G6PD deficiency (favism)

G6PD is an enzyme that shields red blood cells from oxidative stress. When it's deficient, fava beans, certain drugs and infections can make red cells break down. It's X-linked, so it more often affects males.

What the G6PD A- variant does

G6PD is the enzyme that keeps red blood cells supplied with the antioxidant they need to survive everyday oxidative stress. This variant, part of the African A- form of the gene, leaves the enzyme working but unstable, so activity fades as a red cell ages. Under ordinary conditions that is fine. Under oxidative stress, the oldest cells rupture, which is what an episode of haemolytic anaemia is.

That is why the condition is invisible most of the time and then arrives suddenly, usually within a day or two of a trigger, as fatigue, dark urine and jaundice.

Reading this result on an X chromosome

G6PD sits on the X chromosome, which changes how a genotype should be read. Males have a single copy, so one variant copy means deficiency with no second gene to compensate. Females have two, and a female with one variant copy is a genuine intermediate: X inactivation is random, so the proportion of deficient red cells varies from person to person, and some heterozygous women have close to normal enzyme activity while others are functionally deficient.

A genotype file does not resolve that. The measurement that does is a G6PD enzyme activity assay, which is inexpensive and is what clinicians use before prescribing the drugs that matter here.

How strong the evidence is

This is not a statistical association, it is a well-established enzyme defect. ClinVar records it as pathogenic with 47 submitters, under G6PD deficiency, non-spherocytic haemolytic anaemia and malaria susceptibility. G6PD deficiency in all its forms affects more than 400 million people, and averages around 8% in countries where malaria is endemic, because carrying it offers some protection against the parasite.

It also shows up somewhere less expected. In a genome-wide study of 144,060 people, this variant was among the strongest signals for HbA1c (p below 1e-300), and the reason is mechanical rather than metabolic: shorter-lived red cells accumulate less sugar, so HbA1c reads low. If HbA1c is ever used to diagnose or monitor diabetes in you, that is worth your doctor knowing.

What triggers an episode

The recognised triggers are specific rather than general. Fava beans are the classic food trigger, and the reaction gives the condition its old name, favism. Medicines that commonly need avoidance or specialist supervision include primaquine and tafenoquine for malaria, dapsone, rasburicase, methylene blue, nitrofurantoin and some sulfonamide antibiotics. Infection alone can also set off haemolysis.

Most people with the A- form live without restriction between episodes. The practical value of knowing is that it belongs on your medical record before someone prescribes one of those drugs, not that daily life needs changing.

What this variant does not tell you

More than 200 G6PD variants are known, and the 2022 WHO classification sorts them by how much enzyme activity is left. This file reads one of them. The Mediterranean variant common around the Mediterranean, the Middle East and South Asia is more severe than A- and is not read here, so a result showing no A- variant does not rule out G6PD deficiency.

It also cannot tell you your enzyme activity, which is what actually determines how you respond to a trigger, and which varies among people with the same genotype.

What each rs1050828 genotype means

rs1050828 has three possible genotypes: CC, CT and TT.

Normal G6PD (rs1050828 CC). You don't carry this G6PD deficiency variant, so the enzyme that protects your red blood cells from oxidative stress works normally. Foods like fava beans and certain medications shouldn't pose the special risk they do for people with G6PD deficiency.

G6PD carrier (rs1050828 CT). You carry one copy of the G6PD deficiency variant. Because this gene sits on the X chromosome, women with one copy are usually fine but can have somewhat reduced enzyme activity, and you can pass the variant on. In some situations your red cells may be a little more sensitive to certain drugs or fava beans.

G6PD deficient (rs1050828 TT). You carry the G6PD deficiency variant on both copies (or, for men, on the single X). The enzyme that shields red blood cells from oxidative stress works poorly, so fava beans, certain medications (such as some antimalarials and sulfa drugs), and infections can make red cells break down. Knowing and avoiding your triggers is the main thing.

Evidence & sources

This variant appears in 16 published genetic studies: PubMed 23446634 · PubMed 23696099 · PubMed 28453575 · PubMed 28898252 · PubMed 31213470 · PubMed 33887194 · PubMed 34014839 · PubMed 34059833 · PubMed 34376796 · PubMed 36395887 · PubMed 36575460 · PubMed 38964323 · PubMed 39280063 · PubMed 39379762 · PubMed 40968291 · PubMed 41298473.

Common questions

Is G6PD deficiency dangerous? For most people with the A- form, it is silent until something triggers it, and episodes usually resolve once the trigger is removed. It matters most around specific medicines, fava beans and severe infection, and in newborns, where it raises the risk of jaundice. Severe episodes need medical care, so sudden dark urine, jaundice or unusual fatigue after a known trigger is a reason to seek it.

Can women have G6PD deficiency? Yes. The gene is X-linked, so a woman with two variant copies is deficient, and a woman with one can fall anywhere between normal and deficient depending on how X inactivation played out in her blood cells. A genotype alone does not settle it for heterozygous women, but an enzyme activity test does.

Does a normal result here mean I do not have G6PD deficiency? No. This reads the A- variant only, and other forms, including the more severe Mediterranean variant, are not covered. Symptoms or a family history still warrant an enzyme activity test.

Related

Alpha-1 antitrypsin deficiency · Gaucher disease type 1 (carrier) · Hereditary hemochromatosis (HFE gene)