Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Wang, Z.; Chen, H.; Bartz, Traci M.; Bielak, Lawrence F.; Chasman, Daniel I.; Feitosa, M. F.; Franceschini, Nora; Guo, Xiuqing; Lim, Elise; Noordam, Raymond; Richard, Melissa A.; Wang, H.; Cade, Brian E.; Cupples, L. Adrienne; Vries, Paul S. de; Giulanini, Franco; Lee, J.; Lemaître, Rozenn N.; Martin, Lisa W.; Reiner, Alexander P.; Rich, Stephen S.; Schreiner, Pamela J.; Sitlani, Colleen M.; Smith, Jennifer A.; Dijk, Ko Willems van; Yao, Jie; Zhao, Wei; Fornage, Myriam; Kardia, Sharon L.R.; Kooperberg, Charles; Liu, Ching‐Ti; Mook‐Kanamori, Dennis O.; Province, Michael A.; Psaty, Bruce M.; Redline, Susan; Ridker, Paul M.; Rotter, Jerome I.; Boerwinkle, Eric; Morrison, Alanna C.

doi:10.1101/561225

Cited by 3 publications

(6 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The only cardiovascular-related traits showing any association with variants at the SOST locus were circulating triglyceride and HDL levels. This association has been reported multiple times previously and attributed to a nearby gene, CD300LG (38-45), approximately 100kb upstream of the SOST gene. A functional missense variant in CD300LG (rs72836561, Arg82Cys) drives the associations in this region (43).…”

Section: Discussionsupporting

confidence: 69%

“…rs9899889 was associated with lower triglyceride levels and higher HDL cholesterol and apolipoprotein A levels (Tables S6). There is a known genetic association with these lipid measures with the nearby CD300LG gene (38-45), in particular with its missense variant rs72836561, and after adjusting the rs9899889 lipid results for rs72836561 there were no longer any significant associations (all p-values > 0.05; Table S6). Moreover, with this adjustment the associations with cardiovascular phenotypes are in-line with what would be expected by chance, with all the circulatory associations either falling within or nearby the 95% confidence interval (94.2% of the associations fall within the confidence interval) in the quantile-quantile plot (Figure 3b(iii)).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Holdsworth

Staley

Hall

et al. 2020

Preprint

View full text Add to dashboard Cite

The sclerostin antibody romosozumab increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density and bone strength, and reduced fracture risk. In a clinical study versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) events driven by an increase in myocardial infarction (MI) and stroke was observed.To investigate whether inhibition of sclerostin in atherosclerotic plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability. Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenome-wide association study (PheWAS).Sclerostin expression was absent (67%) or reduced in atherosclerotic plaques and when present was in deeper regions of the plaque/wall and not in areas considered relevant to plaque stability (fibrous cap and endothelium). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between sclerostin inhibition and increased risk of serious cardiovascular events.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Holdsworth

Staley

Hall

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The only cardiovascular‐related traits showing any association with variants at the SOST locus were circulating triglyceride and HDL levels. This association has been reported multiple times previously and attributed to a nearby gene, CD300LG , ( 68–75 ) approximately 100 kb upstream of the SOST gene. A functional missense variant in CD300LG (rs72836561, Arg82Cys) drives the associations in this region.…”

Section: Discussionsupporting

confidence: 69%

“…The risk of major adverse cardiovascular events ((MACE): stroke, myocardial infarction or cardiovascular death) increases with age (60)(61)(62) . To assess the influence of age on sclerostin staining or endarterectomy location, sclerostin staining was stratified for comparison in women younger than 75 respectively). In contrast, plaques were more frequently collected from the femoral/iliac arteries of patients in the younger cohort (39/50; 78%) and sclerostin expression was slightly more frequently observed in these samples: 18% compared with 9% staining positive for the older group.…”

Section: Biobankmentioning

confidence: 99%

“…rs9899889 was associated with lower triglyceride levels and higher HDL cholesterol and apolipoprotein A levels (Tables S6). There is a known genetic association with these lipid measures with the nearby CD300LG gene (68)(69)(70)(71)(72)(73)(74)(75) , in particular with its missense variant rs72836561, and after adjusting the rs9899889 lipid results for rs72836561 there were no longer any significant associations (all p-values > 0.05; Table S6). Moreover, with this adjustment the associations with cardiovascular phenotypes are in-line with what would be expected by chance, with all the circulatory associations either falling within or nearby the 95% confidence interval (94.2% of the associations fall within the confidence interval) in the quantilequantile plot (Figure 3b (Figure 4b).…”

Section: Exploration Of Phenotypes Of Genetic Variants Associated Witmentioning

confidence: 99%

See 1 more Smart Citation

Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Holdsworth

Staley

Hall

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Inhibition of sclerostin increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density and bone strength, and reduced fracture risk. In a clinical study of the sclerostin antibody romosozumab versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) adverse events driven by an increase in myocardial infarction (MI) and stroke was observed. To explore whether there was a potential mechanistic plausibility that sclerostin expression, or its inhibition, in atherosclerotic (AS) plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability in 94 carotid and 50 femoral AS plaques surgically collected from older female patients (mean age 69.6 ±10.4 years), sclerostin staining was absent in most plaques (67%) and when detected, it was of reduced intensity compared with normal aorta, and was located in deeper regions of the plaque/wall but was not observed in areas considered relevant to plaque stability (fibrous cap and endothelium). Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenome-wide association study (PheWAS). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between the presence of sclerostin, or its inhibition, in the vasculature and increased risk of serious cardiovascular events.

show abstract

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Yang

Jackson

Smith

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

show abstract

Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Abstract: current word count 268, AJCN limit: 300): 1 Background: Alcohol intake influences plasma lipid levels and such effects may be 2

Cited by 3 publications

References 60 publications

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Contact Info

Product

Resources

About