Cranberrry pas sur que ca marche ....

CLINICAL QUESTION: Are cranberry products (juice, tablets, capsules, and syrup) associated with prevention of urinary tract infections (UTIs) compared with placebo or other treatments? BOTTOM LINE: Cranberry products are not associated with prevention of UTIs. However, lack of association of cranberry products with a reduced incidence of UTIs in clinical trials may be due to lack of participant adherence, lack of sufficient active ingredient in the cranberry product, or lack of sufficient statistical power.
JAMA. 310(13):1395-1396, October 2, 2013.
Jepson, Ruth

Techniques "sensibles" pour détecter les DSA, une perte de chance ?

Influence of test technique on sensitization status of patients on the kidney transplant waiting list.

Gombos P, Opelz G, Scherer S, Morath C, Zeier M, Schemmer P, Süsal C.

Source

Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany.

Am J Transplant. 2013 Aug;13(8):2075-82

The exquisitely sensitive single antigen bead (SAB) technique was shown to detect human leukocyte antigen (HLA) antibodies in sera of healthy male blood donors. Such false reactions can have an impact on critical decisions, especially with respect to the determination of unacceptable HLA-antigen mismatches in patients awaiting a kidney transplant. We tested pretransplant sera of 534 patients on the kidney waiting list using complement-dependent cytotoxicity (CDC), enzyme-linked immunosorbent assay (ELISA) and SAB in parallel. Evidence of HLA antibodies was obtained in 5% of patients using CDC, 14% using ELISA, and 81% using SAB. Among patients without history of an immunizing event, 77% showed evidence of HLA antibodies in SAB. In contrast 98% of these patients were negative in ELISA and CDC. In patients without an immunizing event, SAB-detected antibodies reacted not always weakly but with mean fluorescence intensity (MFI) values as high as 14 440. High-MFI-value antibodies were found in some of these patients with HLA specificities that are rather common in general population, consideration of which would lead to unjustified exclusion of potential kidney donors. False SAB reactions can be unveiled by testing with additional antibody assays. Denial of donor kidneys to recipients based on HLA-antibody specificities detected exclusively in the SAB assay is not advisable.

Mieux au début mais pas après, Meier-Kriesch AJT 2004

Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies?

Meier-Kriesche HU, Schold JD, Kaplan B.

Source

Department of Medicine, University of Florida, Gainesville, FL, USA. meierhu@medicine.ufl.edu

Impressive renal allograft survival improvement between 1988 and 1995 has been described using projections of half-lives based on limited actual follow up. We aimed, now with sufficient follow up available to calculate real half-lives. Real half-lives calculated from Kaplan-Meier curves for the overall population as well as subsets of repeat transplants and African Americans recipients were examined. Real half-lives were substantially shorter than projected half-lives. As a whole, half-lives have improved by about 2 years between 1988 and 1995 as compared to the earlier projected 6 years of improvement. The improvement seems to be driven primarily by the improvement in graft survival of re-transplants. First transplants showed a cumulative increase in graft survival of less than 6 months. Projected half-lives are a risky estimation of long-term survival especially when based on short actual follow up. First transplant survival has only marginally improved during the early years of post transplant follow up while no significant improvement in long-term survival could be detected between 1988 and 1995. Redirection of attention from early endpoints towards the process of long-term graft loss may be necessary to sustain early gains in the long term.

Un contrat d'adhérence ....

Improving Outcomes of Renal Transplant Recipients With Behavioral Adherence Contracts: A Randomized Controlled Trial.

Chisholm-Burns MA, Spivey CA, Graff Zivin J, Lee JK, Sredzinski E, Tolley EA.

Source

University of Tennessee College of Pharmacy, Memphis, TN.

Am J Transplant. 2013 Jul 2. doi: 10.1111/ajt.12341.

The objective of this randomized controlled trial was to assess the effects of a 1-year behavioral contract intervention on immunosuppressant therapy (IST) adherence and healthcare utilizations and costs among adult renal transplant recipients (RTRs). The sample included adult RTRs who were at least 1 year posttransplant, taking tacrolimus or cyclosporine and served by a specialty pharmacy. Pharmacy refill records were used to measure adherence and monthly questionnaires were used to measure healthcare utilizations. Direct medical costs were estimated using the 2009 Medicare Expenditure Panel Survey. Adherence was analyzed using the GLM procedure and the MIXED procedure of SAS. Rate ratios and 95% confidence intervals were estimated to quantify the rate of utilizing healthcare services relative to treatment assignment. One hundred fifty RTRs were enrolled in the study. Intervention group RTRs (n = 76) had higher adherence than control group RTRs (n = 74) over the study period (p < 0.01). And 76.1% of the intervention group compared with 42.7% of the control group was not hospitalized during the 1-year study period (RR = 1.785; 95% CI: 1.314, 2.425), resulting in cost savings. Thus, evidence supports using behavioral contracts as an effective adherence intervention that may improve healthcare outcomes and lower costs.

Rejet aiguë cellulaire > rejet humoral > inflammation > impact sur la durée de vie du greffon

Kidney Allograft Survival After Acute Rejection, the Value of Follow-Up Biopsies.

