Monday, July 07, 2008

CD38 polymorphisms

Why are we all so different? The plain answer is genetic polymorphisms. Perhaps the best known example is sickle cell anemia. Most people have hemoglobin A, but an unlucky few have a polymorphism at position 6 of the beta chain of hemoglobin so that what would normally be a glutamic acid is replaced by a different amino acid, valine. The effect of this is that under certain stressful conditions, the hemoglobin molecules line up as needle like crystals that distort the shape of the red cells so that they can't get through the narrow holes in the blood vessels and therefore cause ischemia in organs supplied by those blood vessels.

But sickle cell anemia is just the most severe of hundreds of polymorphisms of the hemoglobin molecule. Some cause anemia but many are entirely asymptomatic and people have no idea that they have them. So it is for just about every molecule in the body, but together they determine our every physical characteristic.

I have written about CD38 several times before. CD38 also has a polymorphism characterised by a C>G variation in the regulatory region of intron 1. A study from the excellent group in Turin, Italy has studies 248 patients with CLL, but find that this polymorphism is no commoner in patients than in controls. However, those with the polymorphism were more likely to have bad prognostic markers, more likely to have enlarged lymph nodes and spleen, and in particular, more likely to develop Richter's syndrome.


Anonymous said...

Does it matter what percentage of CD38 one has if they are positive? I know that you once said in regard to Zap 70 that you were either positive or negative and the percentage really didn't matter. Is it the same with CD38? And, why is it still a 20% cutoff at some CLL clinics, yet a 30% cutoff at others?

Jenny Lou Park

Terry Hamblin said...

The original cut-off as selected by Nick Chiorazzi's group was 30%. I don't know why they chose that. When we looked at it our object was to have the greatest sensitivity with the greatest selectivity. To do that you apply a techniwue known as Youden's Index. We found that either 20% or 30% gave the same answer, so we went along with Nick's selection. There is little difference because generally there are very few patients with between 20% and 30%. Later Durig et al chose 20% - I don't think it matters much. Another German group however chose 7% as the cut-off. They chose this as the result that gave the greatest p value for the difference between the good and bad prognoostic groups. This is an invalid way of doing it since the p value depends on how many by chance you happen to have in each group. We arranged a sample exchange between the German group, Chiorazzi's group and our own. The American and British groups got exactly the same answers, but the German results were very different. We thought that the Germans were making a gating error. Since then the Catovsky group have favored the 7% cut-off. We have looked at 7%, 20% and 30% on our patients and we get different groups. Less than 7% gives a group that seldom need treatment. 7-30% gives a group that needs treatment but tends to live a long time. More than 30% are the poor prognosis group. The Italians describe biphasic CD30 results. This means that they see two populations of cells, one CD38+ and one CD38 negative. We agree that there are a few patients like this. They suggest that these patients are the ones that go from negative to positive over time.