Appraising screening, making risk in/visible. The medical debate over Non-Rare Thrombophilia (NRT) testing before prescribing the pill.

Non-rare thrombophilia (NRT) are hereditary predispositions to thromboembolism, the most severe side effect of combined hormonal contraception. In the mid-1990s, the identification of NRT stirred up a controversy over the possibility of investigating these genetic variants in women wishing to use contraception. Through a review of literature, this article reconstructs the debate over whether and how this genetic test should be prescribed as a way to reconfigure the risk visibility on pharmacological contraception. The main arguments identified concern the epidemiological, social, economic and clinical aspects of the test. In a context where the overall thrombotic risk for hormonal contraception is largely invisible, the genetic tests turn to embody the thrombotic risk itself. Those who opt for selective screening argue that a better estimation of risk implies a test prescription embed in a global medical assessment of women's individual risk. To advocates of universal or 'extended' screening, the tests are valuable tools to inform women on the thrombotic risk and, as such, appraised as a moral/legal obligation, whatever their predictive power. Risk visibility thus appears as an insightful concept to analyse a complex setting associating clinical, political, social and cultural considerations that touches upon medical power, women's responsibility and drug safety.

'It has to become true genetics': tumour genetics and the division of diagnostic labour in the clinic.

Tumour genetics is currently turning into a massive clinical approach. This paper is an enquiry into its practices as they expand beyond expert and experimental contexts and become routinised in clinical hospital settings. Studying a French university hospital, we unpack the content and everyday organization of diagnostic labour in this context. Exploring the sociotechnical frictions that arise in the process, we describe the ways in which they are collectively controlled, and stabilized through organizational fictions, that are instrumental in making tumour genetics doable in the hospital, at a large scale. We further show that the new role of external regulations in the production of clinical values for mutations has a strong impact on diagnostic work, making it possible to be performed locally without resorting to expert bioclinical collectives, and outside the professional jurisdiction of clinical geneticists. This division of labour appears as a necessary condition for the rise in clinical productivity required by a new function assigned to genetics: to guide the prescription of drugs for common diseases. This turn in the way genetics is embedded in the clinic calls for a thorough reassessment of its impacts on clinical discourses, practices and decisions.

[Genomics from bench to bedside: a change in perspective]. / Génomique, de la recherche à la clinique - questions autour d'un changement de perspective.

While genomics is sometimes presented as an area of ​​research where results can be rapidly translated into clinical practice, the facts are more ambiguous. To illustrate some of the pitfalls of translation, this article focuses on the applications of genome-wide association studies (GWAS) results. Following a brief scientific contextualization of GWAS, two emblematic examples are presented as illustrations. The case of Crohn's disease emphasizes the limits of GWAS results for individual risk prediction. The case of warfarin highlights the difficulties of demonstrating the clinical utility of genetic data in treatment decisions. The article outlines the simplification of disease causation that underlies the GWAS methodology. Whereas this reductionist approach is fruitful for exploratory research purposes, it shows its limits when applied to clinical conditions.

E-prescription and invisible work in genomics in France.

This article aims to analyze the transformations in medical prescription work and infrastructures brought by digitalization. Our fieldwork takes place in the context of precision medicine development based on genomics High Throughput Sequencing (HTS) in France, through the Plan France Médecine Génomique (PFMG 2025). The Plan aims at industrializing the production of genomic testing in clinical context at a national scale, particularly in oncology. To ensure the intensified flow of information between hospitals and HTS platforms required, a centralized process has been organized around two sequencing platforms and the introduction of a new e-prescription software (E-PRES). We start by analyzing how the e-prescription software changes the practices of health professionals by imposing new technological and professional standards. We show that, more than a mere prescription tool, this software is also a monitoring tool for the platforms and prescribers' work, and a support tool for the logistical and work organization. Secondly, we question the division of labor among the different professionals involved in the organizational or technical tasks required. We show that the feasibility of this new form of digitalized prescription relies on an important datawork performed by "small hands" to select, translate and process a vast amount of heterogeneous data.

Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism.

A variable (GT)(n) repeat in the 5'-regulatory region of N-methyl-D-aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject-control analysis included 206 alcohol-dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P-value = 0.001) in alcohol-dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol-dependent subjects (odds ratio = 0.58, P-value = 7 × 10(-4)). These results could be replicated in an independent sample of 116 alcohol-dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.

Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31-34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9 x 10(-5)). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3 x 10(-2). Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5 x 10(-4)) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8 x 10(-5)) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.

Genomic susceptibility in practice: The regulatory trajectory of non-rare thrombophilia (NRT) genetic tests in the clinical management of venous thrombo-embolism (VTE).

The use of individual genomic risk factors to predict the onset of common diseases is one of the main promises of personalized medicine. This paper aims to contribute to the understanding of how genetic susceptibility shapes clinical practice, by drawing on non-rare thrombophilia (NRT) tests, a common diagnostic technique for congenital predisposition to venous thromboembolism (VTE). Adopting a diachronic approach, we describe the trajectory of NRT usage and its professional regulation since the discovery of NRT variants in the mid-90s. Empirical materials combine biomedical literature, guidelines and recommendations, and interviews with key actors. We show a rapid adoption of these tests by clinicians, followed by a controversy over their clinical utility after epidemiological evaluations of NRT test demonstrated a low capacity to predict VTE in individual carriers. Indeed, alternative views on what should count as clinical utility led to heterogeneous professional regulations. Some clinicians favoured statistical and individualized predictions of risk and proposed a cessation of test prescription in the management of VTE. Others praised the context-specific clinical values of the tests that integrated their connection with aetiology and implications for prevention in healthy relatives, and therefore adopted less stringent regulatory principles. We identify three features of these genetic susceptibility tests that are central in this regulatory trajectory: two epistemological interpretations of the tests - as a molecular determinant of disease and as a multifactorial risk factor for VTE - that are alternatively aligned or opposed to each other; the connections established between different clinical contexts through test use and the correlated possibility of proposing preventive actions "for relatives; the centrality of the tests" in various clinical contexts regarding decisions about pharmacological treatment.

A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12.

Large genealogies are potentially very informative for linkage analysis. However, the software available for exact non-parametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub-families meeting complexity constraints. Different methods have been proposed to "best" split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub-pedigree sets from the genealogy instead of using just a single sub-pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome-wide linkage analysis on asthma. The detection of a genome-wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach.

A common SNP near BMP2 is associated with severity of the iron burden in HFE p.C282Y homozygous patients: a follow-up study.

BACKGROUND AND OBJECTIVES: It is now generally admitted that penetrance of the common HFE p.C282Y/p.C282Y genotype is incomplete, and identification of modifier genes is the concern of a growing number of research projects. We recently identified a significant association between pretherapeutic serum ferritin level and the common rs235756 single nucleotide polymorphism (SNP) of the BMP2 gene region. Our results further suggested an interactive effect between the BMP2 rs235756 SNP and the rs16827043 SNP in HJV, with a small additive effect of the rs4901474 SNP in BMP4. DESIGN AND METHODS: The present study has been designed as a replication study in an independent cohort of 450 HFE p.C282Y homozygous patients from a nearby French region (Brittany). Information on individual alcohol consumption and amount of iron removed by phlebotomy being available for a substantial part of this cohort, additional analyses were conducted. RESULTS: Only the use of the Amount of Iron Removed by phlebotomy (AIR) as marker of iron burden has provided positive results. Indeed, a significant association was detected between rs235756 and AIR adjusted for sex and age, with a mean AIR increasing with the number of BMP2 T alleles in the genotype groups. The effect of rs235657 was not strong enough to detect effects of gene combinations. Still, the trend in two-locus genotype risks involving BMP2 and HJV for AIR was concordant with the specific interactive effect described in the initial study. INTERPRETATION AND CONCLUSIONS: Although we failed to replicate results of the initial study, we argue that, altogether, our results help to consider genes involved in the regulation of hepcidin synthesis as potential modifiers of the p.C282Y/pC282Y genotype expression and especially BMP2.

Linkage analysis with dense SNP maps in isolated populations.

OBJECTIVE: SNP maps are becoming the gold standard for genetic markers, even for linkage analyses. However, because of the density of SNPs on most high throughput platforms, the resulting significant linkage disequilibrium (LD) can bias classical nonparametric multipoint linkage analyses. This problem may be even stronger in population isolates where LD can extend over larger distances and with a more stochastic pattern. We investigate the issue of linkage analysis with SNPs from the Affymetrix 500K GeneChip array in extended families from the isolated Hutterite population. METHODS: We minimized LD between SNPs by two methods based on a LD block pattern (Merlin and SNPLINK) and by MASEL, a new algorithm that we proposed to select SNP subsets with minimum LD and with no prior hypothesis about the LD pattern. RESULTS: Simulations, performed using the real LD pattern observed in the Hutterite population, show that sizeable inflation of linkage statistics persist when LD between SNPs is minimized by Merlin and SNPLINK. Inflation of linkage statistics is better controlled with MASEL. CONCLUSION: In this population, it may be difficult to extract from standard GeneChip arrays a SNP map without LD-driven bias that is more informative than a dense microsatellite map.

