The human genome contains around 20,000 protein-coding genes, and a meaningful share of them are involved, directly or indirectly, in taking food apart and absorbing it. Carbohydrates, proteins and fats are the three macronutrients that supply energy, and each is digested by a different set of enzymes, transporters and hormones. Genetic differences in those systems explain why people can react so differently to the same meal.

The clearest examples come from carbohydrates, which is where we start.

Digestion of carbohydrates

Starch digestion begins in the mouth with salivary amylase, encoded by AMY1. Unusually, the gene exists in a variable number of copies. Populations with traditionally high-starch diets carry more copies on average, and copy number tracks the amount of amylase in saliva, which made AMY1 one of the first documented cases of dietary selection on copy number in the human genome.[1Genetic associationDiet and the evolution of human amylase gene copy number variationPerry et al. 2007 · Nature Genetics 39:1256–1260People from populations with high-starch diets have, on average, more copies of the salivary amylase gene (AMY1), and copy number tracks salivary amylase levels.Click for the full reference]

Further along the gut, brush-border enzymes finish the job: sucrase-isomaltase (SI) splits sucrose and starch fragments, lactase (LCT) splits lactose, and transporters such as SGLT1 and GLUT2 move the resulting sugars into the blood.

Two well-studied examples of genetic variation:

• Lactase persistence. Most mammals, and most humans worldwide, lose lactase activity after weaning. In some populations a regulatory variant keeps the gene switched on into adulthood. A variant near LCT (C/T-13910) explains persistence in Europeans,[2Genetic associationIdentification of a variant associated with adult-type hypolactasiaEnattah et al. 2002 · Nature Genetics 30:233–237A single DNA variant upstream of the lactase gene (C/T-13910) tracks with whether adults keep digesting lactose.Click for the full reference] and different variants arose independently in African pastoralists, a textbook case of convergent evolution driven by dairying.[3Genetic associationConvergent adaptation of human lactase persistence in Africa and EuropeTishkoff et al. 2007 · Nature Genetics 39:31–40African herding populations evolved lactase persistence through different variants than Europeans, a selective sweep over roughly the past 7,000 years.Click for the full reference]
• Sucrase-isomaltase. Rare variants that severely impair the enzyme cause congenital sucrase-isomaltase deficiency, and less severe, more common loss-of-function variants 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]

Digestion of proteins

Protein digestion starts in the stomach with pepsin, continues in the small intestine with pancreatic enzymes such as trypsin and chymotrypsin, and finishes with peptidases and transporters that absorb amino acids and small peptides. This is a robust, redundant system, and in contrast with carbohydrates I'm not aware of common variants with clear dietary consequences for healthy people. Most known variants matter in rare disease (for example, some forms of hereditary pancreatitis), which is why this section is short.

Digestion of fats

Fat digestion relies on bile acids for emulsification, on pancreatic lipase (and its cofactor colipase) for breaking triglycerides down, and on intestinal proteins that package fatty acids into chylomicrons for transport. A frequently discussed variant is FABP2 Ala54Thr, which encodes a fatty-acid-binding protein in the gut. The Thr54 form binds fatty acids more tightly, and the variant was linked to insulin resistance in Pima Indians.[7Genetic associationAn amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistanceBaier et al. 1995 · Journal of Clinical Investigation 95(3):1281–1287In Pima Indians, the Ala54Thr variant of FABP2 was linked to higher insulin resistance and higher fatty-acid binding in vitro.Click for the full reference]

Take-home

• The strongest genetic effects on macronutrient digestion involve carbohydrates: lactase persistence is well established, and sucrase-isomaltase variants matter for some people with gut symptoms.
• Effects on protein and fat digestion in the general population are less clear.
• Whether genetic variation in digestion should change what you eat is a separate, much harder question than whether it exists.