Publications by authors named "Salma Kotti"

18 Publications

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Plasma and genetic determinants of soluble TREM-1 and major adverse cardiovascular events in a prospective cohort of acute myocardial infarction patients. Results from the FAST-MI 2010 study.

Int J Cardiol 2021 Sep 15. Epub 2021 Sep 15.

Sorbonne Université, Université Pierre et Marie Curie site St Antoine, F-75012 Paris, France; FACT (French Alliance for CV clinical Trials), F-CRIN Network, Inserm U-1148, Paris, France; Hôpitaux de Paris, Clinical Pharmacology Department, Plateforme de Recherche Clinique de L'Est Parisien (URCEST-CRCEST-CRBHUEP-SU), Hôpital Saint Antoine, Paris, France.

Introduction: Triggering receptor expressing on myeloid cells (TREM)-1 is involved in the pathophysiology of ischemic heart disease. Plasma soluble TREM-1 levels (sTREM-1) has been associated with increased risk of major adverse cardiovascular events (MACE) in acute myocardial infarction (AMI) patients. However, the causative link between TREM-1 and MACE remains unknown and requires further investigation before developing potential therapeutic approaches.

Methods And Results: Using the serum and DNA data bank from the prospective, nationwide French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI 2010, N = 1293), we studied the association of plasma levels of sTREM-1 with 9 common genetic variants at the TREM1 locus and their relationship with recurrent MACE over a 3-year follow up. Plasma levels of sTREM-1 were associated with an increased risk of MACEs (death, recurrent MI or stroke) (adjusted HR = 1.86, 95%CI = 1.06-3.26 and HR = 1.11, 95%CI = 0.61-2.02 respectively for tertiles 3 and 2 versus tertile 1, P < 0.001). The study of common variants identified two major genetic determinants of sTREM-1 (rs4714449: beta = -0.11, P = 7.85 × 10 and rs3804276: beta = 0.18, P = 2.65 × 10) with a potential role on maintenance and/or differentiation of hematopoietic stem cells. However, associated variants only explained 4% of sTREM-1 variance (P = 2.74 × 10). Moreover, the rs4714449 variant, individually and in haplotype, was not significantly associated with MACE (HR = 0.61, 95%CI: 0.35-1.05, P = 0.07).

Conclusions: Despite its relationship with increased risk of death, recurrent MI and stroke, genetic determinants of plasma levels of sTREM-1 were not found to be causal prognostic factors in patients with acute myocardial infarction.
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http://dx.doi.org/10.1016/j.ijcard.2021.09.018DOI Listing
September 2021

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 08 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020

Association between rs4149056 variant in and early discontinuation of statin after acute myocardial infarction.

Pharmacogenomics 2020 02;21(3):163-172

FACT (French Alliance for Cardiovascular Trials), an F-CRIN Network, Paris, France.

Data from two French surveys were used to analyze the association between in-hospital statin discontinuation and polymorphism (rs4149056) in patients with acute myocardial infarction. Using TaqMan allelic discrimination assay, 1674 and 1708 patients were genotyped for in 2005 and 2010, respectively. The association with in-hospital statin discontinuation was assessed after adjusting for confounding factors. In 2005, homozygosity for the reduced-function allele was associated with an increased risk of in-hospital statin discontinuation (OR: 3.68; p = 0.004) compared with the wild-type allele but this association disappeared in 2010. However, statin type and intensity-dose differed significantly between the surveys. polymorphism (rs4149056) does not seem to be a major determinant of early 'in-hospital' statin discontinuation after acute myocardial infarction.
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http://dx.doi.org/10.2217/pgs-2019-0109DOI Listing
February 2020

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

Circ Genom Precis Med 2019 04 21;12(4):e002470. Epub 2019 Mar 21.

Department of Pharmacotherapy and Translational Research, Centre for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.), University of Florida, Gainesville.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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http://dx.doi.org/10.1161/CIRCGEN.119.002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629546PMC
April 2019

Adverse effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after 6 months of treatment.

Blood 2017 11 28;130(21):2354-2356. Epub 2017 Sep 28.

