Virtual Clinical Trials: One Step Forward, Two Steps Back

Virtual clinical trials have entered the medical research landscape. Today’s clinical trials recruit subjects online, obtain informed consent online, send treatments such as medications or devices to the subjects’ homes, and require subjects to record their responses online. Virtual clinical trials could be a way to democratize clinical research and circumvent geographical limitations by allowing access to clinical research for people who live far from traditional medical research centers. But virtual clinical trials also depart dramatically from traditional medical research studies in ways that can harm individuals and the public at large. This article addresses the issues presented by virtual clinical trials with regard to: (1) recruitment methods; (2) informed consent; (3) confidentiality; (4) potential risks to the subjects; and (5) the safety and efficacy of treatments that are approved

Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23. 1-q23.3

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by the triad of tyrosinase-positive oculocutaneous albinism, bleeding diathesis due to storage-pool deficiency of platelets, and a lysosomal ceroid storage disease. The disorder is particularly frequent in Puerto Rico and in an isolated village in the Swiss Alps. We have used a linkage disequilibrium mapping approach to localize the HPS gene in both of these groups to a 0.6 centiMorgan interval in chromosome segment 10q23.1-q23.3. These results indicate that the Puerto Rican and Swiss forms of HPS are either allelic or that they result from mutations in very closely linked genes in this region. This region of distal chromosome 10q is syntenic to the region of mouse chromosome 19 that includes ‘pale ear' (ep) and ‘ruby-eye' (ru), which must be considered as potential murine homologues to human HP

Common variants in FOXP1 are associated with generalized vitiligo

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10−8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10−7)

NALP1 in vitiligo-associated multiple autoimmune disease.

BACKGROUND: Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease. METHODS: We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail. RESULTS: Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease. CONCLUSIONS: DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders

Frontiers in Pigment Cell and Melanoma Research

We identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution

The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma

Generalized vitiligo (GV) is the most common pigmentation disease, in which white spots of skin and overlying hair result from loss of melanocytes from the involved regions. GV is a complex disease involving both genetic predisposition and unknown environmental triggers. Whereas various pathogenetic mechanisms have been suggested, most evidence supports an autoimmune basis for this disease. Recently, three different genome-wide association studies of GV have been reported, identifying a total of 17 confirmed GV susceptibility loci. Almost all of these genes encode immunoregulatory proteins, together highlighting pathways by which melanocytes might be recognized and killed. Moreover, the biological interaction between two of these GV susceptibility genes, HLA-A and TYR (encoding tyrosinase), points to an apparent inverse relationship between susceptibility to GV versus malignant melanoma, suggesting that GV may result, in part, from dysregulation of normal processes of immune surveillance against melanoma

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10 ), MC1R (P = 1.82 × 10 ), a region near TYR (P = 1.57 × 10 ), IFIH1 (P = 4.91 × 10 ), CD80 (P = 3.78 × 10 ), CLNK (P = 1.56 × 10 ), BACH2 (P = 2.53 × 10 ), SLA (P = 1.58 × 10 ), CASP7 (P = 3.56 × 10 ), CD44 (P = 1.78 × 10 ), IKZF4 (P = 2.75 × 10 ), SH2B3 (P = 3.54 × 10 ) and TOB2 (P = 6.81 × 10 ). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration

Mutation and association analysis of the PVR and PVRL2 genes in patients with non-syndromic cleft lip and palate

Orofacial clefts (OFC; MIM 119530) are among the most common major birth defects. Here, we carried out mutation screening of the PVR and PVRL2 genes, which are both located at an OFC linkage region at 19q13 (OFC3) and are closely related to PVRL1, which has been associated with both syndromic and non-syndromic cleft lip and palate (nsCLP). We screened a total of 73 nsCLP patients and 105 non-cleft controls from the USA for variants in PVR and PVRL2, including all exons and encompassing all isoforms. We identified four variants in PVR and five in PVRL2. One non-synonymous PVR variant, A67T, was more frequent among nsCLP patients than among normal controls, but this difference did not achieve statistical significance