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Stanford Report, February 19, 2003

Variations of gene levels in blood affect immunity

By AMY ADAMS

Differences in people seem to run in the blood, according to a study of which genes are active in blood cells. The work, published last week in the online issue of the Proceedings of the National Academy of Sciences, found that the levels of several genes used by blood cells vary from person to person.

"Nobody had taken this broad a look at genetic variation in the blood of healthy people," said David Relman, MD, associate professor of medicine and a co-author of the study.

People vary in their reactions to bacteria and viruses; some fall prey to every bug while others go through winter sniffle-free. Relman, along with Patrick Brown, PhD, professor of biochemistry, and research assistant Adeline Whitney thought these differences might show up when looking at which genes are active in circulating blood cells.

To learn the extent and nature of the differences in gene activity in blood, Relman and his colleagues drew blood from 75 healthy people and extracted a molecule called RNA. RNA is produced by active genes and can be used to identify which genes are being expressed in a given sample. They then attached a fluorescent molecule to the RNA and applied the samples to a gene chip — a glass slide dotted with human genes. If a sample contained RNA corresponding to a gene on the chip, the fluorescently labeled RNA would bind to the spot and produce a visible signal. The bigger the signal, the more RNA was present, and therefore the greater the gene expression. Whitney then compared which spots varied in brightness among the samples.

The blood used in this analysis contained a variety of cells, including red blood cells that carry oxygen to the tissues and immune cells that fight disease. The red blood cells don’t contain nuclei and therefore don’t produce RNA. That leaves immune cells as the only cells making RNA in the blood sample. Any differences found in the pattern of active genes resulted from these disease-fighting cells.

A few genes stood out as being used at varying levels in different people. Some of these could be used to distinguish between men and women. For example, women use different levels of genes whose proteins respond to an immune protein called interferon. Researchers had suspected that genes in the interferon pathway might have a role in the higher risk of autoimmune diseases in women.

The researchers also found variations in two genes that weren’t previously documented as being active in blood cells. One is a gene that makes the prion protein — the protein altered in people who have Creutzfeldt-Jakob disease. Another surprisingly variable gene was BRCA1, which is mutated in an inherited form of breast cancer. It could turn out that levels of the prion protein or BRCA1 in the blood play some role in determining the risk for prion-related diseases or cancer.

In addition to the variation of gene expression among different people, the researchers found genes that varied according to the time of day that blood was drawn. Other genes were used at higher or lower levels depending upon the age of the blood donor — a finding that could help doctors understand why older people are more prone to some illnesses.

Relman said it’s too early to know why people use genes at higher or lower levels in blood cells. "It may be that some people confronted a virus or had a cold the week before, or had different environmental experiences," he said.

He added that despite the differences, there was close similarity in the genes used in the blood cells among the study subjects. "It was surprising that the degree of variability was as small as it turns out to be," he said. This finding bodes well for using gene expression in blood to distinguish between healthy people and those with an infectious disease. Because people are usually quite similar, any disease-related variation should stand out.

Other researchers who contributed to the paper include MD/PhD students Maximillian Diehn, PhD, and Ash Alizadeh, PhD; postdoctoral fellow Stephen Popper, DSc; and medical student Jennifer Boldrick.




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