Recent progress in the genetics of generalized vitiligo

Abstract

Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a “complex trait”, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRP1 and XBP1, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes. Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.

Introduction

Vitiligo is an acquired, non-contagious disease in which progressive, patchy, multifocal loss of pigmentation of skin, overlying hair, and often mucous membranes results from loss of melanocytes from the involved areas (Taïeb and Picardo, 2009). In generalized vitiligo (GV), the predominant form of the disorder (includes acrofacial vitiligo, vitiligo universalis, vitiligo vulgaris, and non-segmental vitiligo), patches of depigmented skin result from autoimmune destruction of melanocytes (Birlea et al., 2010).

GV is perhaps the most common pigmentation disorder, occurring at a frequency of approximately 0.2–1.0 percent in different populations around the world (Spritz, 2008). Because of its visually striking phenotype, vitiligo has been recognized for thousands of years (Nordlund et al., 2006). Nevertheless, the pathobiological basis of GV has remained surprisingly controversial, with many different theories suggested (Picardo and Taïeb, 2010), most supported by little compelling evidence (Boissy and Spritz, 2009). Indeed, it is only the results of recent genome-wide association studies (GWAS), identifying GV susceptibility genes which almost universally involve immune regulation and immune targeting of melanocytes, that have led to the general consensus that GV is a primary autoimmune disease, though the biological triggers of the autoimmune process remain unknown.

In fact, there has long been considerable evidence in favor of an autoimmune basis of GV. Many, but not all GV patients have circulating antibodies to melanocytes and various melanocyte protein components, though most investigators believe these to be humoral responses to melanocyte destruction rather than a primary cause (Kemp et al., 2007). Perhaps of greater importance may be the occurrence of circulating skin-homing melanocyte-specific cytotoxic T lymphocytes (Ogg et al., 1998) and sparse infiltrates of activated and cytotoxic T cells at the margins of active lesions (Gross et al., 1987, Badri et al., 1993, Le Poole et al., 1996), though the fraction of GV patients with such infiltrates is uncertain (Harsoulis et al., 1978, Ongenae et al., 2003). Nevertheless, the strongest evidence for an autoimmune process underlying GV is its close epidemiological association with other autoimmune diseases, both in GV patients and in their close relatives (Alkhateeb et al., 2003a). In 1855 Addison reported a patient with idiopathic adrenal insufficiency, vitiligo, and pernicious anemia (Addison, 1855). Subsequently, Schmidt described concomitant occurrence of multiple autoimmune diseases, including GV, in what came to be called “Schmidt syndrome” (Schmidt, 1926). Much later, Neufeld and Blizzard categorized the so-called “autoimmune polyglandular syndromes” (APS), with Schmidt syndrome denoted type II (Neufeld and Blizzard, 1980). Over the past few years it has become clear that APS II is more complex than previously thought, and that GV is part of an autoimmune disease diathesis that also includes autoimmune thyroid disease (AITD, particularly Hashimoto’s thyroiditis and Graves’ disease), rheumatoid arthritis, adult-onset type 1 diabetes mellitus, psoriasis, pernicious anemia, Addison’s disease, and systemic lupus erythematosus (SLE), 10%–15% or more of patients with GV also manifesting one or more of these other autoimmune diseases (Alkhateeb et al., 2003a, Laberge et al., 2005, Sun et al., 2006). Moreover, these same autoimmune diseases also occur at increased frequency in GV patients’ first-degree relatives, regardless of whether or not those relatives have vitiligo themselves (Alkhateeb et al., 2003a, Laberge et al., 2005). Together, these findings indicate that GV patients and their close relatives have genetically determined susceptibility to this specific group of autoimmune diseases, most likely mediated by shared susceptibility genes that predispose to these diseases, other genes and exposure to environmental triggers determining the occurrence of GV and other specific autoimmune diseases in individual patients (Spritz, 2008).

Epidemiological studies have shown that GV is a complex trait, involving combinatorial pathogenic effects of multiple susceptibility genes and also environmental risk factors. Clustering of GV cases occurs in some families, almost always in non-Mendelian patterns indicative of polygenic, multifactorial causation (Alkhateeb et al., 2003a, Laberge et al., 2005). Indeed, the concordance of GV in monozygotic twins is only 23% (Alkhateeb et al., 2003a), highlighting the importance of environmental triggers, which as yet remain unknown.