Skin pigmentation is a complex trait determined by the type, amount, and distribution of melanin produced in the epidermis by specialized organelles known as melanosomes28. Several candidate genes with a role in human skin color have been identified that affected skin pigmentation which may be partially driven by pleiotropic effects. Recent research has extended the hypotheses that the evolution of genetic skin pigmentation has driven changes in VD levels, emerging of interest in the linking. Based on the large Latin American populations (CANDELA) study9, we analyzed eight genetic variants associated with skin pigmentation in the Mexican-mestizo population. Our analysis revealed significant associations with seven variants, underscoring their importance in determining skin pigmentation in this population. These findings shed light on the genetic factors contributing to the diverse range of skin tones observed among Mexican-mestizo individuals. Our study supports the association of the variants rs1042602-A and rs1126809-A in the TYR gene which result in non-synonymous substitutions p.S192Y and p.R402Q, respectively, have been associated with lighter skin phototype9,29.
Additionally, rs16891982-G and OCA2-rs1800404-C were also associated with lighter skin. In this regard, the membrane transport proteins SLC24A5, SLC45A2, and OCA2 have been implicated in modulating melanosomal pH. The missense variant rs16891982 in SLC45A2 replaces a leucine for a phenylalanine in residue 374. This alteration is believed to accelerate the proteasomal degradation of this transporter, without altering its localization, disturbing the deacidification of melanosomes and impairing melanin synthesis30. The variant rs1800404 in OCA2 is a synonymous variant at codon 335, which codifies for alanine31. Pathogenic variants in this gene are the cause albinism oculocutaneous type II the most common form of albinism32. The C allele of this variant has been associated with darker skin, interestingly in our study population the proportion of CC homozygous increased from the skin pigmentation type I-II to the type IV, concurring with the reported association33.
On the other hand, genetic variants rs12203592-T and rs12913832-G involved in melanocyte development, were also associated with lighter skin in the Mexican population. The derived T allele of the rs12203592 in IRF4 reduces the ability of TFAP2A to bind to the intronic enhancer of IRF4, suppressing its expression and therefore, impairing the cooperative induction of TYR34. Whereas the rs12913832 in HERC2 is part of an enhancer involved in the recruitment of transcription factors promoting OCA2 expression. The G allele of this variant reduces the binding of the transcription factors and decreases OCA2 expression35. Thus, the genetic changes produce the impairment of melanin synthesis and result in a lighter phenotype.
In contrast, two of the eight SNPs investigated, rs1426654-G and rs2240751-G, were found to be correlated with darker skin. It has been proposed that rs1426654 was driven independently after the divergence of Europeans and Asians, resulting in reduced levels of heterozygosity in Europe, but not East Asia, and high allele frequency differences between modern populations36,37. Although the rs1426654-G light skin allele is almost fixed in Europe and associated with a lighter skin phototype in Africans and other Latin American populations, e.g., Brazil9,38, a possible hypothesis is that the SLC24A5 promotes a wide gamut of moderately pigmented phenotypes in the Mexican population as a way could influence cutaneous VD synthesis.
So far, the reports have shown that the variant rs2240751 in the MFSD12 gene is common only in East Asians and Native Americans. Adhikari et al. reported that the MFSD12 region shows significant evidence of selection in East Asians (dated after their split from Europeans) and that the frequency of the Y182H variant correlates with the intensity of solar radiation9. Recently, other variants of MFSD12 have been shown to impact skin pigmentation in Africans39, these variants are not in linkage disequilibrium with the variant analyzed in this study, which could suggest that they could also have a relevant role in skin pigmentation in our population. This study highlights the crucial role of noncoding and coding variants in determining human skin color and underscores the importance of studying Latin American populations with high levels of genetic and phenotypic variation.
At present, information on the relationship between skin color polymorphisms and VD is scarce. VD is a hormone pleiotropic, synthesized 80% endogenously in the keratinocytes after UVB light40. The importance of cutaneous vitamin D synthesis sparked a process of human evolution due to the need for its synthesis in geographic regions with lower levels of UVB radiation. Furthermore, VD status also depends on the surface of the skin exposed, for example, darker-skinned individuals require more time of sun exposure compared to light-skinned populations. This is due to the amount of epidermal melanin that obstructs the UVR-B. Given the limited current understanding of the relationship between skin color polymorphisms and VD, our study provides valuable insights into this complex interplay. By elucidating the impact of genetic variants associated with skin pigmentation on VD levels, we contribute to a deeper understanding of the biological mechanisms underlying VD synthesis and its potential implications for human health.
In our study, a genetic risk score was constructed using MFSD12-rs2240751 and SLC24A5-rs1426654, suggesting that gene–gene interactions impact VD levels and VDD. Similarly, Batai et al. reported a GSR where the genetic variant rs2675345, close to SLC24A5, was strongly associated with skin pigmentation and VDD in African Americans12. Further, a recent study showed that a decreased VD availability with increasing degrees of skin pigmentations is associated with reduced microvascular endothelial function in healthy young adults and may predispose darkly pigmented individuals to an increased risk of endothelial dysfunction41. In addition, we created a weighted genetic risk score using all eight genetic variants (and divided it into quartiles) and observed similar trends with serum VD levels. However, the association did not persist with VDD. One possible explanation for this discrepancy could be the size of the sample. Larger sample sizes are typically needed to detect associations with binary outcomes such as VDD compared to continuous outcomes like serum VD levels. Further investigation with larger cohorts may help elucidate the relationship between the GRS and VDD.
