Decoding Sex Differences: Genes, Proteins, and Your Health

You know, it’s pretty obvious that men and women experience health and disease a bit differently. Sometimes diseases show up at different ages, are more common in one sex than the other, or even have different levels of severity. But honestly, figuring out *why* this happens has been a bit of a puzzle for ages. We’ve often scratched our heads, wondering just how much of this is down to our genes.

What We Studied

So, we decided to dive deep into the human plasma proteome. Think of the plasma proteome as all the thousands of different proteins floating around in your blood – they’re like tiny workers doing all sorts of jobs, from carrying oxygen to fighting off invaders. We wanted to see how these proteins, and more importantly, the genetic instructions that influence their levels, might differ between sexes. We gathered data from two massive groups of people, tens of thousands of males and females, and used some seriously advanced tech to measure over 5800 different protein targets. It was a huge undertaking!

Big Differences in Protein Levels

First off, we looked at the sheer *amount* of these proteins in plasma. And wow, did we see differences! It turns out that the levels of about two-thirds of the proteins we looked at were significantly different between males and females. That’s a big chunk! We saw things you might expect, like proteins related to sex-specific tissues (hello, prostate-specific antigen in males, or follicle-stimulating hormone which plays a big role in female biology). But we also saw differences in proteins linked to body composition, like leptin and adiponectin, and even important markers for heart health, like NT-proBNP and troponin T. It’s clear that the protein landscape in your blood isn’t the same depending on whether you’re male or female. We tried adjusting for things like hormone therapy or lifestyle factors like BMI and smoking, and while they explained *some* of the differences, a lot still remained.

We even found differences in proteins that are targets for existing drugs. For instance, plasmin, targeted by some stroke medications, showed different levels. This could potentially help us understand why some drugs might work differently or cause more side effects in one sex compared to the other.

The Genetic Angle: More Similar Than You’d Think

Now, here’s where it gets really interesting. While the *levels* of proteins are often different, we wanted to know if the *genetic switches* that control these levels also differ by sex. These genetic switches are called pQTLs (protein quantitative trait loci). We looked for “sex-differential pQTLs” (sd-pQTLs) – basically, genetic spots where the effect on protein levels is significantly different between males and females.

Despite finding *thousands* of pQTLs in both males and females when we looked separately, we were quite surprised. Only a tiny fraction – less than 3% of the protein targets – showed strong evidence of this sex-differential genetic regulation. That means, for the vast majority of proteins, the genetic influences on their levels seem pretty similar whether you’re male or female.

The “Sex-Discordant” Few

Among that small group of sd-pQTLs, about a third were what we call “sex-discordant.” This is fascinating because it means the genetic effect either:

• Is significant in *only one* sex, or
• Has *opposite* effects in males and females (like a genetic variant that increases a protein in males but decreases it in females!).

Most of the sd-pQTLs we found just had different *strengths* of effect between sexes, but these sex-discordant ones are the real rule-breakers.

We found some cool examples. For instance, we saw a genetic spot influencing Pregnancy Zone Protein (PZP) that was only significant in females, which makes sense given its name! Similarly, genetic influences on proteins involved in male fertility (PATE4 and SPIT3) were significant only in males. These are clear cases where the genetic control aligns with sex-specific biology.

But then there are the head-scratchers. Take CDH15, a protein involved in cell adhesion. We found a genetic variant for CDH15 where the effect on protein levels was *opposite* in males and females! This is the kind of thing that gets completely hidden if you just study everyone together. Another protein, CPE, involved in activating hormones, also had genetic influences that were stronger in males. These examples show that while rare, these sex-discordant genetic effects exist and could be really important.

Connecting Genetics to Disease?

Naturally, we wondered if these specific sex-differential genetic spots could explain why certain diseases affect men and women differently. We looked at associations with hundreds of diseases in the UK Biobank data. We did find quite a few links between these sd-pQTLs and disease risk in *at least one* sex.

However, when we specifically looked for strong evidence that the *genetic effect on disease risk itself* was significantly different between sexes, we didn’t find much that passed our strict criteria. This suggests that while these genetic variants might influence protein levels differently by sex, that difference doesn’t seem to translate directly into a strongly sex-differential risk for the diseases we looked at, at least for most of these specific genetic spots.

There was one intriguing hint though: the well-known APOE ε4 variant, linked to Alzheimer’s risk, showed nominal evidence (meaning, a suggestion that didn’t quite meet our super-strict bar, but is still interesting) for a stronger effect on dementia risk in females, which lines up with previous findings about women having a higher risk.

What Does It All Mean?

So, the big takeaway? While your blood is swimming with proteins that vary dramatically by sex, the *genetic instructions* for making them and regulating their levels are surprisingly similar for most proteins. The fact that we see huge differences in protein *levels* but only tiny differences in their *genetic regulation* tells us something crucial: other things must be playing a much bigger role in causing those level differences. We’re talking about things like hormone profiles, lifestyle choices, environmental exposures, and other biological factors that aren’t directly encoded as simple genetic variants influencing protein production. This aligns with what we see in complex diseases – sex differences exist, but often aren’t explained by simple genetic differences at individual spots.

This is actually pretty good news for folks trying to find new medicines. It suggests that for most protein targets, studying their genetic links in one sex will likely give you findings that are relevant for the other sex too. Of course, those rare sex-discordant cases are super important exceptions and highlight why we still need to pay attention to sex in research.

A Few Caveats

Science is always a work in progress! Our study focused on proteins in plasma – there might be more sex-specific genetic regulation happening within tissues. We also looked mainly at middle-aged people of European ancestry, so future studies need to look at different age groups and ancestries. And we’re still only scratching the surface of all the proteins and genetic variations out there.

Ultimately, our work adds another piece to the puzzle. It shows that while sex differences in health are real and widespread at the protein level, the genetic blueprint influencing those proteins is largely shared. The big differences in protein levels are likely driven by a complex interplay of genetics, hormones, environment, and lifestyle. Understanding this complexity is key to truly cracking the code of sex-specific health.

Source: Springer