[Susceptibility genetics of common conditions in clinical practice]. / Des tests génétiques pour prédire des maladies communes.

The genetic tests for "non-rare thrombophilias" (TNR) were introduced into clinical setting immediately after the identification of genetic variants in the mid-90s to predict and prevent venous thromboembolism (VTE). Although being a rare example of a genetic test of susceptibility for complex diseases that has been integrated in medical routine, it is the most widespread post-natal genetics inquiry in France nowadays. Yet, determining whom to test and how to use the results is still controversial. This article outlines the trajectory of its clinical regulation and illustrates the importance of the context of use to understand its diffusion. This analysis is intended to feed a more general reflection on the issues raised by the clinical integration of genetic surveys for common diseases, particularly with regard to the clinical utility of a test (statistical vs. biological), the subjects to be tested (the case index and/or her/his relatives), and the criteria underlying access to these tests (modalities of medico-economic assessment).

TITLE: Des tests génétiques pour prédire des maladies communes. ABSTRACT: Introduit au lendemain de l'identification des « thrombophilies non rares ¼ (TNR), au milieu des années 1990 afin de prédire et de prévenir la maladie thromboembolique veineuse (MTEV), le bilan génétique pour ces thrombophilies est un exemple assez rare de test génétique de susceptibilité pour une maladie complexe, à avoir franchi le pas d'un véritable usage de routine en clinique. Bien que ce test soit le plus répandu des tests de génétique post-natale en France, son usage (À qui proposer le test ? Que faire des résultats ?) fait encore l'objet de débats. Cet article analyse la trajectoire de régulation clinique de ce test et illustre l'importance du contexte spécifique d'usage pour comprendre sa diffusion. Cette analyse vise à nourrir une réflexion plus générale sur les enjeux que pose l'intégration clinique des tests génétiques pour les maladies communes, en considérant notamment les modalités de définition de l'utilité clinique d'un test (statistique versus biologique), des sujets du test (le cas index versus ses apparentés), et des critères en sous-tendant l'accès (modalités des calculs médico-économiques).

Imperfect biomarkers for adjuvant chemotherapy in early stage breast cancer with good prognosis.

The proliferation of biomarkers has raised concerns regarding the possibility for clinical judgment to be improperly removed from clinician's jurisdiction and included in laboratory tests. To evaluate the ways in which the diffusion of biomarkers questions the autonomy of clinicians, we consider the case of chemotherapy prescription to women with early stage breast cancer and a good prognosis. Drawing on a qualitative study of clinicians working in a diversity of institutional contexts, we follow three biomarkers available to guide this routinely made decision. We show that, biomarkers able to reduce all the uncertainties associated with, what we analyse as an uncomfortable decision, are sought more than dreaded by clinicians. If such ideal tools are unavailable, the fact is well acknowledged by the profession. Rather than precluding their usage, the imperfection of existing biomarkers is controlled by the profession, through their integration as additional tools in the decision process. The fact that the biomarkers are recognized as imperfect biomedical entities reinforces the importance of local material, organizational and financial constraints over that of international science, technology and clinical data, in their diffusion. The regulation of the uncertainties associated with these imperfections is organized at the professional level. Through an important work, relying on guidelines and enforced in collective bodies, the series of heterogeneous bioclinical evidences available are articulated. Biomarkers tend to be subordinated to the clinic. While maintaining the professional autonomy, the process also strengthens the internal professional hierarchy. When the most expert clinicians manage to inhabit a space for clinical autonomy, the nonexpert are torn between stronger professional rules and patient preferences. In this alliance between biomarkers and experts, their clinical autonomy tends to be the price for the professional autonomy.

Geneva Statement on Heritable Human Genome Editing: The Need for Course Correction.

As public interest advocates, policy experts, bioethicists, and scientists, we call for a course correction in public discussions about heritable human genome editing. Clarifying misrepresentations, centering societal consequences and concerns, and fostering public empowerment will support robust, global public engagement and meaningful deliberation about altering the genes of future generations.

