Two people eat the same breakfast. One digests the milk without a thought, the other spends the morning in the bathroom. One's blood level of vitamin B12 stays comfortable on a modest diet, the other's runs low. One clears the morning's coffee in a couple of hours, the other lies awake at night.

These differences are not random, and they are not all about willpower or "metabolism" in the loose sense. Much of the variation comes from small differences in DNA that change how much of a protein your body makes, how well it works, or whether it works at all. This post explains the mechanisms, one step of a nutrient's journey at a time.

The journey, and where genes act

Every nutrient goes through roughly the same stages: it is broken down (digestion), taken up into the blood (absorption), carried to where it's needed, and chemically transformed by enzymes into usable or excretable forms. Genes shape each stage in a few distinct ways:

Way a gene can matter	What changes	Example
How much protein is made	Regulation or copy number of a gene	Lactase persistence; amylase (AMY1) copies
How well each protein works	An amino-acid change alters speed, stability or cofactor binding	MTHFR, BCMO1, ADH/ALDH, CYP1A2
Whether it works at all	Loss-of-function mutation	Phenylketonuria; NPC1L1; sucrase-isomaltase
How nutrients are carried or sensed	Transport, binding and regulation proteins	FUT2 and vitamin B12; HFE and iron; GC and vitamin D

The rest of the post follows the journey, then explains why the effects are usually smaller than the headlines suggest.

Step 1: Digestion, or "how much enzyme?"

The simplest way a gene can change digestion is to change the quantity of an enzyme.

Lactase breaks down the milk sugar lactose. In most mammals, and in most humans worldwide, the lactase gene (LCT) is switched down after weaning. In some people it stays on for life. The difference is not in the enzyme itself but in a regulatory DNA variant near the gene: a change about 14 kb upstream, found in Europeans, tracks with adult lactase activity.[1Genetic associationIdentification of a variant associated with adult-type hypolactasiaEnattah et al. 2002 · Nature Genetics 30:233–237A DNA variant about 14 kb upstream of the lactase gene (C/T-13910) tracks with whether adults keep digesting lactose.Click for the full reference] African herding populations evolved lactase persistence independently through different variants, which enhanced transcription from the LCT promoter in laboratory tests.[2Genetic associationConvergent adaptation of human lactase persistence in Africa and EuropeTishkoff et al. 2007 · Nature Genetics 39:31–40Three African variants, on different haplotype backgrounds from the European one, each enhance transcription from the lactase promoter in vitro.Click for the full reference] Same outcome, different DNA: more or less of the same enzyme.

Amylase works at the other end of the dial. The salivary amylase gene (AMY1) exists in a variable number of copies, and more copies mean more amylase protein in saliva. Populations with high-starch diets carry more copies on average.[3Genetic associationDiet and the evolution of human amylase gene copy number variationPerry et al. 2007 · Nature Genetics 39:1256–1260Copy number of the salivary amylase gene (AMY1) correlates positively with salivary amylase protein level, and high-starch populations carry more copies on average.Click for the full reference] Here the DNA change is not a spelling difference but a difference in dosage.

At the extreme, a variant can cut an enzyme's activity so far that symptoms appear. Reduced-function variants of sucrase-isomaltase, which finishes digesting sucrose and starch fragments at the gut lining, are over-represented in people with irritable bowel syndrome.[4Genetic associationFunctional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndromeHenström et al. 2018 · Gut 67:263–270Variants that reduce sucrase-isomaltase function were over-represented in people with irritable bowel syndrome (1,887 cases and controls).Click for the full reference] (More on carbohydrate digestion in our post on the genetics of macronutrient digestion.)

Step 2: Absorption and transport

Once food is broken down, nutrients must cross the gut wall and be carried around the body. Genes act here through transporters, carriers and the signalling systems that control them.

