HbA1c: Exploring the Role of Genetics in 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 term ‘artificial changes’ to A1c 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.

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.

HbA1c Genotype Report:

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I’m going to leave out the genetic variants related to blood sugar which naturally would also cause HbA1c to rise. You can find these variants in the diabetes report and the blood glucose article.

Instead, the variants below are the ones unrelated to glucose levels and, therefore, may cause your HbA1c reading not to be a true reflection of your long-term blood glucose levels. Most of these variants affect red blood cells.

G6PD gene: X chromosome (men have 1 copy); Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme utilized by red blood cells for protecting against oxidative damage. Variants that decrease the function of G6PD can cause hemolytic anemia.

Check your genetic data for rs1050828 v98M (23andMe v4, v5; AncestryDNA):

C/C or C: typical
C/T or T: G6PD deficiency carrier (A- variant, usually milder); artificially lower HbA1c by 0.81 units (men)
T/T or T: G6PD deficiency carrier (A- variant, often milder)[ref]; artificially lower HbA1c by 0.68 units (women)[ref]

Members: Your genotype for rs1050828 is —.

HBB gene: hemoglobin subunit; mutations here are linked to sickle cell anemia.

Check your genetic data for i3003137 (rs334, 23andMe v4, v5; AncestryDNA):

T/T: typical
A/T: sickle cell trait carrier; lower HbA1c by 0.31% units[ref]
A/A: two copies, sickle cell anemia likely

Members: Your genotype for i3003137 is — or for rs334 is —.

HFE gene: encodes a protein important in regulating iron absorption. Too much iron can cause hemochromatosis. The most common type of hemochromatosis is Type 1, or Classic, usually caused by variants in the HFE gene. The C282Y variant increases the risk of type 2 diabetes due to damage to the pancreas when iron is stored there. However – the variant is also linked to higher overall hemoglobin levels, which then causes the HbA1c test to be low compared to actual blood sugar levels.[ref]

Check your genetic data for rs1800562 C282Y (23andMe v4, v5; AncestryDNA):

A/A: two copies of the C282Y variant, most common cause of hereditary hemochromatosis, highest ferritin levels; lower HbA1c levels (due to higher hemoglobin levels)[ref]
A/G: one copy of C282Y, increased ferritin levels, hemochromatosis possible but less likely[ref], lower HbA1c levels
G/G: typical

Members: Your genotype for rs1800562 is —.

TMPRSS6 gene: encodes a protein in the liver controlling iron homeostasis through hepcidin. The variant below is linked to lower ferritin and iron and is thus linked with lower hemoglobin levels. This throws off the glucose-to-hemoglobin ratio calculations causing HbA1c to read higher. (The opposite of the HFE variant above)

Check your genetic data for rs855791 (23andMe v4, v5; AncestryDNA):

G/G: typical
A/G: lower ferritin levels (Caucasian men); higher HbA1c levels (due to lower hemoglobin levels)
A/A: lower ferritin levels (Caucasian men)[ref]; higher HbA1c levels (due to lower hemoglobin levels)[ref]

Members: Your genotype for rs855791 is —.

HK1 gene: Encodes the hexokinases enzyme, which phosphorylates glucose to produce glucose-6-phosphate (G6P) in red blood cells. It is involved in both glucose metabolism and red blood cell function. Rare mutations in the gene cause hemolytic anemia.

Check your genetic data for rs16926246 (23andMe v4, v5; AncestryDNA):

C/C: typical
C/T: slightly lower HbA1c levels
T/T: lower HbA1c levels[ref][ref]

Members: Your genotype for rs16926246 is —.

ANK1 gene: stabilizes the cell structure in red blood cells. Variants and mutations are linked to altered red blood cell shapes as well as a faster turnover of RBCs.

Check your genetic data for rs4737009 (23andMe v4, v5; AncestryDNA):

A/A: higher HbA1c levels[ref][ref][ref]
A/G: slightly higher HbA1c
G/G: typical

Members: Your genotype for rs4737009 is —.

MYO9B gene: encodes a myosin protein associated with regulating cell migration.

Check your genetic data for rs11667918 (23andMe v5; AncestryDNA):

C/C: higher HbA1c levels[ref]
C/T: slightly higher HbA1c levels
T/T: typical

Members: Your genotype for rs11667918 is —.

FNK3 gene: encodes the fructosamine 3-kinase enzyme, which is involved in protein glycation.

Check your genetic data for rs1046875 (23andMe v4, v5; AncestryDNA):

A/A: higher HbA1c levels[ref]
A/G: slightly higher HbA1c levels
G/G: typical

Members: Your genotype for rs1046875 is —.

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.

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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