Service de Biologie de la Reproduction, Centre d'Etudes et de Conservation des œufs et du Sperme Humains (CECOS), Hôpital Tenon, Université Paris 06, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.

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http://dx.doi.org/10.1182/blood-2017-03-771857DOI Listing
November 2017

Cardiometabolic risk factors in primary centred and rotator cuff-related shoulder osteoarthritis: a comparative study.

RMD Open 2017 29;3(1):e000429. Epub 2017 Jun 29.

Rheumatology Department, Saint-Antoine hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Univ Paris 06, Inserm UMRS_938, DHU i2B, Paris, France.

Background: Risk factors for shoulder osteoarthritis (SOA) have been poorly studied. SOA has two anatomical subtypes: primary centred SOA (centred SOA) and rotator cuff-related OA (non-centred SOA). We examined whether cardiometabolic risk factors are preferentially associated with centred than mechanical-induced non-centred SOA.

Methods: This 2004-2012 retrospective multicentric study included patients with SOA. Data on clinical characteristics, especially cardiometabolic risk factors, were collected. We compared patients with radiographic-centred and non-centred SOA and tested the association between cardiometabolic risk factors and subtypes of SOA.

Results: We included 147 patients (101 women (68.7%); mean age 75.8±10 years); 99 had centred SOA. As compared with patients with non-centred SOA, those with centred SOA were older (77.5±9 vs 72.4±11 years; p=0.004) with no difference in cardiometabolic disturbances or their accumulation. Multivariable analyses indicated that older age was independently associated with centred SOA (OR 1.06;95% CI 1.02 to 1.1; p=0.004), and cardiovascular diseases were less associated with this subtype (OR 0.27; 95% CI 0.089 to 0.824; p=0.02) than with the non-centred one.

Conclusion: Cardiometabolic risk factors were not more prevalent with primary centred than rotator cuff-related SOA. They may participate in the pathophysiology of both SOA subtypes through cartilage and tendon disruption.
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http://dx.doi.org/10.1136/rmdopen-2016-000429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604608PMC
June 2017

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6).

J Clin Oncol 2016 11;34(31):3773-3780

Jérémie H. Lefevre, Salma Kotti, Yann Parc, Tabassome Simon, and Emmanuel Tiret, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Sorbonne Universités; Mehdi Karoui, Centre Hospitalier Universitaire (CHU) Pitié-Salpétrière; Anne Berger, CHU Hôpital Européen Georges-Pompidou; Jérome Loriau, Hôpital Saint-Joseph; Renato Lupinacci, Hôpital Croix Saint-Simon; Nicolas Goasgen, Hôpital des Diaconesses-Croix Saint-Simon, Paris; Laurent Mineur, Sainte-Camille Institut, Avignon; Eric Rullier, CHU Saint-André, Bordeaux; Philippe Rouanet, Val d'Aurelle Institut, Montpellier; Cécile de Chaisemartin, Paoli-Calmettes Institut, Marseille CHU, Marseille; Bernard Meunier, CHU Rennes, Rennes; Jafari Mehrdad, Oscar Lambret Center; Guillaume Piessen and Alain Saudemont, Centre Hospitalier Régional Universitaire, Lille; Eddy Cotte, CHU Lyon-Sud, Pierre-Bénite; Jérome Desrame, Jean Mermoz Institut, Lyon; Stéphane Benoist, CHU Bicètre, Le Kremlin-Bicêtre; Sylvain Kirzin, CHU Purpan, Toulouse; Yves Panis, Hôpital Beaujon, Université Paris VII, Clichy; Michel Prudhomme, CHU Carémeau, Nîmes; Frédérique Peschaud, CHU Ambroise-Paré, Boulogne-Billancourt; Anne Dubois, CHU Estaing, Clermont-Ferrand; Jean-Jacques Tuech, CHU, Rouen; and Guillaume Meurette, CHU Hôtel-Dieu, Nantes, France.

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.
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http://dx.doi.org/10.1200/JCO.2016.67.6049DOI Listing
November 2016

Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.

Cell Metab 2015 Sep 30;22(3):460-71. Epub 2015 Jul 30.

Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, and Université Paris-Descartes, Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. Electronic address:

Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.cmet.2015.07.004DOI Listing
September 2015

Impact of age-adjusted insulin-like growth factor 1 on major cardiovascular events after acute myocardial infarction: results from the fast-MI registry.

J Clin Endocrinol Metab 2015 May 20;100(5):1879-86. Epub 2015 Feb 20.

Assistance Publique-Hôpitaux de Paris (O.B.), Department of Diabetology, Pitié Salpétrière Hospital, 75634 Paris, France; Sorbonne Universités (O.B., Y.L.B., T.S.), Université Paris Medical Center, Université Paris 06, and INSERM (O.B.), Unité Mixte de Recherche en Santé 1138, Centre de Recherche des Cordeliers, and INSERM (Y.L.B., N.B.), Unité Mixte de Recherche 938, Plateforme de Microdosages, 75006 Paris 06, France; Assistance Publique-Hôpitaux de Paris (Y.L.B.), Trousseau Hospital, 75571 Paris, France; Centre Hospitalier St Joseph-St Luc (B.R.), 69372 Lyon, France; Hôpital Arnaud de Villeneuve (F.L.), 34295 Montpellier, France; Centre Hospitalier Jacques Coeur (X.T.), 18000 Bourges, France; Assistance Publique-Hôpitaux de Paris (L.B., S.K., E.D., T.S.), URCEST, St Antoine Hospital, 75571 Paris, France; Société Française de Cardiologie (G.M.), 75012 Paris, France; Assistance Publique-Hôpitaux de Paris (N.D.), Hôpital Européen Georges Pompidou, Department of Cardiology, 75475 Paris, France; and Université René-Descartes (N.D.), 75014 Paris 05, France.

Background: The GH/IGF-1 axis is being targeted for therapeutic development in diseases such as short stature, cancer, and metabolic disorders. The impact of IGF-1 in cardiovascular disease remains controversial. We therefore studied whether IGF-1 at admission for acute myocardial infarction (AMI) predicted death, recurrent AMI, and stroke over a 2-year follow-up.

Methods: Using data from the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction registry, we measured IGF-1 among all the 1005 patients with AMI who participated in the serum data bank. Because IGF-1 decreases with age, a standardized IGF-1 score was calculated as previously described [IGF-1 score = (log [IGF-1 (micrograms per liter)] + 0.00625 × age - 2.555)/0.104]. Impact of IGF-1 score (continuous and quartiles) on outcomes were compared using Cox proportional hazards regression models.

Results: During follow-up, 190 patients died or had a recurrent AMI or stroke. Patients in the lowest quartile of IGF-1 were older and more frequently female and diabetic compared with patients in the other quartiles. After adjustment for known cardiovascular factors, an increase of five units of IGF-1 score was associated with a 30% decrease of the risk of events during follow-up (adjusted hazard ratio 0.70; 95% confidence interval 0.54-0.92; P = .0093). Similarly, the lowest quartile of IGF-1 was associated with an increased risk of events (adjusted hazard ratio 1.52, 95% confidence interval 1.11-2.08; compared with others quartiles, P = .010).

Conclusions: Low IGF-1 score is associated with an increased risk of all-cause death, recurrent myocardial infarction, and stroke in AMI patients. Whether patients treated by IGF-1 axis inhibitors have a specific clinical course after AMI would be worth studying.
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http://dx.doi.org/10.1210/jc.2014-3968DOI Listing
May 2015

Results of myringoplasty in children with cleft palate: a patient-matched study.

Otol Neurotol 2014 Jun;35(5):838-43

*Otolaryngology/Head and Neck Surgery department, Armand-Trousseau Children Hospital, Paris, France; †University Medical Center Utrecht, The Netherlands; and ‡Unité de Recherche Clinique de l'Est Parisien, AP-HP, Hôpital Saint Antoine, Paris, France.

Objectives: To assess the anatomic and functional outcome of underlay cartilage myringoplasty in children with cleft palate, at different postoperative periods compared with a patients-matched control group

Study Design: Case control study, tertiary referral center.

