Chronic pain may have a unique genetic basis in women

An excellent meta-analysis of data from the United Kingdom Biobank revealed a different genetic basis for chronic pain in women compared to men.

The results are still preliminary, but to date this is one of the largest genetic studies on chronic pain for separate analysis of female and male sex.

“Our research emphasizes the importance of considering sex as a biological variable and has shown subtle but interesting gender differences in the genetics of chronic pain,” says population geneticist Keira Johnston of the University of Glasgow in Scotland.

Chronic pain conditions are among the most common, disabling, and expensive conditions in public health. In the United States, chronic pain affects more people than heart disease, diabetes and cancer combined, and yet receives a fraction of the total funding.

Even when studies are done, they often overlook basic gender differences, and that is a huge and damaging oversight. Compared to men, women are much more likely to develop multiple chronic pain disorders, and yet, in history, 80 percent of all pain studies have been conducted on male mice or men. This means that we know very little about how and why females suffer more and which treatments can best help them.

Although multiple biological and psychosocial processes are likely to be involved in this sexual discord, the current genome study suggests that there is a genetic factor in the combination.

Comparing gene variants associated with chronic pain in 209,093 women and 178,556 men from the British Biobank, the researchers tried to find at least part of the answers in our biology.

Finally, the researchers found 31 genes associated with chronic pain in women and 37 genes associated with chronic pain in men that barely overlap. The authors acknowledge that some differences here may result from their smaller sample size of males, but the results are intriguing nonetheless.

When the researchers tested the expression of all these genetic variants in different tissues of mice and humans, they noticed that the vast majority are active in a set of nerves inside the spinal cord, known as the dorsal root ganglion, that carries messages from the body to the brain.

Several genes on the men-only or women-only list were associated with psychiatric problems or immune function, but only one gene, known as DCC, was on both lists.

DCC encodes a receptor that binds to a protein crucial for the development of the nervous system, especially the dopaminergic system; in addition to being a reward center, the latter has recently been linked to modulation of body pain.

DCC is also thought to be a risk gene for the pathology of depression, and DCC mutations occur in those with congenital mirror movement disorder, resulting in multiplication of one side of the body on the other.

It remains unclear exactly how DCC is associated with chronic pain, but the authors say their results support several theories of “strong nervous system and immune involvement in chronic pain in both sexes,” which they hope will be used to develop better treatments in the future.

For example, if chronic pain is more strongly associated with immune function in women, the side effects of drugs that target the immune system can be very different from men’s. On the other hand, treatments such as chronic opioid use may also have different outcomes. Opioids are known to negatively affect immune function, suggesting that they could worsen and not improve women who have chronic pain.

At least for now, these are just ideas. The way to do more pain research and do a lot more among women before we really start to understand the real gender differences in the game and what we can do about it.

“All of these lines of evidence together suggest the alleged central and peripheral neuronal role of some of these genes, many of which have not been historically well studied in the field of chronic pain,” the authors conclude.

The study was published in PLOS genetics.

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