El Ters M, Grande JP, Keddis MT, Rodrigo E, Chopra B, Dean PG, Stegall MD, Cosio FG.

Source

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

Am J Transplant. 2013 Jul 19. doi: 10.1111/ajt.12370. [Epub ahead of print]

Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long-term graft survival is debated. We examined this relationship focusing on graft histology post-AR and assessing specific causes of graft loss. Included are 797 recipients without anti-donor antibodies (DSA) at transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no-AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and transplant glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92-4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune-mediated graft losses, particularly transplant glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year posttransplant (no-AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post-AR events are associated with increased risk of graft loss.

AMR, apoptose et complément

Polyreactive Antibodies Developing Amidst Humoral Rejection of Human Kidney Grafts Bind Apoptotic Cells and Activate Complement.

1. Porcheray F, Fraser JW, Gao B, McColl A, Devito J, Dargon I, Helou Y, Wong W, 
   Girouard TC, Saidman SL, Colvin RB, Palmisano A, Maggiore U, Vaglio A, Smith RN, 
   Zorn E.

1. Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
2. Am J Transplant. 2013 Aug 6. doi: 10.1111/ajt.12394.

Antibody mediated rejection (AMR) is associated with a variety of graft-reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a patient with AMR. In a previous study, we showed that six clones were reacting to multiple self-antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non-AMR patients. Overall, our studies show the development of polyreactive antibodies cross-reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR.

Le rein induirait une tolérance, greffe coeur + rein chez le porc

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Induction of Cardiac Allograft Tolerance Across a Full MHC Barrier in Miniature Swine by Donor Kidney Cotransplantation

M. L. Madariaga, S. G. Michel, M. Tasaki, V. Villani, G. M. La Muraglia II, S. Sihag, J. Gottschall, E. A. Farkash, A. Shimizu, J. S. Allan, D. H. Sachs, K. Yamada and J. C. Madsen

Am J Transpl 22 AUG 2013 | DOI: 10.1111/ajt.12423

We have previously shown that tolerance of kidney allografts across a full major histocompatibility complex (MHC) barrier can be induced in miniature swine by a 12-day course of high-dose tacrolimus. However, that treatment did not prolong survival of heart allografts across the same barrier. We have now tested the effect of cotransplanting an allogeneic heart and kidney from the same MHC-mismatched donor using the same treatment regimen. Heart allografts (n = 3) or heart plus kidney allografts (n = 5) were transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. As expected, all isolated heart allografts rejected by postoperative day 40. In contrast, heart and kidney allografts survived for >200 days with no evidence of rejection on serial cardiac biopsies. Heart/kidney recipients lost donor-specific responsiveness in cell-mediated lympholysis and mixed-lymphocyte reaction assays, were free of alloantibody and exhibited prolonged survival of donor, but not third-party skin grafts. Late (>100 days) removal of the kidney allografts did not cause acute rejection of the heart allografts (n = 2) and did not abrogate donor-specific unresponsiveness in vitro. While kidney-induced cardiac allograft tolerance (KICAT) has previously been demonstrated across a Class I disparity, these data demonstrate that this phenomenon can also be observed across the more clinically relevant full MHC mismatch. Elucidating the renal element(s) responsible for KICAT could provide mechanistic information relevant to the induction of tolerance in recipients of isolated heart allografts as well as other tolerance-resistant organs.

Approximately 100,000 individuals in the United States currently await kidney transplantation, and 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidneyfunction would address donor organ shortage and the morbidity associated with immunosuppression. Such abioengineered graft must have the kidney's architecture and function and permit perfusion, filtration, secretion, absorption and drainage of urine. We decellularized rat, porcine and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, a collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells and perfused these cell-seeded constructs in a whole-organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused through their intrinsic vascular bed. When transplanted in an orthotopic position in rat, the grafts were perfused by the recipient's circulation and produced urine through the ureteral conduit in vivo.

Nat Med. 2013 Apr 14. doi: 10.1038/nm.3154. [Epub ahead of print]

Regeneration and experimental orthotopic transplantation of a bioengineered kidney.

Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC.

Source

1] Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.

Nat Med. 2013 Apr 7. doi: 10.1038/nm.3145. [Epub ahead of print]

Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL.

Source

1] Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. [2] Center for Cardiovascular Diagnostics & Prevention, Cleveland Clinic, Cleveland, Ohio, USA.

