Abstract Background and methods Seven genetic biomarkers previously associated with melanoma were analysed in a meta-analysis conducted in three South European populations: five red hair colour (RHC) ...MC1R alleles, one SLC45A2 variant (p.Phe374Leu) and one thermosensitive TYR variant (p.Arg402Gln). The study included 1639 melanoma patients and 1342 control subjects. Results The estimated odds ratio (OR) associated with carrying at least one MC1R RHC variant was 2.18 (95% confidence interval (CI): 1.86–2.55; p -value = 1.02 × 10−21 ), with an additive effect for carrying two RHC variants (OR: 5.02, 95% CI: 2.88–8.94, p -value = 3.91 × 10−8 ). The SLC45A2 variant, p. Phe374Leu, was significantly and strongly protective for melanoma in the three South European populations studied, with an overall OR value of 0.41 (95% CI: 0.33–0.50; p -value = 3.50 × 10−17 ). The association with melanoma of the TYR variant p.Arg402Gln was also statistically significant (OR: 1.50; 95% CI: 1.11–2.04; p -value = 0.0089). Adjustment for all clinical potential confounders showed that melanoma risks attributable to MC1R and SLC45A2 variants strongly persisted (OR: 2.01 95% CI: 1.49–2.72 and OR: 0.50, 95% CI: 0.31–0.80, respectively), while the association of TYR p.Arg402Gln was no longer significant. In addition, stratification of clinical melanoma risk factors showed that the risk of melanoma was strong in those individuals who did not have clinical risk factors. Conclusion In conclusion, our results show without ambiguity that in South European populations, MC1R RHC and SCL45A2 p.Phe374Leu variants are strong melanoma risk predictors, notably in those individuals who would not be identified as high risk based on their phenotypes or exposures alone. The use of these biomarkers in clinical practice could be promising and warrants further discussion.
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral ...myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models. We thus hypothesized that a polytherapeutic approach using several drugs, previously approved for other diseases, could be beneficial by simultaneously targeting PMP22 and pathways important for myelination and axonal integrity. A combination of drugs for CMT1A polytherapy was chosen from a group of authorised drugs for unrelated diseases using a systems biology approach, followed by pharmacological safety considerations. Testing and proof of synergism of these drugs were performed in a co-culture model of DRG neurons and Schwann cells derived from a Pmp22 transgenic rat model of CMT1A. Their ability to lower Pmp22 mRNA in Schwann cells relative to house-keeping genes or to a second myelin transcript (Mpz) was assessed in a clonal cell line expressing these genes. Finally in vivo efficacy of the combination was tested in two models: CMT1A transgenic rats, and mice that recover from a nerve crush injury, a model to assess neuroprotection and regeneration. Combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol, termed PXT3003, improved myelination in the Pmp22 transgenic co-culture cellular model, and moderately down-regulated Pmp22 mRNA expression in Schwannoma cells. In both in vitro systems, the combination of drugs was revealed to possess synergistic effects, which provided the rationale for in vivo clinical testing of rodent models. In Pmp22 transgenic CMT1A rats, PXT3003 down-regulated the Pmp22 to Mpz mRNA ratio, improved myelination of small fibres, increased nerve conduction and ameliorated the clinical phenotype. PXT3003 also improved axonal regeneration and remyelination in the murine nerve crush model. Based on these observations in preclinical models, a clinical trial of PTX3003 in CMT1A, a neglected orphan disease, is warranted. If the efficacy of PTX3003 is confirmed, rational polytherapy based on novel combinations of existing non-toxic drugs with pleiotropic effects may represent a promising approach for rapid drug development.
Primary Sjögren disease (pSD) is an autoimmune disease characterized by lymphoid infiltration of exocrine glands leading to dryness of the mucosal surfaces and by the production of autoantibodies. ...The pathophysiology of pSD remains elusive and no treatment with demonstrated efficacy is available yet. To better understand the biology underlying pSD heterogeneity, we aimed at identifying Consensus gene Modules (CMs) that summarize the high-dimensional transcriptomic data of whole blood samples in pSD patients. We performed unsupervised gene classification on four data sets and identified thirteen CMs. We annotated and interpreted each of these CMs as corresponding to cell type abundances or biological functions by using gene set enrichment analyses and transcriptomic profiles of sorted blood cell subsets. Correlation with independently measured cell type abundances by flow cytometry confirmed these annotations. We used these CMs to reconcile previously proposed patient stratifications of pSD. Importantly, we showed that the expression of modules representing lymphocytes and erythrocytes before treatment initiation is associated with response to hydroxychloroquine and leflunomide combination therapy in a clinical trial. These consensus modules will help the identification and translation of blood-based predictive biomarkers for the treatment of pSD.
•Unsupervised gene classification of Sjögren's patients' whole blood identifies thirteen consensus genes modules (CM)•Interpretation of the CMs as representing cell types or cellular functions, validated using independent measurements•Identification of a consensus signature reconciling molecular stratifications of Sjögren's patients•The Lymphoid CM is overexpressed in responders to hydroxychloroquine and leflunomide combination in the RepurpSS-1 trial
Background
The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to ...estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.
Methods
Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases).
Results
Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93,
P
= 0.001) and 0.95 (95% CI 0.93–0.97,
P
= 8 × 10
−6
). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12,
P
= 3 × 10
−7
). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07,
P
= 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease.
Conclusions
This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.
Background TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been ...reported. Objective To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc). Methods Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel–Haenszel meta-analysis. Results The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10−7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10−8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10−9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10−6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10−5). Conclusion These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.
