MLXIPL
Protein:
MLX-interacting protein-like, also known as Carbohydrate-responsive element-bindnig protein (ChREBP)
SNP ID:
MLXIPL is a transcription factor expressed in liver cells. There, it binds to a set of regulatory regions on the DNA known as Carbohydrate-responsive element to activate the expression of genes involved in glycolysis and lipid production 1. Fatty acids were shown to regulate MLXIPL activity, although the mechanisms behind this phenomenon are not yet understood 2. Several SNPs in MLXIPL were associated with changes in low-density lipoprotein cholesterol (“bad cholesterol”) and triglyceride levels 3 4, with one SNP detailed below showing an interaction effect with fish oil supplementation 5.
| rsID Number | Major Allele | Minor Allele | Minor Allele Frequency (%) | Major Amino Acid | Minor Amino Acid |
|---|---|---|---|---|---|
| rs799157 | c | t | 3.5 | Ser | Ser |
Risk Description
The careers of the rare T allele associate with increased low-density lipoprotein (‘bad cholesterol’) levels 5. Fish oil supplementation showed a positive interaction effect on cholesterol levels for this SNP, meaning that it tends to amplify rather than counteract the genetic effects and is therefore likely more beneficial for the careers of the common C allele. Because of this unusual effect, and solely for the purposes of calculating the score for the benefits of fish oil supplementation, we designated the C allele as the “risk” allele.
rs799157 localises in the protein-coding region of the MLXIPL gene but does not result in a modified MLXIPL protein sequence (and is therefore a so-called synonymous SNP). It is quite unusual for synonymous SNPs to cause physiological effects. It could be that this region has another function, for example, in regulating the expression of MLXIPL or even other genes in the vicinity.
The Gene x Environment genome-wide association study (GxE GWAS) for lipid levels with and without fish oil supplementation that detected this interaction effect 5 was high-powered and used a replication cohort, followed by a joint meta-analysis of both cohorts. Therefore, these results deserve our attention. However, it must be noted that interpreting GxE interaction effects such as this one can be tricky and the true phenomena behind them may sometimes be counterintuitive 6. In addition, the mechanism through which this synonymous variant may affect MXLIPL activity remains to be investigated. Therefore, acting on this association requires some caution.
Nutritional Contraindications:*
| Ingredient | Active Ingredient | Effect |
|---|---|---|
| Fish oil | Omega-3 Fatty Acids |
Fish oil may be counterproductive for reducing levels of low-density lipoproteins (“bad cholesterol”) in the carriers of the rare T allele of rs799157 (TT or TC genotypes). |
Discuss this information with your doctor before taking any course of action.
Citations:
- Xu X, So JS, Park JG, Lee AH. Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin Liver Dis. 2013 Nov;33(4):301-11. doi: 10.1055/s-0033-1358523.
- Jump DB, Tripathy S, Depner CM. Fatty acid-regulated transcription factors in the liver. Annu Rev Nutr. 2013;33:249–69.
- Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, Warnes GR, et al. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008;40(2):149–51.
- Zeng X-N, Yin R-X, Huang P, Huang K-K, Wu J, Guo T, et al. Association of the MLXIPL/TBL2 rs17145738 SNP and serum lipid levels in the Guangxi Mulao and Han populations. Lipids Health Dis. 2013;12(1):156.
- Francis M, et al. Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci. PLoS Genet. 2021 Mar 24;17(3):e1009431. doi: 10.1371/journal.pgen.1009431.
- Thompson WD. Effect modification and the limits of biological inference from epidemiologic data. J Clin Epidemiol. 1991;44(3):221-32. doi: 10.1016/0895-4356(91)90033-6.