Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of tolerance to self-antigens and interferon responses dysregulation. SLE manifestations are diverse; the condition can affect almost any organ in the body (Ghodke-Puranik and Niewold, 2015). Patients with Hispanic, African, and Asian ancestry develop SLE earlier than European populations. These patients also have more acute disease onset, more severe clinical manifestations, higher disease activity, chronic organ damage, and higher mortality (Carter et al., 2016). Hispanic SLE prevalence is ∼138/100000 per inhabitants per year, which is higher than in Asian and European populations (Atisha-Fregoso et al., 2011). Many differences in the disease presentation across the ethnic barrier have been explained throughout genetic predisposition. One of the most studied systems is the Major Histocompatibility Complex (MHC) class I and class II genes, known as Human Leukocyte Antigen (HLA) Class I and II. The HLA variability among populations is helpful to explain many characteristics of SLE (Tsokos et al., 2016), and it continues to give more information about the genetic predisposition and pathophysiological mechanism of the disease.

As mentioned before, HLA haplotypes confer susceptibility or protection in an ethnic-dependent manner (Vargas-Alarcón et al., 2001; Vasconcelos et al., 2009; Furukawa et al., 2014; Alarcón-Riquelme et al., 2016; Molineros et al., 2019). In Mexico, susceptibility varies as the ethnic admixture does, the admixture in Mexico is very heterogeneous across the Country, contributing to the disease variability (Moreno-Estrada et al., 2014; Barquera et al., 2020b). Therefore, the admixture diversity has contributed to the enrichment of susceptibility markers and an ample SLE phenotypes specter in Mexicans (Salgado-Galicia et al., 2020). For instance, the most common susceptibility allele, HLA-DRB1^∗03:01, previously identified in Mexico City, was not found in Tapachula Chiapas SLE patients. Otherwise, HLA-DR2 Chiapas patients showed a higher risk of developing SLE once infected with Zika or Chikungunya viruses common in that region but absent in Mexico City (Sepúlveda Delgado et al., 2018). Besides, population genetic studies revealed significantly different admixture estimates for Mexico City and Tapachula, Chiapas (Barquera et al., 2020e).

Equally important, conserved extended haplotypes (CEHs) help to defined susceptibility, and the alleles help MHC genetic diversity measurements in autoimmune conditions. CEHs are DNA blocks defined as combinations of HLA-B, -DR, complement, and other immune-related genes. CEHs are known as DNA stretches with fixed alleles, including those at loci not tested (Wescott et al., 1987). Thus, CEHs have a high genetic load, so determining HLA CEHs gives information about the aggregated risk confer by non-classical and non-HLA genes linked to HLA. The frequency and allele combination of CEHs varies between major ethnic groups. Hence, the determination of CEH and the ethnic admixture print allows knowing immunogenetic variants and blocks of anthropological origin and evolution but biomedical importance in Mexican mestizo patients.

Thus, this study aimed to describe SLE patients’ ethnic admixture proportions compared with healthy Mexican Mestizo individuals. We searched the distribution of HLA class I and class II blocks and CEH and their most likely ancestral origins using high-resolution HLA typing in a Mexican SLE group of admixed-ancestry.

The HLA sequencing has led both to identify a new susceptibility block HLA-A^∗29:02∼C^∗16:01∼B^∗44^∗03∼DRB1^∗ 07:01∼DQB1^∗02:02 and to determine the admixture print which distinguishes patients and healthy individuals in Mexico City. Therefore, alleles and haplotypes of susceptibility and protection found, both the previously described and the new one, will be analyzed, emphasizing discussing the influence of ethnic admixture and the genetic load of parental populations in the development of lupus.

