A Rare Variant in Mexico with Far-reaching Implications

This was once a guest post by Karol Estrada, who was a postdoctoral research fellow in the Analytic and Translational Research Unit at Massachusetts General Hospital and the Broad Institute of MIT and Harvard.

It was written in memory of Laura Riba. We have briefly summarised her thoughts and findings from that post below.

Karol discusses her new paper, which was published in the Journal of the American Medical Association. It discusses the low-frequency missense variant in the gene HNF1A that increases the risk of type 2 diabetes by five times and was only seen in Latinos.

It was the largest study to date, with a sample of nearly 4,000 people. They undertook whole-exome sequencing of 1,794 type 2 diabetes cases and 1,962 healthy controls from four studies of Mexicans and also Latinos.

A rare variant in Mexico with far-reaching implications

What were the findings? 

A paper from 2013 called Nature found that a set of four variants in the SLC16A11 gene increases the risk of type 2 diabetes. The variants are from the same haplotype which is common in people from Latin America but rare in people of European ancestry.

In accordance with the Nature paper, their JAMA study reinforces the importance of studying populations that have not yet participated in genomic research. They found the low-frequency variant HNF1A in 2% of type 2 diabetes cases and 0.4% of healthy controls.

This is the largest ever effect seen of a type 2 diabetes variant that’s found in more than 0.1% of the population. The variant was only identifiable in Latio people as well and could not be found in public genetic databases.

Their study did not find any other low-frequency or rare variants associated with type 2 diabetes above genome-wide statistical significance, the HNF1A was the only one.

However, they did note that to identify rare causal variants will require a higher sample of cases and controls, often in the tens of thousands.

The variant HNF1A that they discovered has indications beyond its design insinuating that a case study into how perceptions of the disease are not subtle enough to match reality. 

HNF1A is one of the 13 known MODY (maturity-onset diabetes of the young) genes, however, the people who carried the HNF1A gene in their study don’t have the typical recognizable attributes of MODY.

These people look more than like regular type 2 diabetes patients who are either overweight to obese and who developed diabetes later on in life, additionally not everyone who carried the HNF1A variant had diabetes, they found 12 carriers who were completely healthy.

They soon discovered that MODY and other rare diseases are a lot more complicated than they initially thought, this was backed up by a previous study at the Framingham Heart Study that showed that 1.5% of the randomly selected participants carried the MODY mutation but had completely normal glucose levels.

This reinforces that mutations of rare diseases can also be identified in healthy people, but because studies have only been done on the mutations in people who have diseases, it’s hard to clarify.

The article concludes with them stating how much work remains to still be done in this area but also puts forth the idea that genotyping a single low-frequency variant could help hundreds of thousands of people suffering from not just diabetes, but other deadly diseases whilst also contributing to the reduction of the cost of healthcare.