Epidemiology, pathology, and genetics of histiocytic sarcoma in the Bernese mountain dog breed.

Histiocytic sarcoma (HS) refers to a highly aggressive and frequently disseminated neoplastic disease belonging to the class of canine histiocytic proliferative disorders. Disseminated HS (previously called malignant histiocytosis) is highly breed specific, with Bernese mountain dogs (BMDs), rottweilers, and retrievers having a high prevalence with a frequency of approximately 25% in the BMD breed. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by HS. To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. The mean age of onset was 6.5 years, males and females being equally affected. The clinical features, biochemical parameters, and pathological features have been determined. The life span after diagnosis has been estimated to be 49 days. A large BMD pedigree of 327 dogs, 121 of which are affected, was assembled. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Whole-genome linkage scans as well as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. Altogether, these complementary approaches are expected to localize the genes for HS in the BMD, leading to advances in our knowledge of histiocyte diseases in dogs and humans.

Progressive retinal atrophy in the Border Collie: a new XLPRA.

BACKGROUND: Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG). RESULTS: Ophthalmic examinations performed on 487 dogs showed that affected dogs present a classical form of PRA. Of those, 274 have been sampled for DNA extraction and 87 could be connected through a large pedigree. Segregation analysis suggested an X-linked mode of transmission; therefore both XLPRA1 and XLPRA2 mutations were excluded through the genetic tests. CONCLUSION: Having excluded these mutations, we suggest that this PRA segregating in Border Collie is a new XLPRA (XLPRA3) and propose it as a potential model for the homologous human disease, X-Linked Retinitis Pigmentosa.

[Acquired and genetic factors influencing the penetrance of HFE haemochromatosis]. / Facteurs acquis et génétiques de modulation de la pénétrance de l'hémochromatose HFE.

C282Y homozygosity is necessary (but insufficient in isolation) for the onset of hemochromatosis, as indicated by its low biochemical penetrance (75 % in men and 50 % in women) and clinical penetrance (25 % in men and 0 % in women). Factors modulating iron load may be acquired (diet, alcohol, metabolic syndrome, drugs, etc.) or, more importantly, genetic (digenism, polymorphism of genes involved in the regulation of hepcidin synthesis). Factors modulating iron-related organ damage include alcohol consumption, the metabolic syndrome, and the TGF-beta1 (hepatic fibrosis) and superoxide dismutase genes (cardiomyopathy). Further studies of these modifiers are needed to improve the management of C282Y homozygotes, at both the individual and the population levels.

Are genome-wide association studies all that we need to dissect the genetic component of complex human diseases?

With the availability of dense maps of anonymous and frequent SNPs spanning the whole human genome, genome-wide association studies are now becoming a reality. In this paper, we discuss the utility of these approaches to detect genetic risk variants involved in complex disease susceptibility and, in the best case scenario where a signal is detected, how helpful it will be to the understanding of the pathological process.

Complex trait mapping in isolated populations: Are specific statistical methods required?

In this paper, we review the statistical methods that can be used in isolated populations to map genes involved in complex diseases. Our intention is to highlight the fact that if the features of population isolates may help in the identification of susceptibility factors for complex traits, the choice and design of methods for statistical analysis in these populations deserve particular care. We show that methods designed for outbred samples are generally not appropriate for isolated populations and could lead to false conclusions.

Testing for Hardy-Weinberg equilibrium in samples with related individuals.

When the classical chi(2) goodness-of-fit test for Hardy-Weinberg (HW) equilibrium is used on samples with related individuals, the type I error can be greatly inflated. In particular the test is inappropriate in population isolates where the individuals are related through multiple lines of descent. In this article, we propose a new test for HW (the QL-HW test) suitable for any sample with related individuals, including large inbred pedigrees, provided that their genealogy is known. Performed conditional on the pedigree structure, the QL-HW test detects departures from HW that are not due to the genealogy. Because the computation of the QL-HW test becomes intractable for very polymorphic loci in large inbred pedigrees, a simpler alternative, the GCC-HW test, is also proposed. The statistical properties of the QL-HW and GCC-HW tests are studied through simulations considering a sample of independent nuclear families, a sample of extended outbred genealogies, and samples from the Hutterite population, a North American highly inbred isolate. Finally, the method is used to test a set of 143 biallelic markers spanning 82 genes in this latter population.