The CEH associated for the first time with SLE development in Mexicans was the HLA-A^∗29:02∼C^∗16:01∼ B^∗44^∗03∼DRB1^∗07:01∼DQB1^∗02:02. This CEH has been cataloged in previous studies as European (Szilágyi et al., 2010). Only the isolated allele HLA-DRB1^∗07 has been previously associated with antiphospholipid syndrome in SLE patients from Mexico City (Granados et al., 1997). However, this CEH has been a risk factor in Mexican patients diagnosed with Achalasia (Furuzawa-Carballeda et al., 2018). This condition is a motility disorder of the esophagus with abnormalities in the neurons that controls peristaltic movements, whose underlying cause is unknown. Notably, previous studies conducted in other populations suggested that achalasia patients have increased frequency of HLA-DRB1^∗15 and -DQB1(eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1) alleles in an ethnicity-specific manner. This fact proposes an immunogenetic mechanism (Verne et al., 1999; Gockel et al., 2014; Becker et al., 2016). However, in this study, no SLE patient who carries this CEH showed some achalasia symptomatology. Probably, the immunosuppressive treatment might mask achalasia symptoms or prevents the development in predisposed individuals. A congruent reason could be that the mean age of achalasia onset in Mexicans (42.3 ± 15.8 years) is slightly superior to SLE (26.5 ± 12.2 years). The data needs further research because the shared susceptibility conferred by this CEH could mean a share immunopathological mechanism depending on ethnic background. The onset of either lupus or achalasia could rely on the triggers, which might differ for each condition.

Achalasia onset has been associated with varicella herpes zoster virus previous infection (Becker et al., 2016). In contrast, SLE development has been associated with other viruses’ infections as Epstein-Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) (Quaglia et al., 2021). Interestingly, the novel haplotype associated with SLE in Mestizo Mexicans from Mexico City is in 2.8% of these individuals, while only in 0.43% of healthy Mexicans, 3.42% in Spaniards (Enrich et al., 2019), and surprisingly in 3.84% of Achalasia Mexican patients (Furuzawa-Carballeda et al., 2018). Therefore, the increased frequency of this new haplotype in Mexican Mestizo patients may represent the convenience of preserving this haplotype as an immunological advantage against pathogens.

On the other hand, it is observable that the percentages of this haplotype in SLE and Achalasia Mexicans are similar to healthy Spaniards. So, we would expect scenarios with similar prevalence and disease phenotypes if it only depended on HLA susceptibility alleles. Unfortunately, there are no official statistics about the prevalence and incidence of SLE in Mexico. Still, reports of SLE in Hispanics show high SLE prevalence in Hispanics than Spaniards (138/100000 and 17.5 to 34.1/100000 per inhabitants per year, respectively) (Atisha-Fregoso et al., 2011; Izmirly et al., 2017; Rees et al., 2017). Furthermore, some severe manifestations such as kidney damage are also more evident in Hispanics (62%) than Caucasian patients (25%). In addition, activity disease score as Systemic Lupus Activity Measure revised (SLAM-R) has been found highest in Hispanic than Caucasian patients (Fernández et al., 2007). Thus, all the above shows that the severity and clinical manifestations differ in an ethnic-dependent manner even when susceptibility haplotypes like the one found in this study are shared between populations. Therefore, the importance of population genetic studies and admixture estimations on Countries with high variability as Mexico is. No less important, there is a conjunction of variables as the availability and access to medical services and treatments that modify the severity phenotype in different populations. This factor always is important to consider before concluding about ethnicity and admixture disparities among populations.

The ethnic background and admixture influence the development of SLE and autoimmunity in Mexicans. This assumption was introduced because the haplotype HLA-B8-DR3 is found in high frequencies in the Caucasian population and has a considerable prevalence of SLE and other autoimmune diseases (Awdeh et al., 1983; Alper et al., 1986; Szilágyi et al., 2010). In contrast, the Mexican Native American populations lack both the HLA-B8-DR3 haplotype and SLE cases. Therefore, the high frequency of HLA-B8-DR3 in SLE Mexican patients from Mexico City has been explained as the product of the introduced alleles and haplotypes during the Spaniard’s arrival to the Americas. Surprisingly, SLE is more prevalent and aggressive in Mexicans than Europeans. Since the origin of the susceptibility alleles is from Europeans, it would be expected that the severity of the disease and the phenotypes would be similar. However, many elements can intervene to generate a unique scenario in Mexico. For example, the specific interaction of Amerindian, European, and other populations genes influenced by the architecture and tridimensional arrangement of the genes in each mixed population. Not least, the pressure exerted by local triggers and the environment itself.

