Not being exposed to sunlight during adolescence could lower the age at onset of multiple sclerosis (MS), a new study suggests.
The results support a potential protective role of the sun in the pathogenesis of MS, said lead author Julie Hejgaard Laursen, MD, PhD, Danish Multiple Sclerosis Center, Rigshospitalet, Copenhagen.
However, whether the protection comes from the sun's ultraviolet (UV) rays or from vitamin D from sun exposure is still uncertain, they say.
The study also found a link between higher body mass index (BMI) and earlier age of MS onset.
The study was published online October 7 in Neurology.
The analysis included 1161 Danish patients with MS for whom researchers had genotyping data as well as information on age at MS onset from the Danish MS Treatment Registry. The patients had taken part in an earlier study of genetic and environmental determinants of 25-hydroxyvitamin D levels in MS.
Researchers excluded patients with ethnicity other than Danish, leaving a genetically and culturally homogenous study group. They also excluded patients with MS onset before age 20 to reduce the risk for reverse causality.
Summer Sun
From information in questionnaires, researchers categorized patients as having spent time in the sun every day in the summer during adolescence (ages 10 to 19 years) or not spending time in the sun every day during this time.
In the univariate analysis, those not spending time in the summer sun every day had a mean age at MS onset that was1.9 years younger than that in the group spending time in the sun every day (31.0 years vs 32.9 years).
Results from a multivariable model confirmed the link between summer sun habits and MS onset (P = .04).
How sun exposure might affect MS is not an easy question to answer, according to Dr Laursen. On the one hand, research appears to implicate hypovitaminosis D as a contributor to MS risk as well as to the disease course.
"Vitamin D has a strong immunomodulating potential," said Dr Laursen. "Since UV-B irradiation is the main source of human vitamin D, one could be tempted to conclude that the association between sun exposure and MS is caused by an underlying effect of vitamin D."
As well, studies have shown that being exposed to the summer sun for only 30 minutes corresponds to a vitamin D intake of 250 ¼g, which is "way above" the recommended daily intake of 10 ¼g per day in Denmark, said Dr Laursen.
"But until now, no studies in MS have clarified what doses of vitamin D should be recommended to reach levels associated with reduced disease risk and disease activity and at the same time be safe."
On the other hand, research also demonstrates independent and favorable effects of sun exposure in the development of a healthy, tolerogenic immune system. This, said Dr Laursen, implies "confounding mechanisms" or "additive advantages" of sunlight in the context of vitamin D and autoimmun
As with vitamin D, experts don't know the optimal dose of UV-B light needed for MS protection. "Even if we did, we must not forget that sun exposure is also associated with an increased risk of skin cancer and melanoma."
Since the study included several vitamin D–related factors that were not associated with MS age at onset, the protective effects of UV-B light may not necessarily be related to vitamin D, said Dr Laursen.
One such factor was the use of multivitamin/vitamin D supplements during adolescence. The researchers found no correlation between age at onset and the number of years taking such supplements. This lack of association, however, might be due to recall bias, said Dr Laursen.
"We didn't attempt to collect more detailed information about the use of vitamin supplements other than a simple estimate of the number of years of vitamin D supplementation."
There was no association between fatty fish intake at age 20 years and age at MS onset. Again, this could be due to recall bias, said Dr Laursen. "It may be difficult to remember how often you ate fatty fish when you were teenager."
It was a different story with weight. From information on BMI at age 20 years, the study found that the mean age at onset for people with BMI greater than 25 (overweight) was 1.6 years younger than that of people with BMI of 18.5 to 25 (normal range) and 3.1 years lower for BMI <18.5 (underweight).
The relationship between age at MS onset and BMI, which again was confirmed in the multivariable model, might reflect a pathogenic effect of leptin, which is proinflammatory, commented Dr Laursen.
"Our finding indicates some kind of harmful effect of BMI. However, we have to be extremely careful when drawing conclusions on this topic; for example, we can't say that being underweight is protective in MS. But our finding supports that BMI may be an important lifestyle factor in the complex puzzle of MS risk factors."
The researchers also found a relationship between the HLA-DRB1*1501 allele and age at MS onset. Being homo- or heterozygous for the risk allele G was associated with a 2.2-year (95% confidence interval, 1.1 - 3.3 year) lower age at onset compared with the AA genotype.
That finding wasn't surprising because this allele has already been shown to increase the risk for MS among northern Europeans by a factor of 3 to 4, said Dr Laursen. This allele has also been associated with MS age at onset.
Vitamin D and sun exposure have been studied extensively by MS experts. Some research indicates that vitamin D insufficiency from lack of sun exposure during pregnancy may increase the risk for MS in offspring. Other studies have suggested that childhood sun habits and outdoor activities are associated with MS risk.
The authors of the current study chose to concentrate on adolescent summer sun habits since the teen years seem to be a particularly vulnerable period for exposure to harmful environmental factors, said Dr Laursen. "It would definitely have been interesting to include childhood sun habits as well, although risk of recall bias would be even more pronounced if this period of life was included."
Dr Laursen stressed that it may never be possible to rule out reverse causation when it comes to MS and environmental factors. "It would be extremely difficult to design a study that can provide the answer for a causal relationship between sun exposure and MS.
Constant Battle
Invited to comment on the new research, Anthony Reder, professor, neurology, University of Chicago, Illinois, said the researchers used "solid data" from "good databases."
For him, the study findings suggest that "there's a constant battle" between the risk for MS and factors that might trigger it or prevent it "even from a pretty early age."
Current lifestyle habits among adolescents might increase chances of losing that battle. "Imagine you're a teenager sitting in the basement all the time playing video games, not exercising, eating junk food, gaining weight, and maybe smoking," said Dr Reder. "That's like the worst possible picture of someone who is more likely to develop MS."
While sun exposure does increase the risk for melanoma, "the risk is mainly from weekend warriors who go out and get burned once a week," said Dr Reder. "But if you gradually increase your tan without getting burned, the incidence of melanoma is probably actually lower."
As for the lack of association with supplements in the study, Dr Reder pointed out that multivitamins don't contain much vitamin D. He also noted that milk and orange juice are fortified with vitamin D in the United States, which might not be the case in northern Europe. (In Denmark, according to Dr Laursen, except for one type of milk, milk and orange juice are not enriched with vitamin D, although an expert group is currently discussing enriching flour or bread.)
"There is some vitamin D in the environment for everyone, so the question is, where is the threshold? How high should it be to prevent MS and other autoimmune diseases? "
Dr Reder pointed out that the study's findings on fish intake were unlike those of some studies showing a correlation between consuming large amounts of fish and higher vitamin D and less MS.
He also noted that the location of the study — a northern latitude similar to some areas of Alaska — makes it an "ideal place" to look at sunlight effects on MS. Denmark, like other Scandinavian countries with a relatively high incidence of MS, lies at the top of the "geographic gradient" in Europe, with the MS incidence decreasing as you move toward Spain and other more southerly countries, said Dr Reder.
MS is rare in China — about one tenth the rate in the United States — and also rare in African countries. However, Dr Reder says he now has some female patients with MS from Kenya in his practice.
The study was supported by the Danish Multiple Sclerosis Society, the Danish Council for Strategic Research, and Brodrene Rønje Holding. Dr Laursen has received honoraria for lecturing from Merck Serono and has had travel expenses reimbursed by Teva, Almirall, and Merck Serono. Dr Reder has disclosed no relevant financial relationships.
Neurology. Published online October 7, 2015. Abstract