Identification of VLDL as a biomarker for prewarning of androgenic alopecia

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Received: 15 March 2024 Accepted: 8 April 2024
DOI: 10.1111/srt.13712
RESEARCH LETTER
Identification of VLDL as a biomarker for prewarning of
androgenic alopecia
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 Univer-
sity of Bristol, UK, known as the IEU open gwas project (MRC IEU)
OpenGWAS database) (Table 1).
To identify causal links between genes for circulating metabo-
lites 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 (PIVW <0.05) (Figure 1).
TAB L E 1 Detailed information of included data sources.
Traits Sample size Year Population PubMed ID Web source
249 Circulating metabolites
(primary analyses)
115078 2020 European NA https://www.ukbiobank.ac.uk/
Androgenic alopecia 119185 2021 European NA https://gwas.mrcieu.ac.uk/
Note: Pooled-level 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 MRC IEU OpenGWAS database).
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2024 The Authors. Skin Research and Technologypublished by John Wiley & Sons Ltd.
Obesity (body mass index [BMI] and waist circumference), hyper-
tension, 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 respec-
tive 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
(PIVW <0.05) when adjusted for obesity (body mass index [BMI] and
waist circumference), hypertension, and smoking. However, the pres-
ence of a significant association between HDL and AGA disappeared
(PIVW >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
(PIVW =0.328), met-d-M_VLDL_P(PIVW=0.518), met-d-S_VLDL_FC
(PIVW =0.406), and met-d-Val (PIVW =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 mech-
anisms include pro-atherosclerotic effects and a hypercoagulable
condition, which promotes thromboembolism.4Not only that, but
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https://doi.org/10.1111/srt.13712

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FIGURE 1 Results of Single-Variable Mendelian randomization of circulating metabolites and their risk for AGA. The effect of each metabolite
on the occurrence of AGA is discussed. Pooled-level GWAS data for 249 circulating metabolites and androgenetic alopecia-related GWAS datasets
were used. AGA, androgenetic alopecia; CI, confidence interval; IVW, inverse-variance weighted; OR, odds ratio; SNPs, single nucleotide
polymorphisms.
VLDL also promotes aldosterone synthesis and causes hyperten-
sion, 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 folli-
cles. 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.5Further research is needed to deter-
mine if VLDL contributes to the development of AGA by altering the
vasculature.
Our study found that an increase in valine (PIVW <0.05) was associ-
ated 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 asso-
ciated 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.

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FIGURE 3 Bidirectional Mendelian randomization study. AGA was the exposure factor and met-d-M_VLDL_C, met-d-M_VLDL_P,
met-d-S_VLDL_FC, and met-d-Val were used as outcome indicators. AGA, androgenetic alopecia.
FIGURE 2 Multivariable inverse variance weighted estimates for adjusted associations with androgenetic alopecia. Multivariate MR
considered smoking initiation, essential (primary) hypertension, BMI, and waist circumference-related SNPs in conjunction with circulating
metabolite-related SNPs to investigate their respective effects on androgenetic alopecia after adjustment. BMI, body mass index; MR, mendelian
randomization; SNPs, single nucleotide polymorphisms.

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ACKNOWLEDGMENTS
1. Basic Public Welfare Research Project of Zhejiang (NO:
LY23H110001).
2. Science and Technology Major Project of Zhejiang Province and the
State Administration of Traditional Chinese Medicine (NO: GZY-ZJ-
KJ-23035).
3. Health Science and Technology Major Project of Hangzhou(NO:
Z20220040).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
All data of the datasets analyzed during the current study are acces-
sible from the Integrative Epidemiology Unit (IEU) database (http://
gwas. mrcieu. ac. uk/), the GWAS ID for androgenic alopecia used in our
study was finn-b-L12_ALOPECAREATA. Pooled-level GWAS datasets
for 249 circulating metabolites were obtained from UK Biobank
(http://www.ukbiobank.ac.uk/).
PATIENT CONSENT
Not applicable.
Yuqing Shen1
Wen Xu2
Jiayi Sun1
Yuqi Zhu1
Yeqin Dai3
Xiuzu Song3
1Department of Dermatology, Hangzhou Third Hospital Affiliated to
Zhejiang Chinese Medical University, Hangzhou, China
2School of Medicine, Zhejiang University, Hangzhou, People’s Republic of
China
3Department of Dermatology, Hangzhou Third People’s Hospital,
Hangzhou, China
Correspondence
Xiuzu Song, Department of Dermatology, Hangzhou Third People’s
Hospital, Hangzhou, China.
Email: songxiuzu@sina.com
ORCID
YuqingShen https://orcid.org/0000-0002-9609-5109
Wen Xu https://orcid.org/0000- 0002-2055- 9376
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