Interaction of environmental factors with the polygenic risk scores of thinness‐related genes in preventing obesity risk in middle‐aged adults: The KoGES

BACKGROUND: Some persons are genetically resistant to obesity, but only a few studies have evaluated thinness genes for preventing obesity. We aimed to investigate the association of polygenic variants with being underweight and their interaction with the lifestyles of middle-aged and elderly persons and identify potential new genetic approaches for managing body weight. METHODS: . A genome-wide association study was run to identify thinness-related single nucleotide polymorphisms (SNPs) after adjustment for compound factors using Gplink. The generalised multifactor dimensionality reduction program was used to identify the genetic variants with SNP-SNP interactions. The polygenic risk score (PRS) was calculated by summing up the number of risk alleles in each SNP and classifying them into low-, medium- and high-PRS. RESULTS: The best model included the ANK2ᵣs7656666, CASTᵣs28042, SLC1A3ᵣs928431867, CHST12ᵣs2906173, ALOX5ᵣs1051713, RGS6ᵣs17180754, ST8SIA5ᵣs79491311 and DCCᵣs35721894 alleles. The participants with high-PRS had a lower BMI (p < 0. 0001) than those with low-PRS and were 3. 834 (2. 58-5. 70) times more likely to be underweight after multivariate adjustment (p < 0. 001). The selected SNPs were correlated with each other and highly expressed in brain-related genes. The genes with minor alleles of CASTᵣs28042 and CHST12ᵣs2906173 exhibited a higher expression frequency in brain-related tissues. PRS had significant interactions with protein, sodium, indigestible carbohydrates, calcium intake and exercise (p < 0. 05), influencing the underweight state. People with a high-PRS were more underweight than those with low-PRS under high protein, sodium, high calcium, low indigestible carbohydrate intake and low exercise by 3. 75, 3. 88, 7. 05, 3. 18 and 3. 80 times, respectively (p < 0. 0001). CONCLUSIONS: In conclusion, adults having a high-PRS were significantly correlated with being underweight, especially in combination with a particular nutritional status. These results show the potential for thinness genes to be applied to personalised nutrition for preventing obesity through targeted gene therapy.