascular diseases. 99 However, these links between SNPs and cerebrovascular diseases are controversial for different ethnicities, implying that combination of microbiome and genome-wide association studies, called “mGWAS,” is essential to unravel the complexity of cerebrovascular diseases. 100…”

Section: Future Directionsmentioning

confidence: 99%

Microbiota in cerebrovascular disease: A key player and future therapeutic target

Tonomura

Ihara

Friedland

2020

J Cereb Blood Flow Metab

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Stroke is the second leading cause of death and a significant cause of disability worldwide. Recent advances in DNA sequencing, proteomics, metabolomics, and computational tools are dramatically increasing access to the identification of host–microbiota interactions in systemic diseases. In this review, we describe the accumulating evidence showing how human microbiota plays an essential role in cerebrovascular diseases. We introduce the symbiotic relationships between microbiota and the mucosal immune system, focusing on differences by anatomical sites. Microbiota directly or indirectly contributes to the pathogenesis of traditional vascular risk factors including age, obesity, diabetes mellitus, dyslipidemia, and hypertension. Moreover, recent studies proposed independent effects of the microbiome on the progression of various subtypes of stroke through direct microbial invasion, exotoxins, functional amyloids, inflammation, and microbe-derived metabolites. We propose the critical concept of gene-microbial interaction to elucidate the heterogeneity of stroke and provide possible therapeutic avenues. We suggest ways to resolve the vast inter-individual diversity of cerebrovascular disease and mechanisms for personalized prevention and treatment.

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“…A total of 34 families with a family-specific LOD score >0.1 at one of the four QTLs for plaque located at chromosomes 7q36, 11p15, 14q32 and 15q23, were selected for our current study; 12 families were sequenced as part of our discovery analyses and 22 families were genotyped on the Exome Array for our replication analyses. Details of the family selection have been published previously [ 12 ]. Additional replication analyses were performed using an independent sample of 556 unrelated Dominicans from NOMAS.…”

Section: Methodsmentioning

confidence: 99%

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families

et al. 2022

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Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

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Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

Cited by 4 publications

References 47 publications

Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis

Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis

Microbiota in cerebrovascular disease: A key player and future therapeutic target

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families

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