Studies on the interactions between single nucleotide polymorphisms (SNPs) and macronutrient consumption on weight loss are rare and heterogeneous. This review aimed to conduct a systematic literature search to investigate genotype–diet interactions on weight loss. Four databases were searched with keywords on genetics, nutrition, and weight loss (PROSPERO: CRD42019139571). Articles in languages other than English and trials investigating special groups (e.g., pregnant women, people with severe diseases) were excluded. In total, 20,542 articles were identified, and, after removal of duplicates and further screening steps, 27 articles were included. Eligible articles were based on eight trials with 91 SNPs in 63 genetic loci. All articles examined the interaction between genotype and macronutrients (carbohydrates, fat, protein) on the extent of weight loss. However, in most cases, the interaction results were not significant and represented single findings that lack replication. The publications most frequently analyzed genotype–fat intake interaction on weight loss. Since the majority of interactions were not significant and not replicated, a final evaluation of the genotype–diet interactions on weight loss was not possible. In conclusion, no evidence was found that genotype–diet interaction is a main determinant of obesity treatment success, but this needs to be addressed in future studies.
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