La thrombomoduline, un nouvel acteur du SHU atypique

Thrombomodulin mutations in atypical hemolytic-uremic syndrome.
Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM.
VIB-K.U.Leuven Vesalius Research Center, Leuven, Belgium.
BACKGROUND: The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome. METHODS: We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. RESULTS: Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. CONCLUSIONS: Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome. 2009 Massachusetts Medical Society
New Engl J Med Juillet 2009

Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.
Lancaster MA, Louie CM, Silhavy JL, Sintasath L, Decambre M, Nigam SK, Willert K, Gleeson JG.
Biomedical Sciences Program and Departments of Pediatrics and Medicine, University of California-San Diego (UCSD), La Jolla, California, USA.
Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates beta-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
Nature Medecine Septembre 2009

Devenir à long terme des patients avec une malformation congénital des reins (CAKUT): attention aux biais de recrutement

Renal outcome in patients with congenital anomalies of the kidney and urinary tract.
Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Innocenti ML, Somenzi D, Trivelli A, Caridi G, Izzi C, Scolari F, Mattioli G, Allegri L, Ghiggeri GM.
[1] Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA [2] Department of Clinical Medicine, Nephrology and Health Sciences, University of Parma, Italy.
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children. We measured the risk of progression to end-stage renal disease in 312 patients with CAKUT preselected for the presence of anomalies in kidney number or size. A model of dialysis-free survival from birth was established as a function of the renal CAKUT categories of solitary kidney; unilateral and bilateral hypodysplasia; renal hypodysplasia associated with posterior urethral valves; and multicystic and horseshoe kidney. Cox regression analysis took into account the concomitant presence of vesicoureteral reflux, year of diagnosis, and time-varying values of serum creatinine, proteinuria, and hypertension. By 30 years of age, 58 patients had started dialysis, giving a yearly incidence of 0.023 over a combined 2474 patient risk years. The risk for dialysis was significantly higher for patients with a solitary kidney or with renal hypodysplasia associated with posterior urethral valves (hazard ratios of 2.43 and 5.1, respectively) compared to patients with unilateral or bilateral renal hypodysplasia, or multicystic or horseshoe kidney, and was independent of other prognostic factors. Our study shows that sub-clinical defects of the solitary kidney may be responsible for a poorer prognosis compared to more benign forms of CAKUT. Prospective studies are needed to validate these results.
Kidney International advance online publication, 17 June 2009; doi:10.1038/ki.2009.220.

Cette étude rétrospective analyse le devenir à long terme de patients ayant une anomalie congénitale de l'appareil urinaire. 312 patients ont été inclus dans un seul centre (Gènes, Italie). Le critère d'inclusion était la réduction de la taille de l'un ou des deux reins. Cette cohorte est très hétérogène incluant aussi bien des reins uniques, des dysplasies multikystiques, des hypodysplasies rénales (HDR) uni ou bilatérales et des valves de l'urêthre postérieur. Une des conclusionn des auteurs est que le pronostic des reins uniques et des valves de l'urêthre postérieur (VUP) est moins bon que celui des HDR avec un risque de dialyse augmenté ("hazard ratio") de 2.43 et 5.1 respectivement (1.79 pour les HDR bilatérales). Cela peut se comprendre pour les VUP mais moins facilement pour les reins uniques. Ainsi 21 des 79 reins uniques sont en dialyse à un âge moyen de 21+/-13 ans. Il est fortement probable qu'il y ait eu un biais de recrutement des reins uniques qui sont pour la plupart diagnostiqués après la naissance à un âge moyen de 15 ans. Il n'en demeure pas moins que les reins uniques doivent être suivis longtemps (ad vitam), mais de cela nous somme tous convaincus...
Rémi Salomon

Des variants dans les gènes du Bartter et du Gitelman font baisser la pression artérielle

Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP.
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
Nat Genet. 2008 May;40(5):592-9

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

Exemple du rôle de la balance sodée dans le contrôle de la pression artérielle. Les sujets de la cohorte de Framingham (étude des risques cardiovasculaires avec un suivi de 35 ans), hétérozygotes pour une mutation d’un de 3 des gènes responsables du syndrome de Bartter/Gitelman, ont des chiffres de pression artérielle systolique et diastolique significativement plus bas pour toutes les tranches d’âge. Cet effet avait été montré pour de petits groupes, en particulier pour le cotransporteur Na-Cl. Cet article en fait une élégante démonstration dans la durée.
Rosa Vargas Poussou

Un transporteur des hexoses (GLUT9) se charge aussi de l'acide urique ...

SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF.MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, Fischer G, Henke K, Klopp N, Kronenberg F, Paulweber B, Pfeufer A, Rosskopf D, Völzke H, Illig T, Meitinger T, Wichmann HE, Meisinger C.Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.

Un bel exemple de ce que peuvent apporter les études d’association sur génome entier pour comprendre la physiopathologie. En utilisant cette approche, ces deux équipes ont mis en évidence une association entre des polymorphismes introniques ou exoniques du gène SLC2A9 et la concentration d’acide urique. Cette association fortement significative est confirmée sur d’autres populations; l’haplotype moins fréquent est associé à des concentrations d’acide urique plus basses, avec un effet plus fort chez la femme que chez l’homme.
Le gène SLC2A9 code pour GLUT9 qui appartient à la famille de transporteurs des hexoses. GLUT9 participe au transport du fructose et celui-ci était connu pour induire une hyperuricémie (augmentation de la synthèse hépatique). Une de deux équipes montre que GLUT9, exprimé dans l’ovocyte de Xenopus, transporte également de l’acide urique.
Peu-être une piste pour cibler les enfants susceptibles de faire des hyperuricémies par exemple au cours des syndromes de lyse tumorale.
Rosa Vargas-Poussou