Genetic aspects of rheumatic diseases Steinsson, K.; Alarcón-Riquelme, M. E.
Scand J Rheumatol,
06/2005, Letnik:
34, Številka:
3
Journal Article, Book Review
Recenzirano
In this review on the genetic aspects of rheumatic diseases, the approach was taken (i) to discuss, in general, important principles in the identification of susceptibility genes and (ii) to focus on ...five autoimmune rheumatic diseases that have the characteristics of complex diseases and in which important advances have been made in the identification of the genetic component. A decade ago, most reviews on the genetics of rheumatic diseases focused almost exclusively on a discussion of the human leukocyte antigen (HLA) but in this fast-moving field it is now apparent that genes outside the HLA also contribute to susceptibility. Current hypotheses concerning the pathogenesis of autoimmunity have led to the inclusion of hundreds of genes as potential candidates. Almost any molecule involved in immune recognition, cell interaction, intracellular signalling, cytokine pathways or programmed cell death can be reasonably proposed. The identification of the genes involved in complex diseases will contribute to an understanding of disease mechanisms and disease biology. The disease pathways by which the genes exert their effects or functions could lead to the discovery of new therapeutic targets that may be modulated. An increased understanding of the interactions between genes and environment might also be attained.
There are few reports in the literature on the use of a laparoscopic approach for duodenal obstruction, particularly for duodenal atresia. We report here the results of 4 cases treated ...laparoscopically, and discuss the safety, feasibility and long-term results of this approach.
Four pediatric patients presented with duodenal obstruction, one with duodenal atresia, one with annular pancreas, and two with duodenal obstruction due to Ladd's bands but without malrotation. Diagnosis was made by clinical evaluation, simple X-ray film in the Ladd's patients, and contrast gastroduodenal X-ray series for the annular pancreas. All procedures were performed using 3-mm instruments and 3 trocars. Two duodeno-duodenal anastomoses were performed and two lyses of Ladd's bands; all procedures were carried out laparoscopically.
An upper GI contrast excluded obstruction or leakage in all patients 5 - 7 days after surgery and feedings were started. The patient with annular pancreas died of cardiovascular complications after one months. The other 3 patients are asymptomatic and tolerating feedings after a follow-up of 36 months.
We conclude that a laparoscopic approach for duodenal obstruction can be performed safely and effectively and achieves a short hospital stay. Laparoscopic lysis of Ladd's bands is easy to perform, but duodenoduodenostomy requires advanced laparoscopic skills.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. ...Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.
Wastewater-based surveillance (WBS) for disease monitoring is highly promising but requires consistent methodologies that incorporate predetermined objectives, targets, and metrics. Herein, we ...describe a comprehensive metagenomics-based approach for global surveillance of antibiotic resistance in sewage that enables assessment of 1) which antibiotic resistance genes (ARGs) are shared across regions/communities; 2) which ARGs are discriminatory; and 3) factors associated with overall trends in ARGs, such as antibiotic concentrations. Across an internationally sourced transect of sewage samples collected using a centralized, standardized protocol, ARG relative abundances (16S rRNA gene-normalized) were highest in Hong Kong and India and lowest in Sweden and Switzerland, reflecting national policy, measured antibiotic concentrations, and metal resistance genes. Asian versus European/US resistomes were distinct, with macrolide-lincosamide-streptogramin, phenicol, quinolone, and tetracycline versus multidrug resistance ARGs being discriminatory, respectively. Regional trends in measured antibiotic concentrations differed from trends expected from public sales data. This could reflect unaccounted uses, captured only by the WBS approach. If properly benchmarked, antibiotic WBS might complement public sales and consumption statistics in the future. The WBS approach defined herein demonstrates multisite comparability and sensitivity to local/regional factors.
To identify chromosomal regions containing susceptibility loci for systemic lupus erythematosus (SLE), we performed genome scans in families with multiple SLE patients from Iceland, a geographical ...and genetic isolate, and from Sweden. A number of chromosomal regions showed maximum lod scores (Z) indicating possible linkage to SLE in both the Icelandic and Swedish families. In the Icelandic families, five regions showed lod scores greater than 2.0, three of which (4p15–13,Z =3.20; 9p22, Z=2.27; 19q13, Z=2.06) are homologous to the murine regions containing the lmb2, sle2 and sle3 loci, respectively. The fourth region is located on 19p13 (D19S247,Z =2.58) and the fifth on 2q37 (D2S125, Z=2.06). Only two regions showed lod scores above 2.0 in the Swedish families: on chromosome 2q11 (D2S436, Z=2.13) and 2q37 (D2S125, Z=2.18). The combination of both family sets gave a highly significant lod score at D2S125 of Z=4.24 in favor of linkage for 2q37. This region represents a new locus for SLE. Our results underscore the importance of studying well-defined populations for genetic analysis of complex diseases such as SLE.
