Genetics of vitiligo

Vitiligo is an acquired common depigmenting disorder characterized by development of depigmented macules and patches secondary to selective destruction of melanocytes. The prevalence of vitiligo is high ranging from 0.005 to 0.38% cases worldwide. The etiological factors of vitiligo are complex including genetic, immunological, neurohormonal, cytotoxic, oxidative stress and melanocytorrhagy. Most of the currently available evidence supports the occurrence of an autoimmune phenomenon in patients with an underlying genetic predisposition. Genes possibly play a role in all aspects of pathogenesis of vitiligo. Most genes associated with susceptibility to the disease are involved in immune regulation and immune targeting of melanocytes. However the triggers which set off this autoimmune process are not completely clear. With further advancement and research in understanding the pathogenesis of this psychologically devastating disease, newer insights into its etiopathogenesis keep emerging.

Vitiligo was first described by Claude Nicolas Le Cat in 1765.  The first specific consideration of a genetic component in vitiligo came in 1950 when Stűttgen and Teindel simultaneously reported a total of eight families with multiple relatives affected by vitiligo.

The autoimmune and genetic hypothesis was initially supported by

1. Clustering of vitiligo cases in certain families (Multiplex vitiligo families).

2. Increased frequency of autoimmune diseases in patients of vitiligo as in their first degree relatives (with or without vitiligo) more so in multiplex vitiligo families.

This indicated a genetic predisposition to a specific group of autoimmune disorders including vitiligo with exposure to environmental triggers possibly determining the occurrence of vitiligo and other specific autoimmune diseases in individual patients.

Epidemiological studies have shown that vitiligo far from following a single gene locus associated Mendelian pattern of inheritance is more of a complex trait, involving multiple susceptibility genes and also environmental risk factors. Clustering of vitiligo cases occurs in multiplex families almost always in non-Mendelian patterns indicative of polygenic, multifactorial causation.

Various studies have found that the frequency of vitiligo among first-degree relatives varies from 0.14% to as high as 20%. Such figures suggest a definite genetic component but only 23% concordance has been observed amongst monozygotic twins, which suggests that a significant non-genetic component also exists in the pathogenesis of vitiligo.

Large-scale genome-wide association studies principally in European-derived whites and in Chinese have discovered approximately 50 different genetic loci that contribute to vitiligo risk, some of which also contribute to other autoimmune diseases that are epidemiologically associated with vitiligo. At many of these vitiligo susceptibility loci the corresponding relevant genes have now been identified and for some of these genes the specific DNA sequence variants that contribute to vitiligo risk are also now known.  A large fraction of these genes encode proteins involved in immune regulation, a number of others play roles in cellular apoptosis and still others are involved in regulating functions of melanocytes.

Several candidate genes including:

Major histocompatibility complex (MHC),

Angiotensin-converting enzyme (ACE),

Catalase (CAT),

Cytotoxic T lymphocyte antigen-4 (CTLA-4),

Catechol-O-methyltransferase (COMT),

Estrogen receptor (ESR),

Mannan-binding lectin (MBL2),

Protein tyrosine phosphatase,

Non-receptor type 22 (PTPN22),

NACHT leucine-rich repeat protein 1 (NALP1),

X-box binding protein 1 (XBP1),

Forkhead box P1 (FOXP1) and interleukin-2 receptor A (IL-2RA) that are involved in the regulation of immunity have been tested for genetic association.

In patients with various vitiligo-associated autoimmune/auto-inflammatory syndromes, HLA haplotypes, especially HLA-A2, −DR4, −DR7 and −DQB1*0303, have been frequently found to play an important role. At the same time in patients with vitiligo alone, PTPN22, NALP1 and XBP1 have been found to play a causal role. Genome-wide linkage analysis has revealed autoimmune susceptibility (AIS) loci associated with vitiligo. AIS1 was discovered to be located on chromosome 1p31.3–p32.2, AIS2 on chromosome 7 and AIS3 on chromosome 8. AIS1 and AIS2 linkages were found to occur in families with vitiligo along with other autoimmune diseases, while AIS3 was found in the non-autoimmune family subgroup. Another gene systemic lupus erythematosus vitiligo-related gene (SLEV1) located on chromosome 17 was found to be associated with generalized vitiligo present in association with other concomitant autoimmune diseases.

 

While many of the specific biologic mechanisms through which these genetic factors operate to cause vitiligo remain to be elucidated, it is now clear that vitiligo is an autoimmune disease involving a complex relationship between programming and function of the immune system, aspects of the melanocyte autoimmune target and dysregulation of the immune response.

 

Dr. Elangbam Nelson Singh, MD