• Vitamin B12. A variant in FUT2, linked to "secretor status", was strongly associated with plasma B12 levels in a study of Nurses' Health Study participants. The authors suggested that altered B12 absorption is a plausible mechanism.[5Genetic associationCommon variants of FUT2 are associated with plasma vitamin B12 levelsHazra et al. 2008 · Nature Genetics 40(10):1160–1162A variant in FUT2, in strong linkage with a nonsecretor variant, was strongly associated with plasma B12 in 1,658 women plus 1,059 in replication, suggesting a plausible mechanism of altered B12 absorption.Click for the full reference]
• Iron. The body has little ability to get rid of excess iron, so the entry of iron into the blood is tightly controlled, with the hormone hepcidin playing a central role. Hereditary hemochromatosis arises from mutations in proteins of this system. The best known is HFE, discovered in 1996, where two copies of the C282Y mutation were found in 83% of patients in the original study.[6Genetic associationA novel MHC class I-like gene is mutated in patients with hereditary haemochromatosisFeder et al. 1996 · Nature Genetics 13:399–408Identified HFE and its C282Y mutation, found in two copies in 83% of 178 patients with hereditary haemochromatosis.Click for the full reference][7ReviewHereditary hemochromatosis: pathogenesis, diagnosis, and treatmentPietrangelo 2010 · Gastroenterology 139(2):393–408Hemochromatosis arises from mutations in proteins that limit iron entry into the blood, notably the hormone hepcidin pathway; most white people homozygous for HFE C282Y are only predisposed, and complete organ disease develops in a minority.Click for the full reference]
• Cholesterol. NPC1L1 encodes the protein targeted by the cholesterol-lowering drug ezetimibe. About 1 in 650 people carry an inactivating mutation, and carriers had lower LDL cholesterol and about half the risk of coronary heart disease.[8Genetic associationInactivating mutations in NPC1L1 and protection from coronary heart diseaseMyocardial Infarction Genetics Consortium Investigators 2014 · New England Journal of Medicine 371(22):2072–2082About 1 in 650 people carries an inactivating NPC1L1 mutation; carriers had LDL cholesterol about 12 mg/dL lower and a 53% lower risk of coronary heart disease (odds ratio 0.47).Click for the full reference] It is a rare case where a natural genetic "experiment" mirrors what a drug does.
• Vitamin D. Blood levels are influenced by GC, which encodes the vitamin D binding protein that carries it in the blood, together with DHCR7 and CYP2R1.[9Genetic associationCommon genetic determinants of vitamin D insufficiency: a genome-wide association studyWang et al. 2010 · The Lancet 376(9736):180–188In about 34,000 people, variants near GC, DHCR7 and CYP2R1 were associated with vitamin D insufficiency; carrying risk alleles at all three more than doubled the risk.Click for the full reference]

Step 3: Enzymatic transformation, or "how fast?"

Many nutrients must be chemically converted before the body can use them. How fast that happens depends on how much enzyme exists, how efficient each enzyme molecule is, whether its helper molecules (cofactors) are present, and how much substrate there is. Genes can alter each of these, and the interesting part is that diet can sometimes compensate.

A cofactor example: MTHFR and riboflavin

MTHFR helps convert folate into the form used for methylation. A common variant, C677T, changes one amino acid and is found on roughly a third of chromosomes in the original study population.[10Genetic associationA candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductaseFrosst et al. 1995 · Nature Genetics 10:111–113Identified the common C677T substitution in MTHFR, present on about 38% of unselected chromosomes, which alters a highly conserved amino acid.Click for the full reference] People with two copies (the TT genotype) have lower enzyme activity, partly because the enzyme loses its riboflavin (vitamin B2) cofactor too easily.

That points to a diet-based fix, and a randomized trial tested it. Giving adults 1.6 mg a day of riboflavin for 12 weeks lowered homocysteine only in the TT group, by up to 22% (and by about 40% in those with lower riboflavin status), while CT and CC participants did not respond.[11Randomized trialRiboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphismMcNulty et al. 2006 · Circulation 113(1):74–80In a 12-week randomized trial (35 TT, 26 CT and 28 CC adults), 1.6 mg/day of riboflavin lowered homocysteine only in the TT group (by up to 22%, and by 40% in those with lower riboflavin status).Click for the full reference]

A conversion example: beta-carotene to vitamin A

The enzyme BCMO1 converts beta-carotene from plants into vitamin A. Two common variants (carried by 42% and 24% of alleles in the study) reduced the enzyme's catalytic activity by 57% in the laboratory when combined, and women carrying them converted less beta-carotene to vitamin A after a test dose.[12Genetic associationTwo common single nucleotide polymorphisms in the gene encoding beta-carotene 15,15'-monoxygenase alter beta-carotene metabolism in female volunteersLeung et al. 2009 · FASEB Journal 23(4):1041–1053Two common BCMO1 variants reduced the enzyme's catalytic activity by 57% in vitro, and carriers converted less beta-carotene to vitamin A after a test dose.Click for the full reference] That may help explain why some people are "poor converters", which matters for diets that rely on plant sources of vitamin A.

