Stomach cancer is the second most common form of cancer. People that carry the bacterium Helicobacter pylori in their stomachs -- half the world's population -- are between 3 and 6 times more likely to develop it.

In this week's Nature1, Emad M. El-Omar, of the US National Cancer Institute, Maryland, and colleagues show that the risk of stomach cancer also depends on the genetic make-up of H. pylori's human host.

H. pylori bacteria cause inflammation of the stomach tissue in everyone who carries them. That is, the bacteria cause blood flow to the infected area to increase, resulting in swelling and irritation. This can become a medical problem in two main ways. In about 10% of carriers, inflammation of the lower part of the stomach leads to ulcers.

If, instead, the upper part of the stomach becomes inflamed, acid secretion is reduced and the stomach's function impaired. It is this that, in a small percentage of H. pylori carriers, can lead to cancer. Patients get ulcers or cancer, but not both.

To see why, El-Omar and colleagues studied 149 healthy relatives of stomach-cancer patients in the west of Scotland. Of the 103 infected with H. pylori, 45 showed low levels of stomach acid. They also investigated 393 stomach cancer patients in Warsaw, Poland.

The researchers focused on genes that make 'interleukins', a large group of molecules which stimulate the immune system. Part of the body's response to H. pylori is to produce more interleukin-1-beta (IL-1^˜2). This causes inflammation and inhibits the secretion of stomach acid.

El-Omar and colleagues tested their subjects for different forms of the IL-1^˜2 gene, and also for a gene for another interleukin, 'IL-1ra', which counteracts the effects of IL-1^˜2;. A variant of IL-1ra is known to be associated with a range of inflammatory problems.

They found that, among the relatives of cancer patients infected with H. pylori, the 45 with low levels of stomach acid were significantly more likely to carry one particular form of the IL-1^˜2; gene. Carriers of the inflammation-causing form of IL-1ra also produced less stomach acid.

Likewise, the Polish study revealed that, for patients infected with H. pylori, the presence of both 'low acid' genes increased the risk of cancer by about 4--5 times. In all, say El-Omar and colleagues, 38% of stomach cancer cases can be attributed to these interleukin genes.

Carriers of these genes produce especially large amounts of IL-1^˜2;. The interleukin causes a fall in H. pylori, but the drop in acid secretion allows inflammation to spread to the upper stomach.

In its early stages this is reversible, but eventually the acid-producing cells die off permanently. The drop in acid flow prevents carcinogenic toxins -- produced by bacteria and as a result of inflammation -- from being flushed out of the stomach.

The association between humans and H. pylori is complex and ancient, yet its links with disease were only discovered in the past 20 years. Says Martin Blaser, of Vanderbilt University School of Medicine, Tennessee, "Helicobacter is a risk factor, it doesn't cause any diseases. It's how you interact with the organism that's important."

He adds that El-Omar and colleagues have produced "the first information on the human side of the interaction. Up to this point, most studies have focused on the bacterial side." For example, the genetics of H. pylori have been found to affect its disease-causing properties.

The discovery of genetic risk factors in humans could aid cancer prevention. "This is a very exciting prospect," says El-Omar. "Genetic testing could identify those at increased risk of cancer, who could then be offered antibiotics to eradicate H. pylori at an early age."