Risky Business: Nongenetic Factors May Increase Odds of Developing ALS

by Amy Madsen on Mon, 2013-02-04 09:00
Article Highlights:
  • Currently, only a small percentage of ALS is clearly attributable to genetics, leaving a lot of room for the possible involvement of nongenetic risk factors.
  • Age and gender are consistent and accepted nongenetic ALS risk factors; other factors are suspected and have been the focus of many studies, but their contribution to ALS — if any — hasn't been proved.
  • The article features a slideshow detailing the top 10 suspected nongenetic risk factors in ALS.
  • People with ALS can help advance research on nongenetic risk factors in ALS by registering with the National ALS Registry and completing Registry risk factor surveys (see Answer Questions, Help Identify ALS Risk Factors).
  • For more on the search for nongenetic factors, read an interview with ALS researcher Marc Weisskopf.

Everyone is born, and everyone dies. What happens in between — colds and flu, cardiac problems, cancer, amyotrophic lateral sclerosis (ALS) — is anyone's guess. And people do guess. It's common — indeed, almost universal — after receiving a diagnosis for any condition to question whether there's something that could have been done to prevent it.

In some cases, what a person does or doesn't do has no bearing on whether or not they develop a disease later in life. This is because their DNA (genetic "blueprint") may feature certain mutations or variants that cause them to develop the disease, or that raise the risk of developing it. For example, certain mutations in the SOD1, TDP43, FUS and C9ORF72 genes are known to cause ALS, while other genetic flaws such as expansions in the ataxin 2 gene, extra copies of the SMN1 gene and repeat expansion mutations in the NIPA1 gene are associated with a higher risk of developing the disease.

However, some diseases can be caused, at least in part, by things that can't be found in a person's genetic makeup — nongenetic risk factors.

For example, an unhealthy diet is often pinpointed as the cause for certain types of heart disease, and too much exposure to the sun has been identified as a cause of some kinds of cancer.

So, what about ALS? Is there something besides people's genes that can cause the disease, or increase the chance of developing it? What are some of the possible nongenetic risk factors for ALS, what is known about them and what are scientists doing to learn more?

Do nongenetic risk factors contribute to ALS?

Currently, only a small percentage of ALS is clearly attributable to genetics, leaving a lot of room for the possible involvement of nongenetic factors.

Age and gender are consistent and accepted nongenetic ALS risk factors. Older age is positively associated with the risk of developing ALS, and men are slightly more likely to develop ALS than are women. Studies suggest an overall ratio of about 1.2 men to every woman who develops the disorder.

One hint that the environment also may play a role is the history of ALS in Guam, where incidence of the disease between 1940 and 1965 reached 50 to 100 times its worldwide rate and became the leading cause of death among natives.

Most ALS in Guam at that time was associated with Parkinson-dementia complex (PDC), a disorder that combines the tremor of Parkinson’s disease with the memory loss of Alzheimer’s. ALS-PDC wasn’t found among non-native Guamanians.

The high rates of ALS on Guam have since been attributed to inclusion in the native peoples’ diet of poisonous nuts from the indigenous cycad tree, and the incidence of both ALS and ALS-PDC among the native Gaumanians has dropped dramatically over the course of several decades. Such rapid change isn’t consistent with genetics and is a powerful indicator that the environment played a key role in causing the disease.

Risk in the environment

Nongenetic risk factors for disease may exert influence alone or in combination.

Common environmental factors suspected of contributing to ALS include ethnicity, geographic location, diet and nutrition, exercise and sports, alcohol or tobacco use, occupation, electric shock, exposure to chemicals or radiation, and concussion or other physical injury ("trauma").

Some suspicion also falls on: air, water or soil pollution; electromagnetic fields; the materials used in the construction of houses and roads; land management techniques; agricultural methods, including irrigation practices; climate and climate change; economic status and availability of health care.

Nongenetic ALS risk factors slideshow: The top 10 suspects

  • Although age and gender are the only consistently recognized nongenetic risk factors for ALS, a number of others are suspected, although strong evidence does not yet exist that they contribute to the development of the disease. Here are 10 of the most commonly suspected (although unproven) ALS risk factors. Note that some factors might work together, making it hard to assign blame to any single one. For example, it’s difficult to tease out whether physical exercise, head injury or the chemicals used on soccer fields — or all three — could be contributing to a higher incidence of ALS in Italian soccer players.