Clinique.
Multifactorielle, l’obésité peut être à l’origine de nombreuses comorbidités diminuant l’espérance et la qualité de vie des patients. La chirurgie bariatrique permet une réduction de la ...morbi-mortalité mais comporte des risques nutritionnels. Un symptôme aujourd’hui non rapporté dans la littérature a été exploré : la rhinorrhée post-prandiale après chirurgie bariatrique.
Cette étude rétrospective a inclus 82 patients obèses, ayant eu une chirurgie bariatrique et suivis lors des visites post-opératoires à 3, 6, 12, 18 et 24 mois. La présence ou l’absence de rhinorrhée a été recueillie lors de l’interrogatoire médical. Le but de cette étude était de déterminer la prévalence de cette rhinorrhée et dans un second temps, regarder si elle est associée aux changements morphologiques, biologiques ou clinique (dumping syndrome…).
Les comparaisons entre groupes de patients ont été réalisées avec les tests statistiques usuels : test de Student ou le test de Mann–Whitney si conditions du t-test non respectées (normalité, homoscédasticité étudiée par le test de Fisher-Snedecor) pour les variables quantitatives. S’agissant des données répétées longitudinales, des modèles mixtes comme l’ANOVA en données répétées ont été mis en œuvre afin de prendre en compte la variabilité inter et intra patient (considéré comme effet aléatoire d’étudier les effets groupe (rhinorrhée), temps après la chirurgie et leurs interactions.
Parmi les 82 patients (âge 43±12 ans, 78 % femmes, 76 % sleeve gastrectomie vs 24 % by-pass, IMC 47±7kg/m2), 28 patients (34 %) ont développé une rhinorrhée post-prandiale après chirurgie bariatrique. Au sein de la population, les patients ayant une rhinorrhée (R+) sont comparables aux patients sans rhinorrhée (R−) sur le plan morphologique, biologique ou encore clinique avant la chirurgie. Cependant, la rhinorrhée est associée à l’intensité de la perte de poids (effet temps : p<0,001 ; effet rhinorrhée : p=0,056 ; ANOVA). Dans le groupe R+, la perte de poids est de 21, 33, 44, 40, 41kg à 3, 6, 12, 18, 24 mois respectivement, alors que dans le groupe R−, la perte de poids est de 20, 28, 34, 31, 30kg.
La glycémie semble plus faible chez les patients R+(p=0,09) et le dumping syndrome plus fréquent (47 % chez les R+et 8 % chez les R−à 12 mois ; p=0,005). Cependant, aucun lien n’est constaté avec les allergies saisonnières, le type de chirurgie ou le tabagisme. La qualité de vie des patients avec une rhinorrhée n’est pas détériorée selon le score de santé générale du SF-36 (p=0,10).
Cette étude révèle une prévalence significative de rhinorrhée post-prandiale après chirurgie bariatrique en lien avec l’intensité de la perte de poids et le dumping syndrome. Son mécanisme physiopathologique reste encore à élucider.
Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of ...single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P=0.016, OR=0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 5' of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.
PurposeSystemic Lupus Erythematosus is a complex autoimmune disease that leads to important worsening of quality of life and mortality. Flares appear unpredictably during the disease course and ...therapies used are often only partially effective. These challenges are mainly due to the molecular heterogeneity of the disease, such that personalized medicine offers major promise. With this work we intended to advance in that direction by developing My PROSLE, an omics-based workflow for measuring the molecular portrait of individual patients to support clinicians in their therapeutic decisions.MethodsImmunological gene-modules were used to represent the transcriptome of the patients. A dysregulation score for each gene-module was calculated at the patient level based on averaged z-scores. Almost 4300 lupus and 750 healthy samples were used to analyze the association between dysregulation scores, clinical manifestations, prognosis, flare and remission events and transcriptional drug response to Tabalumab. Machine learning-based classification models were built to predict around 90 different clinical parameters based on personalized dysregulation scores.ResultsMy PROSLE allows to molecularly summarize patients in 206 gene-modules, clustered into 9 main lupus signatures (Example in figure 1, the combination of which revealed highly differentiated pathological mechanisms. We show that dysregulation of certain gene-modules is strongly associated with specific clinical manifestations, the occurrence of relapses or the potential presence of long-term remission and drug response. Therefore, My PROSLE could be used to accurately predict these clinical outcomes.Abstract PO.1.5 Figure 1ConclusionsMy PROSLE (https://myprosle.genyo.es) allows molecular characterization of individual Lupus patients and it extracts key molecular information to support more precise therapeutic decisions.
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