A new discovery could someday help identify smokers at risk for chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States.

More than 12 million people in the U.S. have been diagnosed with COPD, and another 12 million may have the condition and not know it.  These people have difficulty breathing due to excessive inflammation in their lungs that has narrowed their airways.  The cause of the inflammation is usually prolonged exposure to an inhaled irritant, most often cigarette smoke. Nine out of ten COPD deaths can be attributed to smoking.

But even though most people with COPD are current or former smokers, not every smoker gets COPD.  Only about 20% will develop the disease, suggesting that there might be genetic factors that make some smokers more susceptible than others. New research, published yesterday in the journal PLoS Genetics, suggests that variation in a genetic region on chromosome 15 previously linked to nicotine addiction, lung cancer and peripheral artery disease might also increase the risk for COPD.  In light of the mounting evidence for the importance of this stretch of DNA, the authors of the new report suggest that genetic screening of smokers in order to find those at the highest risk may be an attractive interventional strategy.

Sreekumar Pillai, a scientist at GlaxoSmithKline, and colleagues from several research institutions studied a total of more than 5,000 people with European ancestry and found that each A at the SNP rs1051730 on chromosome 15 increased odds of COPD by about 1.3 times.  They also found that each C at SNP rs8034191 increased the odds of COPD by about 1.4 times. The two SNPs are very close to each other and probably both mark the same variation affecting COPD risk, although the authors did not test this.

[23andMe customers can check their data for rs1051730 and rs8034191 using the Browse Raw Data feature.  Keep in mind that because the SNPs are closely linked, having the same version of both (either non-risk or risk) is expected.  A riskier version at both does not indicate doubled risk.]

Research has shown that in smokers, each A at rs1051730 is associated with smoking one more cigarette per day.  Whether rs1051730 is linked to lung cancer and peripheral artery disease because of or in addition to its effects on smoking has been controversial.  The authors of the current study say that while their data does not allow them to solve this dilemma with regard to the effects of the chromosome 15 SNPs on COPD, several aspects of their study indicate that the genetic variation has a direct effect on the disease, independent of smoking behavior.

The authors do note, however, that in some subsets of their study population the effect of the riskier versions of the genetic variations was greater in current smokers compared to former smokers.  This could mean that people who have a harder time quitting are more likely to develop COPD.  Alternatively, it could be the case that some people are at higher risk for COPD if they continue to smoke.

The researchers also found evidence for variations contributing to COPD on chromosome 4, although the results were not statistically significant. However, this same region of DNA was correlated with lung function in a different report in same issue of PLoS Genetics.  Both research groups pointed out that the nearest gene to the chromosome 4 variations they identified is involved in lung development, suggesting that future research targeting these variations might reveal more insight into COPD and other lung diseases.

ShareThis

For many common diseases, environment is far more important than genetics in determining whether a person will be affected. One of the best examples of this is lung cancer. Nearly 90% of the cases of this disease can be attributed to smoking.

Today at the American Association for the Advancement of  Science meeting in Chicago, however, Thorgeir Thorgeirsson of deCODE Genetics suggested that genetics may help foster a better understanding of the environmental risk factors for lung cancer.

Several studies published in April 2008, including one authored by Thorgeirsson, showed that a variation on chromosome 15 is associated with increased odds of lung cancer.  Thorgeirsson’s group also showed that this same variation is associated with increased smoking – about one cigarette per day per copy of the riskier version (Read more here.)

Together these findings raise an important question:  does this variation increase the odds of cancer because it increases the amount a person smokes?

According to Thorgeirsson, there should be only a 5% increase in the odds of developing lung cancer based on the increase in smoking associated with the genetic variation. But the data indicate that each copy of the riskier version actually increases odds of the disease by about 30%.

This, Thorgeirsson suggested, could mean that the variation is associated not just with smoking quantity, but also with another behavior, such as how deeply a smoker inhales or how far down he usually smokes his cigarettes.  He noted a recent study published in Cancer Research that found that, compared to smokers without the genetic variation, those with it take in more nicotine and carcinogens with every cigarette.

Another possibility is that the variation has a dual effect.  It could increase not just smoking quantity, but also the vulnerability of a person’s cells to the harmful effects of the smoke.

Although there’s still much work to be done in order to fully understand the effects of this particular genetic variation, the results so far hint at the fact that genes and environment may for more interconnected than previously appreciated.

ShareThis

Each type of cancer has its own idiosyncrasies, but when it comes down to it, they all have one thing in common: failure to control cellular growth. So it’s somewhat surprising that when genome-wide association studies have looked for single common variations associated with the risks for multiple types of cancer, they have for the most part identified only SNPs that are peculiar to just one form of the disease.

A new study published online Sunday in Nature Genetics may signal a change in this trend. A team of researchers led by Thorunn Rafnar and Patrick Sulem of deCODE Genetics in Iceland describes how a SNP they originally found to be associated with the risk for developing basal cell carcinoma (BCC), a type of skin cancer, is also linked to increased odds for four other cancers.

In a study of more than 33,800 cancer patients and 45,800 controls, the scientists found that the C version of rs401681 is associated with increased odds of lung, bladder, prostate and cervical cancer, in addition to the previously found association with BCC. This variation decreases the odds of cutaneous melanoma, another type of skin cancer.

