We can see that the gene near the middle, TCF7L2, is the most statistically significant predictor, with some studies claiming that it roughly doubles your lifetime risk of developing Type 2 Diabetes. In 2015, 9.4% of the US population had diabetes, and over 250,000 people died with diabetes mentioned as a contributing factor. This cost our health system $327 Billion in 2017.

This is a big deal, and that gene is the center of it all.

BUT IT’S NOT ALL GENETICS

Yes, that’s true. The genome describes the code running within our bodies, but our lifestyle certainly matters. The FTO gene in that plot above is the top obesity gene, for example. The MTNR1B gene is a melatonin receptor, which regulates how cells in your body respond to sleeping patterns. Common knowledge indicates that diet, exercise, and sleep all matter.

But are these factors the most important factors? Could there be something else? Perhaps something that explains that top gene, TCF7L2? All diseases are both a product of both our genetics and our environment.

Gene’s aren’t static

While your genome happily sits in your cells nucleus containing the blueprint for how to build everything in your body, those genes must be turned on in specific tissues, and at specific times, to perform useful work. The activation of genes in your body is called “gene expression”, and patterns of these gene expression can tell us about the specific programs that cells are running.

Eat something, and metabolic genes are turning on. Fall asleep, and repair genes are turning on. Run from a tiger, and genes are switching on (HOPEFULLY) to build faster muscles. If the wrong genes switch on however, or if important genes switch off, function of a cell can be lost, and disease can result.

Drugs change gene expression

Exposure of cells to chemical compounds can also change gene expression patterns. This can be bad, in the case of toxins, or good, in the case of drugs.

A diagram indicating the incredible size of the CMap database

The Broad Institute, one of the largest genomic research organizations, has systematically tested gene expression patterns in many different cell types exposed with more than 19,000 substances. This large dataset is the Connectivity Map (CMap). They have made available a fantastic online search tool that exposes the data to exploration from citizen scientists like us!. If you are a nerd like me, you might find yourself digging into the data for months getting lost with the genomes shear complexity.

An overview of what the L1000 assay looks like from this paper

Fortunately for us citizen scientists, YOU can query this data yourself for genes or compounds of interest. This is the interactive portion of this article. FOLLOW THIS LINK RIGHT NOW, and type the command “/conn TCF7L2” to query the database for drugs and genes that “perturb” the top Type-2 Diabetes gene…. TCF7L2

Seriously, do this. I want you to understand that you shouldn’t trust some random Medium blogger, but this dataset is hosted by one of the most respectable biology research institutions funded on a project run by the NIH. This data is quite real, and it isn’t even mine :D

Out of more than 19,000 compounds in the database, the heatmap shown will only include the top positive and negative scoring connections. In general, if a compound has a highly positive score, it means that it causes a shift in gene expression highly similar to the thing you queried for. A negative score implies a shift in the opposite direction.

After querying for TCF7L2, you should see a screen that looks like this. We’ll mostly discuss the compounds in this article, but it’s worth noting that the top associated gene, CDKN2B, was discussed in our previous analysis as the top gene associated with heart disease. It is also one of the shorter peaks in the T2D Manhattan Plot above, and so clearly has a genetic link with diabetes.

Results in CMap for TCF7L2, showing the top connected perturbagens (drugs and gene alterations)

At more than 2 million tons annually, we are still not FREE of BPA

That compound at the very top of the list, bisphenol-a (BPA), is one of the most mass-produced chemicals by man, and is used to make polycarbonate plastic and epoxy resins. It began use in consumer products around 1953. In the 1980s, mankind produced over 1 MILLION TONS annually, and that doubled to NEARLY 2.2 MILLION TONS in 2009. While its use is being phased out in many plastic bottles, to this day, BPA-containing resins still line the inside of every soda can. Incidentally enough, consumption of sugar sweetened beverages, including those from cans, is one of the easiest predictors of diabetes known to the research community. Maybe it wasn’t just the sugar!

But I don’t drink soda pop!

Don’t worry: Traces of BPA are also contained in the PVC water pipes that likely supply your house, and this is thought to be a primary route of exposure. Even more astonishing, BPA is used to coat the paper used to print receipts. Every time you buy a product and take a receipt from the purchase, small amounts of BPA pass through the skin and show up in urine for a period of time longer than if it were ingested! Intriguingly, its been shown that cashiers, who handle receipts daily, have higher levels of BPA in their urine and a higher prevalence of insulin resistance.

In our receipt-filled consumer society, this is an ironic example of how the consumption of anything can still predispose you to diabetes.

Figure from a frightening study demonstrating detectable levels of BPA after just a single contact with a receipt.

As a diabetes geneticist, I can tell you that talks about BPA rarely take center stage at the largest diabetes conferences . This database however indicates that BPA is the strongest compound (out of 19k others in the Broad database!) in perturbing the function of that gene. The Connectivity Map experiments were not performed with any particular hypothesis in mind. They simply threw as many chemicals as they could against as many cells as they could.

What does BPA do, exactly? It disrupts your hormone receptors! It binds to both estrogen receptors, as well as the androgen receptor (AR), which senses the hormone testosterone. Incidentally, the second compound on the list above is Androstenedione, an intermediary byproduct of hormone production in the human body that weakly binds to both receptors as well.

It gets worse. Recall that TCF7L2 is not the only gene behind Type-2 Diabetes, just the most significant. The second most significant gene is CDKAL1.