Why Some People Need More Vitamin D Than Others:
What Your Genes Have to Do With It

A familiar story in clinic goes like this. Someone has been told their vitamin D is low, started a supplement, and retested three months later to find the number has barely moved. A friend took the same product at the same dose and sailed into the normal range within weeks. Neither of them did anything wrong, and the difference is not a matter of discipline or of buying a better brand.

Part of the explanation is practical, and we will get to that. Part of it is genetic, because vitamin D goes through a long chain of steps between the sun on your skin and a working hormone in your cells, and common variation exists at almost every step.

Vitamin D starts in the skin, where ultraviolet light converts a cholesterol-related compound into vitamin D3. From there it travels to the liver, where an enzyme encoded by the CYP2R1 gene converts it into the form measured on a blood test, known as 25-hydroxyvitamin D. A carrier protein, built from the GC gene, transports it around the body, and the kidneys convert it into its active form. Another enzyme, CYP24A1, switches it off again by breaking it down.

The final step happens inside your cells, where the active hormone binds to the vitamin D receptor (a protein, built from the VDR gene, that sits inside cells and switches on the genes vitamin D is meant to influence). Without a working receptor, having plenty of vitamin D in the blood makes much less difference than it should.

Large genetic studies have repeatedly linked variants in GC, CYP2R1 and the gene that governs how much of the skin precursor is available, DHCR7, to lower blood levels of vitamin D. Each variant has a modest effect on its own, but they add up, so a person who carries several can sit consistently lower than a person who carries none, even with identical sun exposure and diet.

Variants in the VDR gene work differently. They may not change how much vitamin D you have, but they can change how well your cells respond to it. Some evidence also suggests that genetic variation influences how far the blood level rises for a given supplement dose, which would help explain why one person needs a lot more than another to reach the same number. The research here is still developing, and effects at the level of an individual are hard to predict from a single result.

Sun exposure remains the biggest driver for most people, and it varies enormously. Skin tone, season, latitude, the hours you spend indoors, the clothing you wear and your sunscreen use all change how much vitamin D you make. Body fat holds on to vitamin D, so people with a higher body weight often need more to reach the same blood level.

Absorption matters as well. Vitamin D is fat-soluble, and conditions or medications that interfere with fat absorption reduce how much of a supplement actually gets through. Transit time × Transit Time Transit time refers to the length of time it takes for food to move through the digestive tract, from when it is eaten until it leaves the body as a bowel motion. Transit time varies considerably between individuals and appears to play an important role in shaping the gut microbiome. Research suggests that transit time may have a greater influence on microbiome composition than diet alone, helping explain why two people eating similar diets can have very different gut microbiomes and gut health play a role here too, as covered in why daily bowel movements are not enough. Magnesium is needed to activate vitamin D, so a shortfall can quietly limit the whole process, and some medications speed up its breakdown.

The form of supplement matters too, and the two you are most likely to meet are cholecalciferol and calcifediol. Cholecalciferol, vitamin D3, is the standard supplement and is chemically the same as the vitamin D your skin makes, which means it still has to be converted by the liver into 25-hydroxyvitamin D before it shows up on a blood test. Calcifediol is that liver product itself, so it skips the first conversion step. In short trials it has tended to raise blood levels faster and more predictably than D3, and it appears to be absorbed less dependently on dietary fat, which is why it is sometimes considered for people with fat malabsorption, liver disease or a higher body weight. In theory it could also sidestep variants that slow the liver step, though that has not been established. Calcifediol is more potent, so levels can overshoot more easily, and long-term comparisons with D3 are limited. Which form suits you is a decision to make with your practitioner and a repeat blood test, rather than a straight swap.

Vitamin D is best known for calcium and bones, but its receptor is found in muscle, immune cells and the brain, and low levels are associated with muscle weakness, frequent infections and low mood. It would be a stretch to say low vitamin D explains every case of persistent tiredness, but when someone is tired despite normal-looking results, it is one of the pieces worth checking properly rather than assuming.

Timing also matters when you read a result. Vitamin D levels rise and fall with the seasons, particularly in the southern states, so a level taken at the end of winter often looks quite different from one taken at the end of summer. A single reading is a snapshot rather than a verdict. Retesting after a couple of months on a consistent plan gives a far clearer picture of whether what you are doing is working, and a result that is only just inside the reference range is worth interpreting alongside your symptoms rather than on its own.

A DNA result can show whether you carry variants that make a lower baseline likely, which helps make sense of a stubborn result and suggests that you may need retesting and adjusting more closely than average. It sits alongside the wider picture described in more than MTHFR, where a single gene is never the whole answer.

What it cannot do is hand you a dose. Vitamin D is not harmless in excess, because too much can raise blood calcium, so the right amount is worked out from your actual blood level and retested rather than inferred from a gene. And in Australia, where the sun is strong and skin cancer rates are high, sensible sun protection still applies. The aim is to understand your pattern, not to replace safe habits with a supplement.

If your vitamin D has refused to budge despite doing everything right, there is usually a reason, and it is rarely effort. Working out whether your skin, your liver, your carrier protein, your gut or your cells is the sticking point turns a frustrating result into something you can act on.