Largest genetic study on circulating retinol reveals new insights into its impact on health

By Dr. Sanchari Sinha Dutta, Ph.D.Feb 21 2024

A study published in the journal Nature Communications provides a comprehensive evaluation of the genetics of circulating retinol and its influence on human health.

Study: Genetic influences on circulating retinol and its relationship to human health

Background

Vitamin A is a fat-soluble micronutrient involved in various physiological processes, including vision, cell division, immune function, and neurodevelopment. Vitamin A refers to a group of compounds, including retinol, retinoids, and provitamin carotenoids.

Retinol is consumed from animal-based diets and is mostly delivered to the liver, the primary organ responsible for retinol storage and metabolism. Retinol secreted from the liver is transported by the systemic transporter retinol-binding protein 4 (RBP4) to be delivered throughout the body. RBP4 forms a complex with tetramer protein transthyretin (TTR) to increase its stabilization and reduce renal filtration.  

Retinol is crucially associated with many therapeutic interventions. Synthetic retinoids that are structurally similar to retinol are widely used for treating dermatological complications and certain cancer types. In addition, endogenous retinoids, such as all-trans retinoic acid and 13-cis retinoic acid, are used in dermatology.

Although retinol supplementation is not currently indicated for individuals without retinol deficiency, existing evidence indicates that a higher level of retinol in the blood is associated with lower all-cause and disease-specific mortality.  

In this study, scientists have conducted the most extensive genome-wide association study of circulating retinol in up to 22,274 participants of European ancestry. 

a Prioritisation pipeline overview for retinol causal estimates [inverse-variance weighted estimator with multiplicative random effects (IVW-MRE)] that survive multiple-testing correction (FDR < 0.01). These estimates are then subjected to tests for heterogeneity and pleiotropy (Online Methods), with a tier then assigned based on how many of the five Mendelian randomization (MR) methods applied are at least nominally statistically significant. In panels b and c, the left-hand plot denotes the Z-score (beta/SE) from the MR IVW-MRE estimates. Positive Z scores denote a positive IVW-MRE estimate of the effect of circulating retinol on that trait and vice versa. The traits are coloured by their broad phenotypic category. The right-hand plot visualizes the Z score using the IVW-MRE model versus that of the MR estimate using the RBP4 IV alone (Wald Ratio). The dotted lines approximately represent nominal statistical significance (P < 0.05). In panel b, just tier #2 traits are plotted (Online Methods), whilst panel c plots both tier #2 and tier #3 traits.

Important observations

The genome-wide association study identified eight common variant loci related to retinol and a novel variant signal. An integrative gene prioritization pipeline uncovered retinol-associated genetic signals outside the main RBP4-TTR transport complex.

These eight genes were highly expressed in the liver and were significantly associated with the carbohydrate metabolism pathway. These genes are known to be broadly associated with hepatic energy metabolism.

Given the mechanistic involvement of lipids in retinol absorption, storage, and delivery, the scientists suggest that the distinct metabolic roles of these genes converge on changes in the abundance of different lipid compounds. The Mendelian randomization analysis conducted in the study also highlighted the role of lipids in controlling the abundance of circulating retinol.

Furthermore, there remains a possibility that blood glucose homeostasis plays a role in controlling circulating retinol abundance via lipid-independent mechanisms. In this context, existing evidence has shown an involvement of insulin-controlled glucose transporter GLUT4 in modulating RBP4 protein levels.

Overall, these findings indicate that the impact of the most identifiable common variant on circulating retinol is either mediated via direct effects on the transport system or via metabolic factors related to lipids.

Among eight prioritized genes, glucokinase regulator (GCKR), forkhead box p2 (FOXP2), RBP4, and TTR showed strong causal associations with circulating retinol abundance. The role of RBP4 and TTR in regulating retinol levels is well-established in the literature.

The GCKR gene encodes a protein that regulates the key metabolic enzyme glucokinase, which is known to play vital roles in glucose- and lipid-related processes. The FOXP2 gene is well-known for its association with neurological functions, such as language processing. However, its association with retinol is not clearly documented. The analysis of transcriptomic correlates of this gene revealed its association with many biological processes, including extracellular matrix biology, glycosylation, and interleukin signaling.

Regarding functional aspects, the study uncovered some less-characterized roles of retinol, including its influence on brain structure and connectivity. Retinol was found to modulate the thickness and surface area of several brain regions, including the right rostral anterior cingulate cortex. An increased thickness of this brain region has been observed in schizophrenia patients. The inverse association observed in the study between the circulating level of retinol and the thickness of the right rostral anterior cingulate cortex indicates a protective role of retinol in schizophrenia.

A phenome-wide Mendelian randomization analysis was conducted using circulating retinol's genetic proxies to estimate retinol's causal association with almost 20,000 clinical phenotypes. The analysis revealed causal effects of retinol on several clinical phenotypes, including inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes. Furthermore, lipids and serum creatinine were identified as factors causally influencing the abundance of circulating retinol.

A retinol polygenic score analysis conducted in the study revealed the impact of genetic factors in determining circulating retinol levels that fall outside the normative range for a given age.