The complex scenario of autoimmunity in Mexico is framed in that the susceptibility varies as the ethnic admixture pattern does. It has been corroborated in SLE studies. For example, SLE Mestizo patients in Guadalajara (northwestern Mexico) have the haplotype HLA-DRB1^∗15-DQA1^∗01:02-DQB1^∗06:02 as a susceptibility factor (Cortes et al., 2004) while SLE Mestizo patients from Tapachula, Chiapas (southeast of Mexico) have the susceptibility alleles HLA-DRB1^∗15 and -DRB1^∗16 (Sepúlveda Delgado et al., 2018). But neither in Guadalajara nor in Tapachula, the HLA-DRB1^∗03:01 is a susceptibility factor. However, HLA-DRB1^∗03:01 is one of the main susceptibility alleles found in this study and other previously conducted in Mexico City (Granados et al., 1996; Vargas-Alarcón et al., 2001). Parallel to these susceptibility differences, independent studies of population genetics have demonstrated de admixture variability among Guadalajara, Tapachula, and Mexico City (current study). The Native American Mexican load in Guadalajara, Tapachula, and Mexico City is ∼44%, ∼72%, ∼63%, respectively, while the European is ∼48%, ∼26%, ∼30%, and the African is ∼8%, ∼2%, ∼6% (Barquera et al., 2020d; Bravo-Acevedo et al., 2020). Therefore, it looks like admixture proportions in each Mexican State or region could drive toward specific susceptibilities for the same disease. However, it is not only the variation of admixture across Mexico. The presence of different triggers in each region could shape a more comprehensive scenery.

Therefore, the influence of admixture variations in SLE susceptibility could be briefly explained as follows: having a more European HLA load increases the chances of carrying a risk haplotype of this origin. Likewise, there are risk alleles and haplotypes of African and Asian origin; however, because the percentage of these ancestries is low in Mexican Mestizos, they are less likely to carry them. HLA alleles have been conserved in the Mexican Mestizo, probably because they represent an immunological advantage against infections by common pathogens in Mexico. However, the cost of efficiency in pathogen clearance has predisposed to immune hyperresponsiveness, prolonging inflammatory pathways, and leading to autoimmunity. Also, the advance in medicine and better treatments have augmented the survival, life expectancy, and quality of life, which allows the preservation of susceptibility alleles. All the above might be part of the eventual increase in statistics of autoimmune diseases in Mexico, a recent phenomenon caused mainly due to better diagnosis, but influenced by the recently acquired HLAs that have contributed to the fitness of Mexican Mestizos against local pathogens, but with less tolerance to the presence of triggers. This means the carriers of susceptibility alleles or haplotypes are “selected” to manifest the disease based on the presence of the triggers. Therefore, this selection includes individuals with susceptibility alleles and, since those with higher European ancestry are those that most likely have susceptibility alleles; these are the individuals that enrich the autoimmune group.

In truth, there are many assumptions for which further investigation should be carried out. However, the above assumptions could explain why the SLE group differs in admixture proportions compared to control individuals. In studies like the current, it is necessary to ensure the comparability of the groups of patients and controls since useful and accurate results depend on that data quality. Recently published characterization of individuals from Mexico City has been an additional resource to validate the admixture estimations in our control group. In this study were studied 1217 individuals northern (N = 751), southern (N = 52), eastern (N = 79), western (N = 33), and central (N = 152) Mexico City and surroundings. Admixture estimates are very similar to the calculations performed by Maximum likelihood in our study, being Native American Mexican 63.85%, European 28.53%, and African 7.61% (Barquera et al., 2020e).

