HbA1c: Heritability of A1C testing

Key takeaways:
~ HbA1c is a test value used to diagnose and manage diabetes.
~ Blood glucose levels affect HbA1c over the course of a few months.
~ HbA1c isn’t always an accurate measure of blood glucose levels, though.
~ Some people have genetic variants in red blood cell related genes that cause higher or lower HbA1c, impacting whether it is a true marker for glucose levels.

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What is HbA1c?

Best known as a marker to check for diabetes, HbA1c is a measure of average blood sugar levels over the past 2-3 months. 

HbA1c stands for hemoglobin A1c, also known as glycated hemoglobin.

High levels of HbA1c indicate that blood glucose has been elevated for a while. This is in contrast to just checking your blood sugar which gives you a snapshot of what is happening at the moment. For someone with diabetes, higher HbA1c levels can show that a medication is not working optimally. High levels are associated with an increased risk of diabetes-related complications such as heart disease, kidney failure, and retinopathy.[ref]

What is glycated hemoglobin?

Glycation is an irreversible change to a protein by the addition of a glucose molecule. When blood sugar levels are elevated for a period of time, the hemoglobin molecules are more likely to become glycated.[ref]

Hemoglobin is the part of the red blood cell carrying oxygen throughout the body.

Red blood cells turn over about every 110 days (~3 months), and the percentage of red blood cells that are glycated is proportional to the blood glucose level. For example, high blood glucose causes a high percentage of glycated hemoglobin.

Thus, HbA1c (percentage of glycated hemoglobin) gives a good estimate of whether blood sugar has been elevated over the past few months.[ref]

It’s a good estimate for most people… I’ll explain the genetic exceptions in a minute.

A1c test results:

For people who don’t have diabetes:

• Normal HbA1c is 4.0%–5.6%
• Prediabetes is 5.7%–6.4%

HbA1c ≥ 6.5% is used as an indicator of diabetes.[ref][ref] This number can vary slightly, depending on which reference you look at.

If you have diabetes and are on medication, the doctor will usually give you a target range for HbA1c.

What influences HbA1c levels?

Your average blood glucose levels impact your HbA1c levels, of course.

However, there are other influences on HbA1c, making the test not as accurate for determining average blood glucose:

• For example, if red blood cells turn over more quickly than average, the HbA1c level will be lower, and thus not a good representation of average blood sugar.
• If hemoglobin levels are low, such as in someone with anemia, this can also throw off the accuracy of HbA1c levels.
• Finally, certain genetic variants impact red blood cells, either increasing or decreasing HbA1c.

Let’s dive into all of these scenarios in more detail:

Heritability of HbA1c

There is a fairly strong genetic component to getting diabetes, so it makes sense that HbA1c would also have some kind of genetic connection.

Genetic variants also influence HbA1c, with heritability estimated at over 50%.[ref]

But… it isn’t as simple as ‘the genes for diabetes cause HbA1c to be high because glucose is high’.

Genetic research shows us that HbA1c levels incorporate both glucose-related genes (which makes sense) and also genetic variants related to red blood cell pathways.[ref]

The implication here is that HbA1c may not be an accurate blood glucose indicator for some people with genetic variants related to red blood cell pathways.

I’m going to use the terms ‘artificial’ and ‘falsely low’  to indicate the factors that influence A1c outside of blood glucose levels. These aren’t actually artificial reasons, but rather the reasons for HbA1c tests not accurately representing average blood glucose levels.

Other factors influencing HbA1c readings:

Age: In non-diabetics, people aged 70+ have a 0.5% increase in HbA1c compared to those aged 30.[ref]

Iron deficiency raises HbA1c, as does thalassemias and other hemoglobin variants. Severe vitamin B12 deficiency causing anemia can also increase HbA1c. This is irrespective of blood glucose levels.[ref]

Hemolytic anemia causes blood cells to turn over more quickly than normal, and this can cause a lower HbA1c reading that doesn’t reflect blood glucose levels.

Smoking increases HbA1c levels by 0.1% on average, but it doesn’t change fasting blood glucose levels.[ref] This is something a doctor will likely consider when looking at your HbA1c levels.

Chronic alcohol consumption or taking a lot of aspirin (salicylates) can also falsely increase HbA1c.[ref]

Recent blood donations will also decrease HbA1c due to lowering hemoglobin levels.[ref]

What happens if HbA1c isn’t a good indicator of your blood glucose levels?

Knowledge is power here.

For people with significant genetic variants that cause HbA1c to read lower than it should for their glucose levels, this can cause doctors to miss out on diagnosing them with diabetes. Additionally, if HbA1c is artificially or falsely low in someone with diabetes, their medications may need to be adjusted.

HbA1c for African Americans

When reading through research studies on HbA1c, I saw several older studies that stated HbA1c levels could be incorrect (falsely low) for African Americans. There are even headlines in mainstream articles stating that HbA1c is less accurate in African Americans.[ref] This is statistically due to a couple of the red blood cell mutations (listed below) being more common in people of African ancestry.

It’s important to understand that most people with African ancestry do not have the mutations that cause HbA1c to be strongly impacted. Statistically, when you look at the population group as a whole, the HbA1c levels are more likely to be off. But this shouldn’t be applied to individuals.

Thus, you need to look at genetic variants (or other tests) to know whether anyone, regardless of race, is likely to have HbA1c levels that differ from the norm.

Hemochromatosis and HbA1c:

Hemochromatosis is a hereditary disorder causing increased iron absorption. For many people with higher iron levels, hemoglobin levels also rise. The increased hemoglobin can then cause the HbA1c test to read lower than actual blood sugar levels.[ref] Of course, there could be other variable at play in someone with hemochromatosis, depending on the amount of damage to the liver or pancreas from stored iron.

Lifehacks for reducing HbA1c:

Talk with your doctor if you have diabetes about how your specific genetic variants may need to be considered when looking at specific HbA1c targets for diabetes. Your doctor can order an HbA1c test, or you can do the test yourself with a home meter or by ordering lab tests yourself.

If your HbA1c is higher than you would like it to be, check to see how your genetic variants impact your risk for diabetes and blood glucose.

There are multiple pathways involved in diabetes and high blood glucose levels. Understanding the pathways affecting your blood glucose can help you to pinpoint which diet and supplements may be more effective. For example, people with MTNR1B variants may find that changing meal timing is essential, while people with SLC30A8 variants may want to ensure they get plenty of zinc in their diet.

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