THAT smoking causes lung cancer is well established. But what causes smoking? This is the question at the heart of a study published in Nature by a group of researchers who work at deCODE, an Icelandic genomics company. They do not, quite, answer it. But they do think they have the answer to the related question of why some smokers smoke in moderation whereas others are rarely found without a fag in their hands—and thus why some people are, genetically speaking, more susceptible to lung cancer than others.

That answer lies in part of human chromosome 15, and depends on what is known as allele T of SNP rs1051730. A SNP, or single-nucleotide polymorphism, to give its full name (the short version is pronounced “snip”), is a place where genomes routinely differ from one another by a single genetic letter. In this case, the variation happens inside a gene for one of the receptor molecules that nicotine attaches itself to when it produces its buzz. Based on a study of 13,945 Icelandic smokers, deCODE's researchers showed that having a T in the appropriate part of the gene correlates very strongly indeed with being a heavy smoker. The team estimates that the chance of their being wrong is less than one in a thousand trillion.

Not surprisingly, having the T variant also correlates with the chance of a smoker getting lung cancer. Each copy (there may be none, one or two, since one can come from a person's father and one from his mother) increases that chance by 30%. The T variant does not, however, increase the likelihood that someone will take up smoking in the first place. That is either a matter of free will or, if it is genetic, is controlled by genes somewhere else.

It all looks neat and simple—and extremely plausible. Genes promote smoking; smoking promotes cancer. However, it might be wrong. For another paper in Nature, and a third in its sister journal Nature Genetics, report similar studies that have drawn rather different conclusions.

Model T?

Paul Brennan and Christopher Amos both agree that something significant is going on in the part of chromosome 15 studied by deCODE. But they have concluded that genetic variation there acts directly on a person's susceptibility to lung cancer, rather than acting indirectly by modifying his smoking behaviour. That does not mean the gene or genes in question actually cause lung cancer. Rather, it means that they amplify the effects of smoking instead of the amount of smoking.

Like deCODE, both Dr Brennan (who works at the International Agency for Research on Cancer, in France) and Dr Amos (who works at the University of Texas) identified rs1051730 as an important SNP. Unlike deCODE, though, both think a second SNP, rs8034191, is involved as well. That, and the fact that the region of chromosome 15 under scrutiny has two other nicotine-receptor genes in it, suggests the situation may indeed be more complex.

On top of this, Dr Brennan and Dr Amos both used a different method from deCODE's. They compared lung-cancer patients directly with otherwise similar cancer-free smokers, in what is known as a case-controlled study, and concluded that genetic variants in the nicotine-receptor-rich part of chromosome 15 are changing not smokers' behaviour, but their susceptibility to cancer. Moreover, Dr Brennan also claims to have discovered an increased susceptibility to lung cancer in non-smokers with the relevant SNPs, though his sample size is small and his result is not supported by Dr Amos's work.

These contradictory conclusions are both puzzling and intriguing. DeCODE has one further piece of evidence in its favour. Besides the correlation with lung cancer, the T variant also seemed to correlate with peripheral arterial disease, another common side-effect of smoking. On the other hand, the firm also acknowledges that the link it thinks it has discovered does not account for the whole of the risk of smoking-induced lung cancer. What is not in doubt, however, is that there is some sort of a link between genetics and lung cancer.

That raises interesting issues, particularly as genetic testing becomes easier. DeCODE has already announced it will add rs1051730 to the standard screen it offers to those who wish to know their susceptibility to diseases. The day is not far off, therefore, when those who take the essentially irrational decision to start smoking tobacco will be able to find out in advance exactly how foolish they are being.