You're eating well and still exhausted. Your genes may be blocking mineral absorption.

MTHFR is an enzyme that converts dietary folate and B12 into their active forms, which your cells need to produce energy, synthesize neurotransmitters, and regulate inflammation. It’s one of the most critical enzymes in your body. Without it working efficiently, nothing else downstream works well.

The most common variant is C677T, carried by roughly 40% of people with European ancestry. If you carry one copy, your enzyme works at roughly 35% efficiency. If you carry two copies (homozygous), your enzyme is 70% less efficient. That means your cells are converting folate and B12 at a fraction of the rate they should be, even if you’re eating spinach and salmon.

You feel this as relentless fatigue, difficulty concentrating, and a sense that your brain is foggy no matter how much sleep you get. Your muscles feel weak. You catch every cold that comes around because your immune system can’t mount a proper response. You may also experience mood instability or anxiety because your brain can’t produce enough serotonin and dopamine. A perfect diet can’t fix this because your genes won’t let your body use what you’re eating.

Vitamin D isn’t just for bone health. It controls mitochondrial biogenesis, which is the process your cells use to build new energy-producing factories. VDR is the receptor that sits on your cell surface and lets vitamin D in. If this receptor doesn’t work well, vitamin D molecules slam against your cell wall and bounce off, unused.

VDR variants are extremely common, appearing in 30-50% of the population depending on which variant (BsmI, FokI, or TaqI) you carry. Even if you supplement with vitamin D, your cells may be taking in only a fraction of what you’re providing. You could have a serum vitamin D level that looks acceptable on paper while your mitochondria are still starved for it.

You experience this as persistent fatigue despite adequate sleep, weak muscles even with exercise, and a sense that your energy crashes in the afternoon no matter how well you’ve eaten. Your muscles ache. Cold hits you harder than it hits others. You feel weak disproportionate to any actual exertion. This is because your mitochondria aren’t being built efficiently, so your cells can’t generate the ATP you need to move, think, or recover.

Iron is essential for building hemoglobin, which carries oxygen in your blood, and for dozens of enzymes that produce energy. HFE is the gene that tells your digestive system how much iron to absorb. It does this by regulating hepcidin, a hormone that controls whether iron gets into your bloodstream or stays trapped in your gut. If HFE doesn’t work properly, this whole system breaks down.

The H63D variant is carried by roughly 15-20% of people with European ancestry. This variant is associated with mild iron dysregulation, reducing absorption and leaving you with chronically low iron and ferritin even when you eat red meat regularly. This is different from the C282Y variant, which causes iron overload, but the fatigue it causes is just as real.

You feel this as bone-deep exhaustion, shortness of breath with minimal exertion, poor exercise tolerance, and the inability to recover from training. Your nails are weak. You may have hair loss. Your skin looks pale. Your heart races when you climb stairs. You might be anemic or your ferritin might be low-normal, a range your doctor dismisses as acceptable but which leaves your cells underfueled.

TMPRSS6 regulates hepcidin, the hormone that controls iron absorption. Where HFE is the master regulator, TMPRSS6 is the fine-tuner. It senses when your iron is dropping and tells your body to absorb more. If TMPRSS6 has a variant, this sensing system becomes sluggish, and your body doesn’t increase iron absorption even when you’re depleting.

The rs855791 variant is carried by roughly 45% of the population. This variant is associated with lower iron absorption and lower ferritin levels, making you susceptible to iron-deficiency anemia even on a meat-rich diet. You can eat steak three times a week and still be functionally iron-deficient because your body isn’t signaling itself to absorb what you’re eating.

You experience this as exhaustion that doesn’t respond to rest, fatigue that worsens as the day progresses, pale skin, and a general sense that your body is running on fumes. You may be cold all the time. You lack the stamina to exercise. Brain fog is constant. Standard iron supplementation might not work well because your body still isn’t absorbing it efficiently without the right support.

Vitamin A is essential for immune function, mitochondrial health, and dozens of metabolic enzymes. But here’s the problem: most of the plant-based sources of vitamin A (carrots, kale, sweet potato) are actually beta-carotene, a precursor that your body must convert into active retinol. BCMO1 is the enzyme that does this conversion. If it’s slow, you can eat mountains of carrots and still be functionally vitamin A deficient.

The R267S and A379V variants are carried by roughly 45% of the population. These variants reduce the enzyme’s efficiency significantly, meaning you convert plant-based beta-carotene to retinol at roughly half the rate of people with normal variants. If you’re vegetarian or vegan, this becomes catastrophic. But even meat-eaters can become deficient if they rely heavily on plant sources.

You feel this as fatigue, muscle weakness, immune suppression (frequent infections), and poor night vision. Your skin becomes rough or flaky. You bruise easily. Wounds heal slowly. Your energy is consistently low because your mitochondria aren’t getting the vitamin A they need to regulate metabolism and produce energy efficiently.

FUT2 codes for an enzyme that secretes ABO blood group antigens into your saliva and digestive tract. This might sound unrelated to nutrition, but it’s actually a critical regulator of your gut microbiome. The bacteria that colonize your gut depend partly on these secreted antigens. If FUT2 function is altered, your microbiome composition shifts, and certain bacteria that help you absorb minerals and produce energy may disappear.

The FUT2 non-secretor variant is relatively common, appearing in roughly 30-40% of some populations. Non-secretors have altered gut bacterial composition, which can impair the absorption of minerals like iron and vitamin B12, even if other genes are functioning normally. Your microbiome is a second genome, and this variant essentially rewrites which microbes live there.

You experience this as fatigue, inconsistent digestion (sometimes constipated, sometimes loose), bloating after meals, and poor recovery from infections. You may have more frequent stomach issues. You feel like your gut doesn’t work well even though nothing is obviously wrong. Your energy dips after meals rather than stabilizing. Your immune system is sluggish. This is because the bacteria that should be helping you absorb nutrients and produce short-chain fatty acids for energy are simply not there.