Thursday April 22 2010
Vitiligo causes pigment loss in skin and hair
People with vitiligo “may have natural protection against skin cancer”, according to BBC News. The condition, which causes pale skin patches due to a loss of pigment, was previously assumed to increase the risk of serious skin cancers, such as malignant melanoma.
The study looked at 1,514 people with vitiligo and 2,813 people without the condition. The researchers identified several genetic variations associated with an increased risk of vitiligo. Two of these variations were also associated with a reduced risk of melanoma, and several others were located in regions containing genes known (or thought) to play a role in other similar immune conditions, such type 1 diabetes and rheumatoid arthritis.
The most important finding of this study was the identification of genetic variations associated with vitiligo. The suggestion of a link with melanoma will no doubt prompt further research, but at this stage it is too soon to say if these findings have major implications for melanoma risk in people with vitiligo. The researchers themselves warn that people with vitiligo should still be careful in the sun as they can sunburn quickly, and even a reduced risk of melanoma does not mean that there is no risk.
Where did the story come from?
This study was carried out by Dr Ying Jin and colleagues from the Human Medical Genetics Program at the University of Colorado School of Medicine, along with international researchers, some of whom were based at universities in Sheffield and London. The study was supported by grants from the US National Institutes of Health and a grant from the Anna and John Sie Foundation. The study was published in the peer-reviewed New England Journal of Medicine.
This research was covered by BBC News, which reported both the strengths and limitations of the study and correctly placed little emphasis on suggestions that the finding could quickly lead to new treatments.
What kind of research was this?
This was a genome-wide association study in which the researchers aimed to identify the areas of the genetic code (called susceptibility loci) associated with generalised vitiligo. The condition involves patchy loss of colour in the skin and hair, caused by the body attacking its own pigment-producing cells (melanocytes). While vitiligo is thought to be partly triggered by environmental factors, the condition is also known to be partially caused by genetics.
The researchers already had an idea of which sections of DNA to examine as previous studies have suggested several potential loci. In addition, patients with generalised vitiligo often have other autoimmune diseases, such as autoimmune thyroid disease, rheumatoid arthritis, psoriasis and adult-onset type 1 diabetes. This suggests that these diseases have shared genetic components.
The research involved genotyping. This is a process of scanning the genetic code found in sections of DNA. In their genotyping, the researchers looked at single-letter variations (579,146 variants or single-nucleotide polymorphisms [SNPs]) across large areas of the genetic code in 1,514 patients with generalised vitiligo.
The results of this genotyping were compared with publicly available genotypes from 2,813 healthy people (the control group). All those tested were of European white ancestry. The results were then confirmed by comparing them to a second set of samples.
What did the research involve?
The researchers took samples of DNA from 1,514 patients from North America and the United Kingdom who met the clinical criteria for the diagnosis of generalised vitiligo. The genotype data from these patients were compared with the genetic sequences of 2,813 control participants drawn from datasets stored in a US database, known as the National Institutes of Health Genotype and Phenotype database.
The researchers assessed how common the different variants (alleles) were at each of the 579,146 genetic sites assessed, looking to see whether any variants were more common in people with vitiligo than in those without it. They also assessed the degree of association (how much more common the variant was) and the probability that any associations could have arisen by chance.
After the researchers had assessed which SNPs were associated with vitiligo, they repeated the analysis, focusing on these SNPs in two independent “replication sets”. These are different sets of samples and are typically used in this type of study to test the reliability of specific SNP associations found in the first analysis.
The first replication set included 677 unrelated patients with generalised vitiligo and 1,106 controls. The second replication set featured a family-based cohort of 183 samples from families where parents and offspring were affected by vitiligo and 332 samples from families with two or more affected family members and their unaffected relatives as controls. These sample sets were tested for the presence of 50 SNPs in nine chromosomal regions that had the strongest associations with generalised vitiligo.
The research was well described and conducted. The use of replication sets increases the reliability of the findings. Also important in these types of study are the quality-control procedures used to ensure that processes, such as DNA purification, are carried out correctly. These procedures were described extensively in supplementary material.
Informed consent was obtained from all the study participants.
What were the basic results?
The researchers found that nine chromosomal regions contained SNPs associated with generalised vitiligo. The acceptable levels for statistical significance in genome-wide association studies are higher than in other types of study, which reflects the fact that they can involve numerous statistical tests that can increase the likelihood that an association will be found by chance. All associations in this study were reported at the significance level of p less than 5 × 10-8. This means that it is highly unlikely they occurred by chance.
The associated SNPs mainly lay in regions that have previously been associated with other autoimmune diseases. The most strongly associated SNPs lay in the region called the major histocompatibility complex, which contains genes important for the immune system. The other regions previously associated with other autoimmune diseases contained the genes PTPN22, LPP, IL2RA, UBASH3A and C1QTNF6. Two other associated regions contained additional immune-related genes, called RERE and GZMB, and one associated region contained the gene TYR.
Two of the associated SNPs in the region containing the TYR gene had previously been associated with susceptibility to malignant melanoma. However, the variants associated with increased risk of vitiligo were also associated with reduced risk of malignant melanoma.
Most of the 50 SNPs tested in the two replication sets showed significant association with vitiligo in at least one of the sets. All nine regions where these SNPs were found featured the same associations observed in the first set of samples.
How did the researchers interpret the results?
The researchers concluded that they had identified genetic variants associated with generalised vitiligo in multiple chromosomal regions, suggesting that multiple genes are involved in susceptibility to this condition. They say that the genes in some of these regions have been associated with other autoimmune diseases, and variants in another region may be associated with both an increased risk of vitiligo and a reduced risk of melanoma.
This study is one of the first to comprehensively establish areas of genetic code that may be involved in development of generalised vitiligo. The researchers comment that their study shows little agreement with the associations reported in previous studies.
They say that the loci identified in this study together account for about 7.4% of the total genetic risk for vitiligo and that, although this is small, their study is an important insight into the condition.
The suggestion that increased risk of vitiligo is accompanied by a reduced risk of malignant melanoma is a puzzling result of the study, but at this stage it is too soon to say if this means anything. It will take further research to understand this genetic association and how it relates to the risk of skin cancer for those with vitiligo. Regardless, everyone, including people with vitiligo, should avoid getting burnt by the sun.