[Interest in the use of polygenic risk scores in breast cancer screening and preventive medicine]. / Intérêt de l'utilisation des scores de risques polygéniques dans le dépistage du cancer du sein et la médecine de prévention.

Despite screening programmes, numerous clinical studies and new breast imaging techniques, breast cancer incidence for women continues to rise. The arrival of predictive and personalized medicine could clearly redefine our screening recommendations. One promising approach to improving screening would be to use tools to predict the risk of developing breast cancer, including polygenic risk scores (PRS). This approach will enable us to offer women risk-based screening by adapting the frequency, type and age of screening. This article reviews some definitions of the PRS and breast cancer screening. We also explain the risk assessment models that have been developed and the various studies underway on personalized screening.

Malgré les programmes de dépistage, les nombreuses études cliniques et les nouvelles techniques d'imagerie mammaire, l'incidence du cancer du sein chez la femme continue à augmenter. L'arrivée de la médecine prédictive et personnalisée pourrait clairement redéfinir nos recommandations de dépistage. Une des approches prometteuses pour améliorer le dépistage serait d'utiliser les outils de prédiction du risque de développer un cancer du sein en incluant les scores de risques polygéniques (PRS). Cette approche permettra de proposer aux femmes un dépistage basé sur le risque en adaptant la fréquence des examens ainsi que le type et l'âge du début du dépistage. Cet article reprend quelques définitions concernant le PRS et le dépistage du cancer sein. Nous allons passer en revue les modèles de prédiction de risque qui ont été développés et les différentes études en cours sur le dépistage personnalisé.

Hypophosphatasia Presenting as a Chronic Diffuse Pain Syndrome with Extra-Articular Calcifications.

Hypophosphatasia is a rare genetic disease characterized by abnormal alkaline phosphatase activity and deficiency of bone and teeth mineralization. Hypophosphatasia is well known in pediatrics with typical presentations in children, but mild forms can also be present in adults and are difficult to detect. We present the case of a 50-year-old woman referred for pain management, with a previous diagnosis of fibromyalgia. The association of clinical features (diffuse pain syndrome, early dental loosening, personal history of two fractures with osteoporosis, and family history of osteoporosis) with radiographic (heterotopic calcifications of the yellow and interspinous lumbar ligaments) and biological (low levels of total alkaline phosphatase) indices was suggestive of hypophosphatasia, which was confirmed by genetic analysis. We review and discuss the association between hypophosphatasia, musculoskeletal pain, and calcium pyrophosphate deposition and the importance of raising the diagnosis of adult-onset hypophosphatasia when facing these two rheumatologic entities.

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Fine-mapping inflammatory bowel disease loci to single-variant resolution.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system.

Fibromyalgia (FM) is a highly disabling syndrome defined by a low pain threshold and a permanent state of pain. The mechanisms explaining this complex disorder remain unclear, and its genetic factors have not yet been identified. With the aim of elucidating FM genetic susceptibility factors, we selected 313 FM cases having low comorbidities, and we genotyped them on the Illumina 1 million duo array. Genotypic data from 220 control women (Illumina 610k array) was obtained for genome-wide association scan (GWAS) analysis. Copy number variants in FM susceptibility were analyzed by array comparative genomic hybridization (aCGH) experiments on pooled samples using the Agilent 2×400K platform. No single nucleotide polymorphism (SNP) reached GWAS association threshold, but 21 of the most associated SNPs were chosen for replication in 952 cases and 644 controls. Four of the SNPs selected for replication showed a nominal association in the joint analysis, and rs11127292 (MYT1L) was found to be associated to FM with low comorbidities (P=4.28×10(-5), odds ratio [95% confidence interval]=0.58 [0.44-0.75]). aCGH detected 5 differentially hybridized regions. They were followed up, and an intronic deletion in NRXN3 was demonstrated to be associated to female cases of FM with low levels of comorbidities (P=.021, odds ratio [95% confidence interval]=1.46 [1.05-2.04]). Both GWAS and aCGH results point to a role for the central nervous system in FM genetic susceptibility. If the proposed FM candidate genes were further validated in replication studies, this would highlight a neurocognitive involvement in agreement with latest reports.

Cluster analysis of clinical data identifies fibromyalgia subgroups.

INTRODUCTION: Fibromyalgia (FM) is mainly characterized by widespread pain and multiple accompanying symptoms, which hinder FM assessment and management. In order to reduce FM heterogeneity we classified clinical data into simplified dimensions that were used to define FM subgroups. MATERIAL AND METHODS: 48 variables were evaluated in 1,446 Spanish FM cases fulfilling 1990 ACR FM criteria. A partitioning analysis was performed to find groups of variables similar to each other. Similarities between variables were identified and the variables were grouped into dimensions. This was performed in a subset of 559 patients, and cross-validated in the remaining 887 patients. For each sample and dimension, a composite index was obtained based on the weights of the variables included in the dimension. Finally, a clustering procedure was applied to the indexes, resulting in FM subgroups. RESULTS: VARIABLES CLUSTERED INTO THREE INDEPENDENT DIMENSIONS: "symptomatology", "comorbidities" and "clinical scales". Only the two first dimensions were considered for the construction of FM subgroups. Resulting scores classified FM samples into three subgroups: low symptomatology and comorbidities (Cluster 1), high symptomatology and comorbidities (Cluster 2), and high symptomatology but low comorbidities (Cluster 3), showing differences in measures of disease severity. CONCLUSIONS: We have identified three subgroups of FM samples in a large cohort of FM by clustering clinical data. Our analysis stresses the importance of family and personal history of FM comorbidities. Also, the resulting patient clusters could indicate different forms of the disease, relevant to future research, and might have an impact on clinical assessment.

Screening for the presence of FMR1 premutation alleles in women with fibromyalgia.

Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, non-restorative sleep and cognitive difficulties that affects 2-4% of the general population. Recently a possible relationship between the FMR1 premutation and fibromyalgia has been pointed out. In attempt to gather more data we screened for the FMR1 CGG expansion 700 DNA samples from unrelated fibromyalgia patients. This data might be useful for evaluating the incorporation of this test in rheumatologic procedures for women with fibromyalgia. The observed frequency of FMR1 premutation carriers (3 of 700, 0.4%) is not significantly different from the estimated rate in the general female population (1/250-1/400) (P=0.539, P=0.716). Clinical examination of the FMR1 premutation carriers identified revealed that all of them had important neurological symptoms with regard to muscular symptoms, neurocognitive alterations and neurovegetative impairments. With regard to other clinical aspects of the disease the cases apparently did not differ from the average fibromyalgia patients. On the basis of our results an FMR1 screening among fibromyalgia female patients would not be recommended. However it would be worthwhile to further evaluate the different clinical presentations that fibromyalgia patients might present based on their FMR1 premutation carrier status.

Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: a study in Spanish and Italian populations and meta-analysis.

OBJECTIVE: The LCE3C_LCE3B-del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C_LCE3B-del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta-analysis including the previous case-control studies. METHODS: We genotyped LCE3C_LCE3B-del and its tag single-nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta-analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed. RESULTS: We observed a significant association between PsA and the LCE3C_LCE3B-del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14-1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta-analysis including data from all previous published studies confirmed an association of PsA with the LCE3C_LCE3B-del tag SNP. CONCLUSION: LCE3C_LCE3B-del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.