Further evidence is shown in the PCA plot; our Mexican admixed samples (SLE and Healthy individuals) are separated from the non-autochthonous populations, which was expected. But, notably, the “Mestizo” sample of SLE patients from Mexico City is not overlapped with Controls.

Systemic lupus erythematosus is closer to non-autochthonous populations, while Healthy individuals are closer to autochthonous populations, congruent with admixture estimations and genetic distances. However, SLE patients retain their identity with the States of Central Mexico, which is expected because SLE patients belong to Mexico City; but, the percentages of ancestry differ, having a greater European load than expected for individuals from Mexico City.

This fact is particularly striking because we are talking about Mestizo Mexican Individuals who share the locality of born and the demographic history of settlement (colonial period) but have notable differences in ancestry proportions. This ambivalence in the SLE group could be explained by the fact that the local Native American alleles that confer identity to the Central zone of Mexico are conserved (which is detected in the PCA). At the same time, the advantageous foreign alleles have also been conserved, slightly modifying the proportions of the ancestry of the patients (admixture estimations and genetic distances) and augmenting the possibilities of carrying susceptibility foreign HLA alleles.

The ancestry variation in individuals with SLE, as said before, could mean that some non-autochthonous HLA alleles have been conserved because these alleles represent an immunogenetic advantage, as demonstrated for HLA-DRB1^∗03. For instance, some naturally processed HLA-DR3-restricted Human herpesvirus 6B (HHV-6B) peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses (Becerra-Artiles et al., 2019). However, this convenient immunogenetic mechanism for clearing infections might be the detonator for immunological hyperreactivity, which marks the onset of the disease. Viruses infections associated with SLE have been described previously and are ethnically associated with SLE pathogenesis, specific HLA class II alleles, and the development of antinuclear antibodies, the hallmark of SLE have been associated in the same studies (Perl et al., 1995; Magistrelli et al., 1999; Quaglia et al., 2021).

Likewise, Nei’s distance data is congruent with the information given by both the susceptibility and protection haplotypes and the admixture analysis. It was found that the SLE group is closer to foreign parental populations (Southwestern European, Sub-Saharan African, and Eastern Asian) than the healthy individuals. In contrast, healthy individuals are nearer to Mexican Native American populations evaluated (Mixtecs, Zapotecans, Tarahumaras, Lacandon, Mixe, and Seri). As expected for intra-specie analysis for the same geographic area, the genetic distance variability is low, but the differences are consistent and significant. Corrected average pairwise differences gave the same information.

The matrix of genetic distances reflects the differences between the Mestizos of Mexico City (SLE and controls), Figure 2. As mentioned before about PCA, SLE and controls are Mestizos from the same geographical area, so it would be expected that there would be no variation in admixture proportions. But indeed, there is. The matrix shows consistent variation indicating SLE patients are genetically more similar to non-autochthonous populations. In comparison, healthy individuals are genetically more similar to Mexican Native American populations. However, some aspects about populations included are worth exploring to substantiate the validity of the comparison.

Regarding the notable genetic variation of the Mexican indigenous groups included, it was expected. The presented Fst matrix and values (Supplementary Figure 1), and the other calculations as coancestry and Slatkin’s Fst (Supplementary Figures 2, 3), reflect a bit of what has been described for the native populations that inhabited Mexico. It has been corroborated a striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups are differentiated as Europeans are from East Asians. Seris and Lacandons are good examples (Infante et al., 1999; Barquera et al., 2020c); these groups are exposed to high levels of genetic drift and isolation. However, the value of including them as Mexican Native American parental populations is that present-day Mexicans’ genetic composition recapitulates ancient Native American substructure, despite the potential homogenizing effect of postcolonial admixture. Fine-scale population structure going back centuries is not merely a property of isolated or rural indigenous communities. Cosmopolitan populations still reflect the underlying genetic ancestry of local native populations, arguing for a strong relationship between the indigenous and the Mexican mestizo population, albeit without the extreme drift exhibited in some current indigenous groups (Moreno-Estrada et al., 2014).

