scholarly journals Critically ill COVID-19 status associated trait genetics reveals CDK6 inhibitors as potential treatment

2021 ◽  
Author(s):  
Joern Klinger ◽  
Charles Ravarani ◽  
Colin Bannard ◽  
Margaretha Lamparter ◽  
Alexander Schwinges ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Critically Ill ◽  
Body Mass ◽  
Drug Target ◽  
Clinical Evidence ◽  
Drug Repurposing ◽  
Cell Types ◽  
Selective Treatment ◽  
Reactive Protein ◽  
Prior Literature

Abstract Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing – the use of an already existing drug for a new indication – could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we matched critically ill COVID-19 cases with healthy controls and screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index. Significant differences in traits that have been associated with critically ill COVID-19 status in prior literature, such as alanine aminotransferase, body mass index, C-reactive protein, and neutrophil cell count, were further investigated. In-depth statistical analysis of COVID-19 associated traits and their genetics using regression modeling and propensity score stratification identified cyclin-dependent kinase 6 (CDK6) as a more promising drug target for the selective treatment of critically ill COVID-19 patients than the previously reported interleukin 6. Four existing CDK6 inhibitors -- abemaciclib, ribociclib, trilaciclib, and palbociclib -- have been approved for the treatment of breast cancer. Clinical evidence for CDK6 inhibitors in treating critically ill COVID-19 patients has been reported. Further clinical investigations are ongoing.

scholarly journals Critically ill COVID-19 associated trait genetics reveals CDK6 inhibitors as potential treatment

2021 ◽  
Author(s):  
Joern E. Klinger ◽  
Charles N. J. Ravarani ◽  
Colin Bannard ◽  
Margaretha R. J. Lamparter ◽  
Alexander R. E. C. Schwinges ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Critically Ill ◽  
Body Mass ◽  
Drug Target ◽  
Clinical Evidence ◽  
Drug Repurposing ◽  
Cell Types ◽  
Reactive Protein ◽  
The Uk ◽  
Propensity Score Stratification

Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing, the use of an already existing drug for a new indication, could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to the lack of clinical evidence. We here report on a methodology to find and test gene drug target candidates for drug repurposing. We matched critically ill COVID-19 cases from the UK Biobank with healthy controls and screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index in cases and controls. Significant differences in traits that have previously been associated with critically ill COVID-19 status, such as alanine aminotransferase, body mass index, C-reactive protein, and neutrophil cell count were further investigated. In-depth statistical analysis of COVID-19 associated traits and their genetics using regression modeling and propensity score stratification identified cyclin-dependent kinase 6 (CDK6) as a more promising drug target to selectively treat critically ill COVID-19 patients than the previously reported interleukin 6. Four existing CDK6 inhibitors abemaciclib, ribociclib, trilaciclib, and palbociclib have been approved for breast cancer. Clinical evidence for CDK6 inhibitors in treating critically ill COVID-19 has been reported. Further clinical investigations are ongoing.

Body Mass Index, but Not Physical Activity, Is Associated with C-Reactive Protein

2003 ◽  
Vol 35 (7) ◽  
pp. 1160-1166 ◽  
Author(s):  
ERIC S. RAWSON ◽  
PATTY S. FREEDSON ◽  
STAVROULA K. OSGANIAN ◽  
CHARLES E. MATTHEWS ◽  
GEORGE REED ◽  
...  
Keyword(s):  
Physical Activity ◽  
Body Mass Index ◽  
Body Mass ◽  
C Reactive Protein ◽  
Reactive Protein

Body Mass Index Is Associated With Hospital Mortality in Critically Ill Patients

2013 ◽  
Vol 41 (8) ◽  
pp. 1878-1883 ◽  
Author(s):  
Peter Pickkers ◽  
Nicolette de Keizer ◽  
Joost Dusseljee ◽  
Daan Weerheijm ◽  
Johannes G. van der Hoeven ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Hospital Mortality ◽  
Critically Ill ◽  
Body Mass ◽  
Critically Ill Patients

Serum C reactive protein levels and genetic variation in the CRP gene are not associated with the prevalence, incidence or progression of osteoarthritis independent of body mass index

2010 ◽  
Vol 69 (11) ◽  
pp. 1976-1982 ◽  
Author(s):  
Hanneke J M Kerkhof ◽  
Sita M A Bierma-Zeinstra ◽  
Martha C Castano-Betancourt ◽  
Moniek P de Maat ◽  
Albert Hofman ◽  
...  
Keyword(s):  
Systematic Review ◽  
Body Mass Index ◽  
Genetic Variation ◽  
Body Mass ◽  
Analysis Of Covariance ◽  
C Reactive Protein ◽  
Knee Oa ◽  
Reactive Protein ◽  
Serum Crp ◽  
The Relationship

ObjectiveTo study the relationship between serum C reactive protein (CRP) levels, genetic variation in the CRP gene and the prevalence, incidence and progression of radiographic osteoarthritis (ROA) in the Rotterdam Study-I (RS-I). A systematic review of studies assessing the relationship between osteoarthritis (OA) and CRP levels was also performed.MethodsThe association between CRP levels and genetic variation in the CRP gene and ROA was examined in 861 patients with hand OA, 718 with knee OA, 349 with hip OA and 2806 controls in the RS-I using one-way analysis of covariance and logistic regression, respectively. PubMed was searched for articles published between January 1992 and August 2009 assessing the relationship between CRP levels and OA.ResultsIn RS-I the prevalence of knee OA, but not hip OA or hand OA, was associated with 14% higher serum CRP levels compared with controls (p=0.001). This association disappeared after adjustment for age and especially body mass index (BMI) (p=0.33). Genetic variation of the CRP gene was not consistently associated with the prevalence, incidence or progression of OA within RS-I. The systematic review included 18 studies (including RS-I) on serum CRP levels and the prevalence, incidence or progression of OA. Consistently higher crude CRP levels were found in cases of prevalent knee OA compared with controls. No association was observed between serum CRP levels and the prevalence of knee OA following adjustment for BMI (n=3 studies, meta-analysis p value=0.61).ConclusionThere is no evidence of association between serum CRP levels or genetic variation in the CRP gene with the prevalence, incidence or progression of OA independent of BMI.

C-reactive Protein, Body Mass Index, and Diabetic Retinopathy

2010 ◽  
Vol 51 (9) ◽  
pp. 4458 ◽  
Author(s):  
Laurence Shen Lim ◽  
E. Shyong Tai ◽  
Paul Mitchell ◽  
Jie Jin Wang ◽  
Wan Ting Tay ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Diabetic Retinopathy ◽  
Body Mass ◽  
Protein Body ◽  
C Reactive Protein ◽  
Reactive Protein

scholarly journals The Metabolic Phenotype of Prader-Willi Syndrome (PWS) in Childhood: Heightened Insulin Sensitivity Relative to Body Mass Index

2011 ◽  
Vol 96 (1) ◽  
pp. E225-E232 ◽  
Author(s):  
Andrea M. Haqq ◽  
Michael J. Muehlbauer ◽  
Christopher B. Newgard ◽  
Steven Grambow ◽  
Michael Freemark
Keyword(s):  
Body Mass Index ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
Density Lipoprotein ◽  
High Sensitivity ◽  
Metabolic Phenotype ◽  
Prader Willi Syndrome ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Total Adiponectin

Context: Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC, but different from those of OCs. Results: Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P < 0.05) and similar to LC. Moreover, high-density lipoprotein levels were lower and triglycerides higher in OCs (P < 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P < 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P < 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1, macrophage chemoattractant protein-1, TNFα, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or alanine aminotransferase. Conclusions: The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high-sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease.

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