Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes1, with epidemiological association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment

Use of admixture and association for detection of quantitative trait loci in the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples (T2D-GENES) study.

Admixture mapping and association testing have been successfully applied to the detection of genes for complex diseases. Methods have also been developed to combine these approaches. As an initial step to determine the feasibility of combining admixture and association mapping in the context of whole genome sequencing, we have applied several methods to data from the Genetic Analysis Workshop 18. Here, we describe the steps necessary to carry out such a study from selection of reference populations and preprocessing of data through to the testing itself. We detected one significant result with a Bonferroni corrected p-value of 0.032 at single nucleotide polymorphism rs12639065. Computing local ancestry for Hispanic populations was challenging because there are relatively few methods by which to handle 3-way admixture, and publicly available Native American reference panels are scarce. However, combining admixture and association is a promising approach for detection of quantitative trait loci because it might be able to elevate the power of detection by combining 2 different sources of genetic signal

Use of admixture and association for detection of quantitative trait loci in the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples (T2D-GENES) study.

Admixture mapping and association testing have been successfully applied to the detection of genes for complex diseases. Methods have also been developed to combine these approaches. As an initial step to determine the feasibility of combining admixture and association mapping in the context of whole genome sequencing, we have applied several methods to data from the Genetic Analysis Workshop 18. Here, we describe the steps necessary to carry out such a study from selection of reference populations and preprocessing of data through to the testing itself. We detected one significant result with a Bonferroni corrected p-value of 0.032 at single nucleotide polymorphism rs12639065. Computing local ancestry for Hispanic populations was challenging because there are relatively few methods by which to handle 3-way admixture, and publicly available Native American reference panels are scarce. However, combining admixture and association is a promising approach for detection of quantitative trait loci because it might be able to elevate the power of detection by combining 2 different sources of genetic signal

Comparison of the Regenerative Potential for Lung Tissue of Mesenchymal Stromal Cells from Different Sources/Locations Within the Body

To date, bone marrow-derived mesenchymal stromal cells (MSCs) have been considered the golden standard among MSC cell-based therapies. However, the harvesting of bone marrow is a highly invasive procedure and the number of MSCs isolated is low, and it declines with increasing age. MSCs with immune-regulatory and regenerative properties can be isolated from many different tissues; however, bone marrow-derived MSCs are so far the most thoroughly characterized MSC population. Despite an increased interest in using MSCs for clinical approaches in severe lung disorders, the biological function of MSCs after administration is not completely known, in particular, of MSCs extracted from other tissues than bone marrow aspirates. MSCs do not engraft after infusion, and data demonstrate that the majority of MSCs tend to be cleared from the lungs within a few days, suggesting a fast, short acting, and paracrine effect. Following activation, MSCs produce and secrete mediators, the secretome, that influence the microenvironment and the surrounding resident cells in order to modulate and repair damaged tissue. Exploring the MSC secretome has attracted much attention, and today it is known to consist of an array of molecules that is important for their regenerative and protective abilities. However, recent data suggest that the secretome profiles differ significantly depending on the MSC source, donor site, and external stimulation. In addition, the microenvironment that the infused MSCs encounter most likely plays an important role in influencing the therapeutic effect of MSCs. The composition of the microenvironment is unique in every tissue type and varies by developmental age. Changes in both stiffness and composition drastically affect MSC fate and function. The aim of this chapter is to provide a comparison of the potential of MSCs obtained from different cellular sources, and how they can be used as therapeutic agents to treat lung disorders