  • Race/ethnicity and cultural background: A 2007 study showed that the incidence of ALS may be lower among African, Asian and Hispanic people than among non-Hispanic whites. Among non-Hispanic whites, ALS was found to occur at the same rates in populations in Europe and North America. Although genetics are involved in this risk factor, ethnicity also is tied to cultural background, socioeconomic and religious factors, and ancestry. Knowing how ethnicity modifies ALS risk could provide insight into the interplay between the genetic and nongenetic factors that drive the disease.

  • Military service: Studies indicate that people who have served in the military (particularly Gulf War veterans) may be at higher risk of ALS. What's behind the connection is uncertain, but suggestions include exposure to certain metals or chemicals, injuries (such as head trauma), viral infections and intense exertion.

  • Alcohol consumption: The risk of ALS has been found to be markedly lower among people who drink alcohol than among those who abstain, according to a 2012 study. Although alcohol consumption was associated with a reduced risk of developing ALS, in those who did get the disease it was not associated with increased survival or an older age at onset.

  • Cigarette smoking: In a 2011 study of more than a million people (562,804 men and 556,276 women), a total of 832 people with ALS were identified. Smokers had a significantly higher risk of developing ALS than people who had never smoked. The risk of developing ALS went up with the number of years a person had smoked and the number of cigarettes smoked per day; similar trends have been found in some smaller studies, but not in others.

  • Chemical exposure: Exposure to organophosphates (chemicals found in herbicides and pesticides), in combination with genetic risk factors, has been scrutinized as a possible link to ALS, with different studies resulting in different conclusions. Despite a lack of any clear evidence linking chemicals to ALS, results from a 2009 study did show increased ALS risk from exposure to formaldehyde. Other chemicals that have come under suspicion for possible associations with ALS include various solvents and the heavy metals mercury and lead.

  • Geographic location: Despite a number of reported clusters in the United States (such as the area surrounding Lake Mascoma in western New Hampshire), the only confirmed occurrence of ALS related to a geographical area was described in Guam, where between 1940 and 1965 the incidence of ALS reached 50 to 100 times its worldwide rate. Factors specific to the area may be the culprits. For example, bacterial toxins in the lake may be the source of the possible link between living near Lake Mascoma and developing ALS. Inclusion in the native peoples’ diet of poisonous nuts from the indigenous cycad tree was found to be responsible for the increased incidence of ALS in Guam.

  • Diet: Chicken, tea, brown rice/wheat/barley, decaffeinated coffee and French fries, and their possible association with a higher risk of ALS were the focus of a 2008 report on a study of dietary factors in ALS. The strongest finding in the study was an inverse association between eating chicken and developing ALS; the more chicken consumed, the lower the risk of ALS. Investigators also found an increased risk for ALS among people who ate greater amounts of brown rice/whole wheat/barley and decaffeinated coffee, and a decreased risk for those who consumed greater amounts of decaffeinated tea and French fries — these associations, however, were not statistically significant.

  • Exercise: A possible relationship between a history of physical activity or longtime participation in sports, and developing ALS has long been suspected, but as of yet has not been proved definitively.

  • Head trauma/injury: In a 2012 evaluation of literature published between 1980 and October 2010, investigators determined that not enough evidence exists to suggest that a single instance of head injury is a risk factor for ALS. Research into the effects of multiple concussions or repetitive head trauma sustained in contact sports (such as American football), however, suggests a possible association.

  • Electrical shock: Data from a 2012 study suggest a slight but significant risk of developing ALS among people who are regularly exposed to high levels of extremely low frequency electromagnetic fields in their line of work. The study team noted, however, that variables such as electric shock, which could be encountered in electrical occupations, could be responsible instead.

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Join a registry

Epidemiology — from the Greek, meaning "the study of what is upon the people" — is the study of the patterns, causes and effects of human health and disease.

Epidemiologists design and conduct studies, collect and analyze data, and often help interpret and disseminate their findings. (Read ALS Research: Q&A with Marc Weisskopf to learn more about epidemiological research in ALS.)

What epidemiologists learn about the nature of disease is used in the practice of medicine and therapy development, and informs policy decisions relating to public health.

One way people can help epidemiologists identify ALS risk factors is by participating in registries that collect information on demographics and lifestyle factors, and biorepositories that collect biological samples.

For more, see the sidebar below and also these registries: fALS Connect, National ALS Registry and MDA's Clinical Neuromuscular Disease Registry.

And for more on the search for nongenetic factors, read an interview with ALS researcher Marc Weisskopf.

The identification of nongenetic risk factors can help scientists better understand and determine the causes of ALS.

The work to uncover these factors is being facilitated by the National ALS Registry, funded by the federal government and headquartered in Atlanta at the Agency for Toxic Substances and Disease Registry (ATSDR).

Read more ...

Amy Madsen
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