In this study, we investigated whether variants in three key pigmentation genes--MC1R, MATP/SLC45A2, and OCA2--were involved in melanoma predisposition. A cohort comprising 1,019 melanoma patients ...(MelanCohort) and 1,466 Caucasian controls without skin cancers were studied. A total of 10 polymorphisms, including five functional MC1R alleles (p.Asp84Glu, p.Arg142His, p.Arg151Cys, p.Arg160Trp, and p.Asp294His), two nonsynonymous SLC45A2 variants (p.Phe374Leu and p.Glu272Lys), and three intronic OCA2 variants previously shown to be strongly associated with eye color (rs7495174 T>C, rs4778241 G>T, and rs4778138 T>C) were genotyped. As expected, MC1R variants were closely associated with melanoma risk (P value <2.20.10⁻¹⁶; odds ratio OR=2.29 95% confidence interval, CI=1.85-2.82 and OR=3.3 95% CI=2.00-5.45, for the presence of one or two variants, respectively). Interestingly, the SLC45A2 variant p.Phe374Leu was significantly and strongly protective for melanoma (P-value=2.12.10⁻¹⁵; OR=0.35 95% CI=0.26-0.46 and OR=0.32 95% CI=0.24-0.43, considering the genotypes Phe/Leu and Leu/Leu, respectively). MC1R and SLC45A2 variants had additive effects on melanoma risk, and after adjusting for pigmentation characteristics, the risk was persistent, even though both genes had a strong impact on pigmentation. Future studies may show whether genetic information could provide a useful complement to physical examination in predicting melanoma risk. Hum Mutat 0,1-7, 2008.
Primary Sjogren disease (pSD) is an autoimmune disease characterized by lymphoid infiltration of exocrine glands leading to dryness of the mucosal surfaces and by the production of autoantibodies. ...The pathophysiology of pSD remains elusive and no treatment with demonstrated efficacy is available yet. To better understand the biology underlying pSD heterogeneity, we aimed at identifying Consensus gene Modules (CMs) that summarize the high-dimensional transcriptomic data of whole blood samples in pSD patients. We performed unsupervised gene classification on four data sets and identified thirteen CMs. We annotated and interpreted each of these CMs as corresponding to cell type abundances or biological functions by using gene set enrichment analyses and transcriptomic profiles of sorted blood cell subsets. Correlation with independently measured cell type abundances by flow cytometry confirmed these annotations. We used these CMs to reconcile previously proposed patient stratifications of pSD. Importantly, we showed that the expression of modules representing lymphocytes and erythrocytes before treatment initiation is associated with response to hydroxychloroquine and leflunomide combination therapy in a clinical trial. These consensus modules will help the identification and translation of blood-based predictive biomarkers for the treatment of pSD.
Islet-1 (Isl1) is a member of the Isl1 family of LIM-homeodomain transcription factors (LIM-HD) that is expressed in a defined subset of motor and sensory neurons during vertebrate embryogenesis. To ...investigate how this specific expression of
isl1 is regulated, we searched for enhancers of the
isl1 gene that are conserved in vertebrate evolution. Initially, two enhancer elements, CREST1 and CREST2, were identified downstream of the
isl1 locus in the genomes of fugu, chick, mouse, and human by BLAST searching for highly similar elements to those originally identified as motor and sensory neuron-specific enhancers in the zebrafish genome. The combined action of these elements is sufficient for completely recapitulating the subtype-specific expression of the
isl1 gene in motor neurons of the mouse spinal cord. Furthermore, by direct comparison of the upstream flanking regions of the zebrafish and human
isl1 genes, we identified another highly conserved noncoding element, CREST3, and subsequently C3R, a similar element to CREST3 with two CDP CR1 recognition motifs, in the upstream regions of all other
isl1 family members. In mouse and human, CRESTs are located as far as more than 300 kb away from the
isl1 locus, while they are much closer to the
isl1 locus in zebrafish. Although all of zebrafish CREST2, CREST3, and C3R activate gene expression in the sensory neurons of zebrafish, CREST2 of mouse and human does not have the sequence necessary for sensory neuron-specific expression. Our results revealed both a remarkable conservation of the regulatory elements regulating subtype-specific gene expression in motor and sensory neurons and the dynamic process of reorganization of these elements whereby each element increases the level of cell-type specificity by losing redundant functions with the other elements during vertebrate evolution.
Abstract Background Tyrosinase ( TYR ) is a key pigmentation gene that is highly polymorphic and responsible for the most common form of autosomal recessive albinism, OCA1. Objective To assess the ...role of frequent and rare TYR variants in predisposition to skin cancer (SK) in the French population. Methods We genotyped a frequent TYR variant (p.R402Q) in 1273 patients {1047 cutaneous melanoma (CM) and 226 basal cell carcinoma (BCC)} and 925 controls, and the full coding region of TYR was sequenced in 287 patients suspected of genetic predisposition to SK (familial and/or multiple SK and/or onset before 40 years) and 187 controls. Results The homozygous p.R402Q variant was significantly associated with SK risk ( P value = 0.008; OR = 1.57), and was mostly associated with multiple CM risk ( P value = 0.021; OR = 2.50) and familial CM risk ( P value = 0.022; OR = 2.16). In addition, 19 rare TYR variants, mainly albinism mutations, were identified in 15 patients and 8 controls. Among these, 3 clearly deleterious mutations (1 non-sense and 2 affecting mRNA splicing) were identified in 3 patients, one of which was homozygous. Conclusion Our data confirmed the association of TYR p.R402Q with SK risk in the French population, and support that rare deleterious TYR variants may also play a role in multi-factorial genetic predisposition to SK. These results should be confirmed by replications studies.
Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the ...occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers.
We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data.
Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma.
These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.
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