(23andMe customers can check their data for this SNP, rs401681, using the Browse Raw Data feature. A table at the end of this post provides details about its effect on different cancers).

The C version of rs401681 was also marginally, although not significantly, associated with increased odds of endometrial cancer and decreased odds of colorectal cancer.

There was no association of the SNP with cancer of the breast, kidney, stomach, thyroid, ovary or pancreas, nor with lymphoma, multiple myeloma or squamous cell carcinoma (a third type of skin cancer). The authors say that further investigation in even larger samples will be needed to determine if there truly is no association, or if they just haven’t picked it up yet.

An association was also found between rs2736098, a nearby SNP, and four of the five cancers that were associated with rs401681. 23andMe does not currently provide data for rs2736098.

Both SNPs are near a gene involved in maintaining the protective stretches of DNA attached to the ends of chromosomes called telomeres. The authors suggest that these SNPs, or other nearby variations, may lead to shortened telomeres, which are associated with several types of cancer.

Telomere length is determined in part by genetics, but environmental factors such as smoking and radiation can also shorten them. The authors note “four of the five cancers associated with the risk variants are cancer types that have strong environmental contributions to risk – smoking and occupational exposures for lung and bladder cancer, UV irradiation for BCC and infection with human papillomavirus for cervical cancer.” More research could help explain the exact relationship between the genetic variations found in this study and the environmental causes of these cancers.

*Effect is the increase or decrease in odds compared with someone with two copies of the T version of rs401681.

ShareThis

When the toxins in cigarette smoke are inhaled, lung cells don’t just sit there and take it. A complex network of proteins is activated with every puff. The proteins break down, modify, or pump out as many of the hundreds of cancer-causing chemicals in tobacco smoke as possible.

But when this system fails or falls behind, toxins have a chance to damage cells. New results published online this week in Cancer show that variants in the genes for ABCB1 and ABCC1, two important pump proteins that transport a variety of toxins out of lung cells, increase the risk of lung cancer.

Haijian Wang and colleagues studied 500 lung cancer patients and 517 healthy controls from Nanjing City and the surrounding area in southeast China. They found that, overall, having one or two Cs at rs3842 in the ABCB1 gene was associated with 1.36 times increased odds of lung cancer compared to having two Ts. For rs212090 in the ABCC1 gene, having one or two As increased the odds by 1.37 times.

(23andMe customers can use the links above to check their data using the Browse Raw Data feature.)

Further analysis showed that the C version (one or two copies) of rs3842 increased the odds of lung cancer in women of all ages by 2.57 times and by 1.5 times in those younger than 60. The A version of rs212090, on the other hand, was not significantly associated with lung cancer in those under 60, but did increase the odds by 1.6 times in those 60 and above. In those people with a history of cancer in a first-degree relative (parent, sibling or child), the C version of rs3842 increased the odds of lung cancer by 1.91 times.

A final correlation the authors found was between the riskier C version of rs3842 in the ABCB1 gene and a specific type of lung cancer called adenocarcinoma. The authors say that the rates of this type of cancer has been increasing in the last few decades, as has the amount of a specific carcinogen in cigarette smoke that is dealt with by the ABCB1 protein.

“Because tobacco smoking is the leading preventable cause of cancer and the cancer –prone genotypes of these genetic components are relatively prevalent in the human population, our findings have important implications for the prevention of tobacco smoking-related cancers,” the authors write.

ShareThis

Despite the success of genome-wide association studies, many experts rightly point out the need to remember that most common diseases have a significant environmental component. For example, cigarette smoking increases one’s risk of lung cancer 10- to 20-fold, according to the National Cancer Institute. But other studies have found that even after controlling for smoking, having first-degree relatives with lung cancer increases one’s own risk by a modest amount, suggesting at least a small genetic component.

A trio of papers published today in Nature and Nature Genetics has found a SNP on chromosome 15 that is linked to lung cancer risk. Two of the studies, by Hung et al. and Amos et al., matched lung cancer cases and healthy controls for smoking behavior and compared their genotypes across 300,000 SNPs. Both studies found that one copy of the A version of rs1051730 increased subjects’ odds of lung cancer by about 1.3 times compared to those with none; having two copies increased subjects’ odds by 1.8 times. (23andMe users can see their genotype at rs1051730 in the Genome Explorer (now called Browse Raw Data).)

A 1.8-fold increase may not seem like much compared to the 10- to 20-fold increase seen for smokers. But if this genetic effect is independent of the effect of smoking, smokers with the AA genotype might find themselves at 18- to 36-fold increased risk compared to nonsmokers with the GG genotype.

A third study questions whether the SNP’s effect on lung cancer risk is truly independent of smoking. Thorgeirsson et al. found evidence that the same SNP, rs1051730, is actually linked to nicotine dependence. On average, each copy of the A version increased the number of cigarettes subjects smoked by about one cigarette per day. The authors also reported that most of the increased risk of lung cancer conferred by the A version was due to its effect on smoking. Thus, an environmental component itself appears to have a genetic component.

However, the effect of rs1051730 on smoking quantity was seen only if a subject smoked at all. Genotype at rs1051730 wasn’t connected with whether subjects smoke, only with how much they smoke once they start.

So in the nature vs. nurture debate, perhaps there is room for free will after all.

ShareThis