Gene–gene interactions have for a long time been postulated to make an important contribution to the determination of human complex traits42. Skin pigmentation plays a crucial role in the response to UV exposure and the efficient synthesis of VD43,44,45. Hence, it seems that the influence of gene–gene interactions should be considered a remarkable factor contributing to the serum VD levels in the Mexican mestizo population. We observed interactions of the rs2240751 in MFSD12 with two SNVs, the rs12203592 in IRF4, and the rs12913832 in HERC2. In addition, a borderline interaction between rs2240751 in MFSD12 and rs1426654 in SLC24A5, highlighting the complexity of these phenotypes. Building upon these findings, a study in Australian population identified an interaction between the genetic variants rs12203592 and rs12913832 in –IRF4 and HERC2, respectively, affecting serum VD levels46. However, no interaction was observed between rs12203592 in IRF4 and rs12913832 in HERC2 in our cohort.
Darker skin provides excellent natural protection against UV-induced damage due to increased melanin production and protection from folate degradation, whereas lighter skin synthesizes VD more efficiently upon UV exposure47. We found that the variant associated with dark skin in MFSD12 on a genetic background of HERC2 related to light skin affects VD levels, a significant interaction that would withstand adjustment for multiple testing if applied. Specifically, individuals with HERC2 light skin alleles (AG + GG) and genotype AA of rs2240751 of MFSD12, compared to those with AA-HERC2, showed higher average levels of VD. In comparison, those with genotype AG + GG of rs2240751 of MFSD12 and genotype AG + GG of rs12913832 of HERC2 showed lower average levels of VD than those with genotype AA of rs12913832 of HERC2. These findings suggest a complex gene–gene interaction between MFSD12 and HERC2 in determining VD levels, which could have important implications for understanding the variability in VD levels in populations with different skin genotypes. Furthermore, it’s noteworthy that although information on the relationship between genetic variants associated with skin pigmentation and VD levels is currently limited, recent studies have revealed that VD availability varies with different degrees of skin pigmentation11,12,17,43, highlighting the importance of investigating such gene–gene interactions in the context of public health. Despite the limited exploration of gene–gene interaction involving genetic variants related to pigmentation, and their role in vitamin D levels in the scientific literature, our study suggests that this phenomenon could be participating in the high prevalence of vitamin D deficiency in Mexican-Mestizo population. Studying genetics and biology of skin pigmentation not only helps deepen our understanding of human evolution, but could also offer insight into possible causes and treatments for other diseases where skin pigmentation is involved, such as melanoma and albinism48. However, additional studies in the Mexican population are required to delve into the complex relationship between skin pigmentation genetics and VD metabolism to validate and expand this hypothesis. These additional investigations will provide a solid foundation for developing more effective management strategies.
The strengths of this study include the incorporation of genetic variants reported in Latin-American population, the inclusion of various potential confounders in the analyses, and the use of reliable and validated measurement methods for data collection. Limitations of the study include the sample size (n = 848 individuals) and reliance on self-report information for skin pigmentation. Unfortunately, there was a shortage of male participants, constraining the exploration of sex interactions. Previous studies have indicated sex interactions, suggesting that sex hormones may modify genetic effects on skin pigmentation12,49. The cross-sectional design of our study limited the ability to establish definitive causal relationships between the investigated variables. While it’s true that genotypes occurred prior to skin pigmentation phenotype and vitamin D levels, the lack of complete knowledge about the function of genetic variants can hinder the identification of causality. It’s important to acknowledge that the complexity of the interaction between multiple genetic variants can also influence the ability to identify clear causal relationships. In this regard, genomic studies of the past two decades have revealed that the genetic plethora of skin pigmentation gene variants is vast, and many combinations of multiple variant genes have contributed to the complex pattern of skin pigmentation phenotypes and genotypes observed today50. Therefore, while our study provides a robust platform for exploring associations between genetic variants and skin pigmentation phenotypes, further research is needed to fully understand the underlying genetic basis and complex interactions that determine these phenotypes. It is conceivable that more significant interactions, particularly when evaluating categorized or dichotomous variables, were not detected due to the limited sample size. Additionally, the absence of ancestry data for adjusting potential population stratification is acknowledged. While efforts were made to adjust for various confounders, it is important to recognize the possibility of residual confounding factors not accounted for in our analyses. However, it is crucial to emphasize that the data are derived from a state in the central region of the country. Addressing these limitations is essential for refining the understanding of genetic complexity related to skin pigmentation and VD synthesis, and future research should consider these factors for a more comprehensive analysis.
In conclusion, our findings reveal a significant association between genetic variants related to skin pigmentation and VD levels in Mexican population. Although individual variants did not directly correlate with VD levels or deficiency, our research uncovered gene–gene interactions that play a crucial role in modulating VD levels and susceptibility to VDD. These results underscore the complexity of genetic factors influencing VD levels and suggest that the interaction between genetic polymorphisms related to skin pigmentation may modulate the risk of VDD in Mexican-Mestizo population. Genetic information related to skin pigmentation could be crucial when assessing individual risk of VDD and designing prevention and treatment strategies. However, further research is needed to validate and expand these findings, and better understand the underlying mechanisms of these genetic interactions in the regulation of VD levels.
