The biological differences between men and women go beyond the things we're aware of like the sex chromosomes and hormones. Some diseases occur with a higher frequency in one sex or the other, showing that there could also be subtle differences in physiology or biochemistry that we don't know about. For example, autoimmune diseases tend to affect women more often, while schizophrenia affects more men and typically does so more severely than women. Coronavirus infections, including COVID-19, SARS, and MERS have all tended to cause more deaths in men compared to women, even though the sexes are infected at similar rates.
Researchers have investigated these differences for decades - although many disease models have eliminated females in order to remove confounding factors like hormonal changes. While the differences in the chromosomes are an obvious place to start looking for an explanation, the X and Y chromosomes have not offered any clear solutions.
New research reported in Nature has suggested that a protein that functions in the immune system, called complement component 4 (C4), which is encoded by the C4 gene, is more abundant in men, where it protects them from lupus but increases their risk of schizophrenia. The protein helps tag cellular trash so the immune system will remove it.
"We all know about illnesses that either women or men get a lot more, but we've had no idea why," said the co-senior study author Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at Harvard Medical School (HMS) and director of genomic neurobiology at the Stanley Center for Psychiatric Research at the Broad Institute. "This work is exciting because it gives us one of our first handles on the biology."
The researchers found that the number and type of C4 gene varies from one person to another, and these variations amount to a common risk factor for three disorders. In individuals with the highest numbers of C4 genes, the risk of systemic lupus erythematosus and an autoimmune disease called Sjögren's syndrome was reduced 7 and 16 fold, respectively, while the risk of schizophrenia was 1.6 times higher. Men tend to produce more of this protein than women, amplifying the impact. "Sex acts as a lens that magnifies the effects of genetic variation," explained the first author of the study, Nolan Kamitaki, a research associate in genetics in the lab of Steven McCarroll at Harvard Medical School and the Broad.
Though this gene makes a significant contribution to the risk of these diseases, many other factors are also involved. "The complement system contributes to the sex bias, but it's only one of probably many genetic and environmental contributors," said Kamitaki.
While this study presents a potential drug target, the protein plays a critical role in the complement system, part of the immune response, so it has to be altered cautiously, and should take the sex of the patient receiving treatment into account.
"For example, researchers will need to make sure that drugs that tone down the complement system do not unintentionally increase risk for autoimmune disease," said McCarroll. "Scientists will also need to consider the possibility that such drugs may be differentially helpful in male and female patients."
This research can help scientists learn more about sex differences.
"It's helpful to be able to think about sex-biased disease biology in terms of specific molecules, beyond vague references to hormones," McCarroll said. "We now realize that the complement system shapes vulnerability for a wide variety of illnesses."
This work also benefited from a diverse cohort that went beyond the European samples that are often used in genetic studies. The same variants are often seen in one population, and when several genetic variants always appear together, it can be very difficult to learn which might be responsible for some effect. The influence of the variants can be assessed by looking at different populations that don't carry the exact same ones.
"It became quite clear which gene was responsible," said McCarroll. "That was a real gift to science from African-American research participants. The question had been unsolved for decades. It will really help for genetics to expand more strongly beyond European ancestries and learn from genetic variation and ancestries all over the world," he added.