Methods: An otologic database was used to select children with cleft palate and perforated tympanic membrane who underwent myringoplasty between 1995 and 2012. These subjects were matched with control patients, without cleft palate, using the following criteria: age, size of perforation, status of contralateral ear, and status of middle ear mucosa. Charts were reviewed for the following: patients characteristics, preoperative findings, surgical data, postoperative anatomic and functional outcomes, and reinterventions. The postoperative findings were divided into 5 different periods.

Results: A group of 32 cleft palate patients as well as 32 control patients were included in this study, with a mean follow up of 63.6 ± 41 months. There were no differences between the groups in anatomic success as it was achieved in 84% in both groups. No differences were seen in functional outcome when compared with each different postoperative period. Using the last available audiogram, the postoperative mean air conduction and the air-bone gap were significantly worse in the cleft group compared with the control group, respectively, 26.1 ± 13.7 dB versus 18.4 ± 10.1 dB, p = 0.042; and 16.5 ± 9.4 dB and 11.3 ± 6.4 dB, p = 0.046. Additionally, the functional success was significantly worse in the cleft group; 58% versus 87% in the control group (OR, 5.5 [95% CI, 1.22-24.81], p = 0.027).

Conclusion: Children with cleft palate can benefit from cartilage underlay myringoplasty in terms of closure of tympanic membrane, although there is a worse functional outcome.
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http://dx.doi.org/10.1097/MAO.0000000000000394DOI Listing
June 2014

Serum level of adiponectin is a surrogate independent biomarker of radiographic disease progression in early rheumatoid arthritis: results from the ESPOIR cohort.

Arthritis Res Ther 2013 ;15(6):R210

Introduction: Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.

Methods: In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥ 5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).

Results: Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).

Conclusion: Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.
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http://dx.doi.org/10.1186/ar4404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978925PMC
November 2014

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction.

Nat Med 2013 Oct 15;19(10):1273-80. Epub 2013 Sep 15.

1] Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, Paris, France. [2] Université Paris-Descartes, Paris, France. [3].

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.
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http://dx.doi.org/10.1038/nm.3284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042928PMC
October 2013

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.

J Am Coll Cardiol 2013 Nov 31;62(21):1966-1976. Epub 2013 Jul 31.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.

Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.

Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.

Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.

Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.

Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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http://dx.doi.org/10.1016/j.jacc.2013.06.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826105PMC
November 2013

Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction.

Eur Heart J 2013 Feb 6;34(8):570-7. Epub 2012 Sep 6.

Department of Clinical Pharmacology, URC-EST, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital St Antoine Paris, University of Pierre et Marie Curie, 27 Rue Chaligny, 75012 Paris, France.

Aim: Interleukin (IL)-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction.

Methods And Results: We used data from 981 patients enrolled in the prospective, multicentre French registry of Acute ST elevation, or non-ST-elevation Myocardial Infarction (Fast-MI, NCT00673036). Serum levels of IL-17 were associated with the risk of all-cause death and recurrent MI at 2 years, with levels of IL-17 below the median indicative of a worse outcome. The impact of IL-17 remained significant after adjustment for known cardiovascular risk factors, C-reactive protein, and treatments including statins: hazard ratio (HR) = 1.40 (1.03-1.91); P = 0.03. IL-17 inhibited mononuclear cell adhesion to endothelium and reduced endothelial vascular cell adhesion molecule (VCAM-1) expression. Patients with low (below the median) IL-17 levels and high (above the median) soluble VCAM-1 (sVCAM-1) levels were at particularly increased risk of death and MI: adjusted HR = 2.22 (1.32-3.75) compared with the high IL-17/low sVCAM-1 group (P = 0.002).

Conclusions: Low serum levels of IL-17 are associated with a higher risk of major cardiovascular events in Caucasian patients with acute MI. Our results raise possible concern about the use of inhibitors of the IL-17 pathway in clinical settings associated with a high cardiovascular risk.

Clinical Trials Registration: NCT00673036.
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http://dx.doi.org/10.1093/eurheartj/ehs263DOI Listing
February 2013

Circulating levels of secretory- and lipoprotein-associated phospholipase A2 activities: relation to atherosclerotic plaques and future all-cause mortality.

Eur Heart J 2012 Dec 17;33(23):2946-54. Epub 2012 Jun 17.

Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.

Aims: Secretory- and lipoprotein-associated phospholipases A2 (sPLA2 and Lp-PLA2) are enzymes both suggested to be of importance for atherosclerosis. We investigated relationships between the activities of these enzymes in the circulation and atherosclerosis as well as future clinical events.

Methods And Results: The population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study included 1016 randomly selected subjects, all aged 70. The prevalence of carotid artery plaques was recorded by ultrasound (n= 954), and arterial stenosis was assessed by whole-body magnetic resonance angiography (WBMRA, n= 302). Secretory-associated phospholipase A2 [odds ratio 1.23 for 1 SD increase, 95% confidence interval (CI): 1.05-1.44, P= 0.007], but not Lp-PLA2 (P= 0.26), activity was significantly related to carotid atherosclerosis and to the amount of stenosis at WBMRA (P= 0.006) following adjustment for multiple risk factors (waist circumference, serum triglycerides, body mass index, C-reactive protein, high density lipoprotein-C, low density lipoprotein-C, triglycerides, GFR, fasting glucose, blood pressure, statin use, and exercise habits). Secretory-associated phospholipase A2 [hazard ratio (HR) 1.45 for 1 SD increase, 95% CI: 1.15-1.84, P= 0.001], but not Lp-PLA2 (HR 0.95, P= 0.55), activity was a significant risk factor for all-cause mortality (114 had died) during 7.0 years follow-up after adjustment for the risk factors described above. In a sample of 1029 post-myocardial infarction (MI) patients (French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction), sPLA2 (adjusted HR 1.32 for 1 unit increase, 95% CI: 1.02-1.71, P= 0.036), but not Lp-PLA2 (HR 1.03, P= 0.90), activity predicted death or recurrent MI during 1-year follow-up (n= 136 cases).

Conclusion: sPLA2 activity was related to atherosclerosis and predicted all-cause mortality in a sample of elderly subjects, as well as death or MI in post-MI patients.
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http://dx.doi.org/10.1093/eurheartj/ehs132DOI Listing
December 2012

Power of the 2-locus TDT for testing the interaction of two susceptibility genes.

BMC Proc 2007 18;1 Suppl 1:S65. Epub 2007 Dec 18.

Université Paris-Sud, UMR-S535, 94817 Villejuif, France.

We recently proposed a new strategy: 2-locus TDT for detecting two susceptibility genes through their interaction in trio families. We apply our method to two candidate genes, A and C, on the Genetic Analysis Workshop 15 (GAW15) simulated rheumatoid arthritis data and study the power to identify an interactive effect of these genes.This study was performed with full knowledge of the answers.
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http://dx.doi.org/10.1186/1753-6561-1-s1-s65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367511PMC
December 2009

Discussing gene-gene interaction: warning--translating equations to English may result in jabberwocky.

Genet Epidemiol 2007 ;31 Suppl 1:S61-7

Center for Quantitative and Computational Biology and Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.

Interest in mapping susceptibility alleles for complex diseases, which do not follow a classic single-gene segregation pattern, has driven interest in methods that account for, or use information from one locus when mapping another. Our discussion group examined methods related to epistasis or gene x gene interaction. The goal of modeling gene x gene interaction varied across groups; some papers tried to detect gene x gene interaction while others tried to exploit it to map genes. Most of the 10 papers summarized here applied newly created or newly modified statistical methods related to gene x gene interaction, while two groups primarily examined computational issues. As is often the case, comparisons are complicated by little overlap in the data used across the papers, and further complicated by the fact that the available data may not have been ideal for some gene x gene interaction methods. However, the main difficulty in comparing and contrasting methods across the papers is the lack of a consistent statistical definition of gene x gene interaction. But despite these issues, two clear trends emerged across the analyses: First, the methods for quantitative trait gene x gene interaction appeared to perform very well, even in families initially ascertained as affected sib pairs; and second, dichotomous trait gene x gene interaction methods failed to produce consistent results. The difficulty of using (primarily) affected sib pair data in a gene x gene interaction analysis is explored.
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http://dx.doi.org/10.1002/gepi.20281DOI Listing
April 2008
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