Clearance examples: alcohol and caffeine

Alcohol is processed in two steps by ADH and ALDH enzymes, and variants in both genes are the strongest known genetic influences on alcohol use disorder.[13ReviewAlcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: a critical reviewEdenberg et al. 2018 · Alcoholism – Clinical and Experimental Research 42:2281–2297Functional variants in ADH1B and ALDH2 are the strongest known genetic influences on alcohol use disorder; the protective ALDH2 variant is essentially confined to people of East Asian ancestry.Click for the full reference] (We cover them in depth in the evolution of alcohol tolerance.) Caffeine is cleared mainly by CYP1A2. In a Costa Rican study, heavy coffee drinking was associated with higher heart-attack risk in people with the slow-metabolizer variant, but not in fast metabolizers.[14Genetic associationCoffee, CYP1A2 genotype, and risk of myocardial infarctionCornelis et al. 2006 · JAMA 295(10):1135–1141In 2,014 heart-attack cases and 2,014 controls, heavy coffee drinking raised risk in slow caffeine metabolizers (CYP1A2*1F carriers) but not in fast metabolizers.Click for the full reference]

Step 4: When the enzyme is missing

At the severe end are inborn errors of metabolism, where a single gene fails and a nutrient accumulates. Phenylketonuria (PKU) is the classic example. Mutations in the phenylalanine hydroxylase gene stop the body from clearing the amino acid phenylalanine. Severity ranges from very mild to severe, and untreated severe PKU causes irreversible intellectual disability. Newborn screening finds it, and a phenylalanine-restricted diet started soon after birth prevents most of the damage. In about 20% of patients a cofactor, tetrahydrobiopterin, boosts the remaining enzyme activity enough to allow a more liberal diet.[15ReviewPhenylketonuriaBlau et al. 2010 · The Lancet 376(9750):1417–1427Mutations in the phenylalanine hydroxylase gene cause a spectrum from mild to severe disease; a phenylalanine-restricted diet started soon after birth prevents most complications, and a cofactor (tetrahydrobiopterin) boosts enzyme activity in about 20% of patients.Click for the full reference]

PKU shows the same three ideas as the examples above (amount of enzyme, efficiency, cofactor), but at an extreme, and it is the clearest example where genetic knowledge directly changes what a person must eat.

Why the effects are usually smaller than headlines

Most nutrient-related genes in everyday life are nothing like PKU. A few reasons:

• Most carriers are fine. In white populations, many people carry two copies of the HFE C282Y mutation, but only a minority develop full organ disease, and modifiers such as alcohol matter.[7ReviewHereditary hemochromatosis: pathogenesis, diagnosis, and treatmentPietrangelo 2010 · Gastroenterology 139(2):393–408Hemochromatosis arises from mutations in proteins that limit iron entry into the blood, notably the hormone hepcidin pathway; most white people homozygous for HFE C282Y are only predisposed, and complete organ disease develops in a minority.Click for the full reference] A risk variant raises the odds. It does not seal the outcome.
• Many genes, small effects. Traits like vitamin D status are shaped by several variants plus sun exposure and diet.[9Genetic associationCommon genetic determinants of vitamin D insufficiency: a genome-wide association studyWang et al. 2010 · The Lancet 376(9736):180–188In about 34,000 people, variants near GC, DHCR7 and CYP2R1 were associated with vitamin D insufficiency; carrying risk alleles at all three more than doubled the risk.Click for the full reference]
• Other systems intervene. Even the gut microbiome, which itself is partly shaped by host genetics, changes how food is handled.[16Cohort studyHuman genetics shape the gut microbiomeGoodrich et al. 2014 · Cell 159(4):789–799In over 1,000 TwinsUK samples, the abundance of many gut microbes was influenced by host genetics, with effects on host metabolism.Click for the full reference]
• Diet can compensate, as with riboflavin and MTHFR above.

Take-home

• Genes change nutrient handling in four main ways: how much protein is made, how well it works, whether it works at all, and how nutrients are carried and sensed.
• Digestion mostly depends on enzyme amount (lactase, amylase), absorption on transporters and regulators (B12, iron, cholesterol), and transformation on enzyme speed and cofactors (MTHFR, BCMO1, CYP1A2).
• Effects range from trivial to life-changing, but most are modest and depend on diet and other genes.
• Whether to act on a result is a separate and harder question, which we discuss in personalized nutrition based on genetics and in genetic variants and nutrient metabolism.

This post is general information, not medical advice. If you have symptoms or a family history, talk to a doctor or dietitian before changing your diet or taking supplements.