A Missense Genetic Variant in <i>LRRC16A</i>/<i>CARMIL1</i> Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline

Yue, Wei; Tejera, Paula; Wang, Z; Zhang, R; Chen, F; L, Su; Lin, Xinhua; Bajwa, Ednan K.; Bt, Thompson; Dc, Christiani

doi:10.1164/rccm.201605-0946oc

Cited by 35 publications

(27 citation statements)

References 53 publications

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“…variables that are potentially linked, they concluded that LRRC16A variants are associated with ARDS risk and that a portion of the association is via influence of LRRC16A on platelet number (90,92). In a subsequent analysis, these investigators also found that the LRRC16A genotype influences the rate of decline in platelet number in patients with ARDS in the 28 days after ICU admission, as well as that an attenuated platelet count decline is associated with greater survival (89). Mediation analysis was again used to evaluate the relationship of decline in platelet number and the association of an apparent functional LRRC16A SNP with mortality.…”

Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 95%

“…Platelet Numbers Are Altered in Critical Illness, Influence the Outcome of ARDS, and Are Regulated by Genetic Determinants in Clinical ALI Thrombocytopenia is common in critically ill patients at risk for, or with, ARDS and is associated with negative outcomes, including death (4,14,(85)(86)(87)(88)(89)(90). In clinical observations and a model of gram-negative pneumonia with sepsis, thrombocytopenia was associated with dysregulated inflammation and impaired host defense (76,91).…”

Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 99%

“…Recent studies identified genetic variants that appear to alter risk and mortality in ARDS by influencing platelet numbers and their decline (89,90). Wei and colleagues discovered a SNP in the gene for a cytoskeletal scaffold protein that influences actin assembly and disassembly, LRRC16A, and found that it is associated with platelet number (platelet count) and with altered risk for ARDS.…”

Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 99%

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Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

Middleton

Rondina

Schwertz

et al. 2018

Am J Respir Cell Mol Biol

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Platelets are essential cellular effectors of hemostasis and contribute to disease as circulating effectors of pathologic thrombosis. These are their most widely known biologic activities. Nevertheless, recent observations demonstrate that platelets have a much more intricate repertoire beyond these traditional functions and that they are specialized for contributions to vascular barrier integrity, organ repair, antimicrobial host defense, inflammation, and activities across the immune continuum. Paradoxically, on the basis of clinical investigations and animal models of disease, some of these newly discovered activities of platelets appear to contribute to tissue injury. Studies in the last decade indicate unique interactions of platelets and their precursor, the megakaryocyte, in the lung and implicate platelets as essential effectors in experimental acute lung injury and clinical acute respiratory distress syndrome. Additional discoveries derived from evolving work will be required to precisely define the contributions of platelets to complex subphenotypes of acute lung injury and to determine if these remarkable and versatile blood cells are therapeutic targets in acute respiratory distress syndrome.

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Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 95%

Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 99%

Section: Platelets Have Complex Effects On Pulmonary and Systemic Endmentioning

confidence: 99%

See 1 more Smart Citation

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

Middleton

Rondina

Schwertz

et al. 2018

Am J Respir Cell Mol Biol

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“…One SNP, studied in detail, causes a single–amino acid change in the LRR domain, decreased expression of mRNA, increased patient survival, and a decreased rate of platelet loss during the course of the illness (Wei et al , 2017). One potential scenario is that decreased CARMIL1 function impairs the actin cytoskeleton of the platelet, which lessens platelet activation and therefore mitigates the loss of circulating blood platelets.…”

Section: Roles Of Carmils At the Cellular And Organismal Levelsmentioning

confidence: 99%

CARMIL family proteins as multidomain regulators of actin-based motility

Stark

Lanier

Cooper

2017

MBoC

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CARMILs are large multidomain proteins that regulate the actin-binding activity of capping protein (CP), a major capper of actin filament barbed ends in cells. CARMILs bind directly to CP and induce a conformational change that allosterically decreases but does not abolish its actin-capping activity. The CP-binding domain of CARMIL consists of the CP-interaction (CPI) and CARMIL-specific interaction (CSI) motifs, which are arranged in tandem. Many cellular functions of CARMILs require the interaction with CP; however, a more surprising result is that the cellular function of CP in cells appears to require binding to a CARMIL or another protein with a CPI motif, suggesting that CPI-motif proteins target CP and modulate its actin-capping activity. Vertebrates have three highly conserved genes and expressed isoforms of CARMIL with distinct and overlapping localizations and functions in cells. Various domains of these CARMIL isoforms interact with plasma membranes, vimentin intermediate filaments, SH3-containing class I myosins, the dual-GEF Trio, and other adaptors and signaling molecules. These biochemical properties suggest that CARMILs play a variety of membrane-associated functions related to actin assembly and signaling. CARMIL mutations and variants have been implicated in several human diseases. We focus on roles for CARMILs in signaling in addition to their function as regulators of CP and actin.

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“…Our previous study indicated that low platelet count was associated with increased ARDS risk [31] and poor survival [32]. Here, we observed that late-onset patients, who had significantly lower platelet count at the time of ARDS onset, had worse prognosis.…”

Section: Discussionmentioning

confidence: 54%

Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study

et al. 2016

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Purpose To evaluate the association between acute respiratory distress syndrome (ARDS) onset time and prognosis. Methods Patients with moderate to severe ARDS (N = 876) were randomly assigned into derivation (N = 520) and validation (N = 356) datasets. Both 28-day and 60-day survival times after ARDS onset were analyzed. A data-driven cutoff point between early- and late-onset ARDS was determined on the basis of mortality risk effects of onset times. We estimated the hazard ratio (HR) and odds ratio (OR) of late-onset ARDS using a multivariate Cox proportional hazards model of survival time and a multivariate logistic regression model of mortality rate, respectively. Results Late-onset ARDS, defined as onset over 48 h after intensive care unit (ICU) admission (N = 273, 31%), was associated with shorter 28-day survival time: HR = 2.24, 95% CI 1.48–3.39, P = 1.24 × 10−4 (derivation); HR = 2.16, 95% CI 1.33–3.51, P = 1.95 × 10−3 (validation); and HR = 2.00, 95% CI 1.47–2.72, P = 1.10 × 10−5 (combined dataset). Late-onset ARDS was also associated with shorter 60-day survival time: HR = 1.70, 95% CI 1.16–2.48, P = 6.62 × 10−3 (derivation); HR = 1.78, 95% CI 1.15–2.75, P = 9.80 × 10−3 (validation); and HR = 1.59, 95% CI 1.20–2.10, P = 1.22 × 10−3 (combined dataset). Meanwhile, late-onset ARDS was associated with higher 28-day mortality rate (OR = 1.46, 95% CI 1.04–2.06, P = 0.0305) and 60-day mortality rate (OR = 1.44, 95% CI 1.03–2.02, P = 0.0313). Conclusions Late-onset moderate to severe ARDS patients had both shorter survival time and higher mortality rate in 28-day and 60-day observations.

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A Missense Genetic Variant in LRRC16A/CARMIL1 Improves Acute Respiratory Distress Syndrome Survival by Attenuating Platelet Count Decline

Cited by 35 publications

References 53 publications

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

CARMIL family proteins as multidomain regulators of actin-based motility

Late-onset moderate to severe acute respiratory distress syndrome is associated with shorter survival and higher mortality: a two-stage association study

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