Identification of VLDL as a biomarker for prewarning of androgenic alopecia

Abstract

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To the Editor,

The most prevalent cause of hair loss is androgenetic alopecia (AGA), while the association between AGA and metabolic lipids has been extensively explored, the relationship between AGA and dyslipidemia remains contentious.1

Mendelian randomization (MR) is an epidemiological technique that uses genetic variations with randomly allocated alleles as tools.2 Genetic variants remain unchanged after birth, so MR can avoid confounding factors such as behavior and reversal of cause and effect.

Pooled‐level Genome‐wide association studies (GWAS) datasets for 249 circulating metabolites were obtained from UK Biobank and androgenetic alopecia‐related GWAS datasets were obtained from FinnGen (both accessible via the database developed by the University of Bristol, UK, known as the IEU open gwas project (MRC IEU) OpenGWAS database) (Table 1).

To identify causal links between genes for circulating metabolites and AGA, we employed the negative variance weighting (IVW) approach as the major analytical tool. To examine the robustness of the results, statistically significant results were subjected to additional heterogeneity tests, such as MR‐Egger weighted median sensitivity analyses, Leave‐One‐Out, and others.

Our findings suggest that Valine, one high‐density lipoprotein (HDL) subcomponent (S_HDL_PL_pct), and seven very low‐density lipoprotein (VLDL) subcomponents (i.e., M_VLDL_C, M_VLDL_FC, M_VLDL_P, M_VLDL_PL, S_VLDL_CE, S_VLDL_FC, VLDL_CE), were associated with the risk of AGA (P_IVW_ < 0.05) (Figure 1).

Obesity (body mass index [BMI] and waist circumference), hypertension, and smoking are frequently seen in patients with AGA, and it may be assumed that these exposures influenced the results we screened for. We further conducted a multivariate MR analysis (MVMR) to adjust for confounders. MVMR focuses on the respective effects of genetic variants in the whole, and who contributes more to the overall effect. The results of the association between M_VLDL_C, M_VLDL_P, S_VLDL_FC, Val, and AGA were also robust (P_IVW_ < 0.05) when adjusted for obesity (body mass index [BMI] and waist circumference), hypertension, and smoking. However, the presence of a significant association between HDL and AGA disappeared (P_IVW_ > 0.05) (Figure 2).

To further investigate the reverse causal effect of AGA on the four identified positive metabolite indicators, a two‐sample reverse MR analysis was performed, primarily using the IVW method.3There was no correlation between AGA and met‐d‐M_VLDL_C (P_IVW_ = 0.328), met‐d‐M_VLDL_P (PIVW = 0.518), met‐d‐S_VLDL_FC (P_IVW_ = 0.406), and met‐d‐Val (P_IVW_ = 0.691) (Figure 3). Combined with the previous results of Figure 1, there is no bidirectional causality between M_VLDL_C, M_VLDL_P, S_VLDL_FC, Val and AGA.

The results showed a positive correlation between increased VLDL subcomponent fractions and AGA. VLDL raises blood viscosity, which increases microvascular events, and other potential mechanisms include pro‐atherosclerotic effects and a hypercoagulable condition, which promotes thromboembolism.4 Not only that, but VLDL also promotes aldosterone synthesis and causes hypertension, which can cause vasoconstriction. Patients with AGA have microvascular anomalies and vascular degradation in the scalp, and vasculature plays an important role in the formation of hair follicles. Few studies have explicitly linked VLDL to AGA, with just one case‐control study finding VLDL to be high in the AGA population and rising with the AGA class.5 Further research is needed to determine if VLDL contributes to the development of AGA by altering the vasculature.

Our study found that an increase in valine (P_IVW_ < 0.05) was associated with AGA. This may be related to the fact that valine can be used as a marker for dyslipidemia metabolism.6

To summarize, our findings suggest that Valine and three VLDL subfractions (M_VLDL_C, M_VLDL_P, S_VLDL_FC) are positively associated with AGA risk. Reverse MR analysis showed that AGA had no effect on these four circulating metabolites. However, our study has the drawback of being confined to patients of European origin, and additional validation in other populations is required.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

PATIENT CONSENT

Not applicable.