Another notable feature is the genetic distances between the selected non-indigenous populations. Mainly, the Fst indicates an unexpected but explainable closeness between Zimbabwe and the Spanish. The characteristics of the Zimbabwe Harare Shona sample and previous periods of European colonization may have had a specific influence on this population that we cannot trace but hypothesize. Non-local HLA alleles may have been conserved as an immunological advantage, which has already been mentioned for Mexican Mestizos, additional to the MHC Class III genes with immunological functions conserved due to the linkage disequilibrium with the possibly acquired HLA Class I and Class II variants. Therefore, it should be noted that although the European load is likely to be low in this group of sub-Saharan Africans, the variants that contribute to fitness can be conserved and detected in the genetic distance calculations.

Furthermore, estimates of admixture by HLA are robust. In other studies, in Mexico City individuals, the admixture estimates are similar to the current study. It should be noted that these studies used HLA parental populations data different from that used in this study. Estimates with other techniques such as STRs have also generated similar results (Juárez-Cedillo et al., 2008). Thus, if the selected parental populations agree with the settlement background in Mexico, they can bring us the correct information about admixture and the genetic distances.

Finally, the CEH described as a susceptibility factor for Europeans the HLA-A^∗01:01∼C^∗07:01∼B^∗08:01∼DRB1^∗02:01 ∼DQB1^∗02:01 has been found as a high-risk factor for developing SLE. This CEH has a powerful influence on SLE development and other autoimmune diseases in mestizo Mexican individuals from Mexico City (Granados et al., 1996) and other populations. At first glance, this haplotype’s relative risk appears to have a summative effect by the alleles that make up it; as more HLA alleles are added to the haplotype, the risk increases. However, the relative risk conferred by HLA-B^∗08:01, HLA-DRB1^∗03:01, and haplotypes containing them confirm that the risk is not summative but conferred by the genes in linkage disequilibrium with these variants. Besides, this linkage has been turned more complicated during the HLA research course. Early in the study of HLA was described a strong linkage disequilibrium not only among HLA genes of the haplotype HLA-B8-DR3 but between HLA and complement (C2, C4a, C4b, and Factor B) (Black et al., 1982; Wescott et al., 1987; Picceli et al., 2016). Currently, it is known that a considerable number of variants, mainly of MHC class three, are in linkage disequilibrium with the variants of B and DR indicated above, which increases the genetic risk load of the individual with lupus.

Models have been developed to confirm the susceptibility conferred by genes in the MHC III region (non-classical HLA and non-HLA genes) linked to HLA-B and -DRB1. The most important linked genes using HLA-DRB1^∗03:01 as covariant are: the proto-oncogene Notch homologue 4 (NOTCH4), the MHC class I polypeptide–related sequence A and B (MIC-A and MIC-B), the steroid 21-hydroxylase (CYP21A2), (Partanen et al., 1988; Morris et al., 2012) the three 70 kDa heat-shock proteins (HSPA1A, HSPA1B, HSPA1L), (Mišunová et al., 2017), natural cytotoxicity triggering receptor 3 (NCR3); nuclear factor kappa light chain gene enhancer in B cells inhibitor-like 1 (NFKBIL1), allograft inflammatory factor 1 (AIF1) (Dorak et al., 2006); and the three Tumor Necrosis Factor genes (Lymphotoxin-beta, Lymphotoxin-alpha, and TNF-α) (Zúñiga et al., 2001; Ramírez-Bello et al., 2018). Important variants of the genes mentioned above have been deeply studied in Caucasians, and linkage disequilibrium with HLA-B^∗08:01 and -DRB1^∗03:01 has been confirmed (Dorak et al., 2006). This type of study is a prospect to be carried out in the Mexican population to determine the integrity of the MHC blocks conserved in Mexican Mestizos and how the variants could have been fixed or discarded, giving the specific characteristics of SLE in Mexicans.

In conclusion, the genetic background and the Mexican admixture heterogeneity define part of the dynamic of SLE in Mestizo Mexican patients. Considering the regional distribution of genetic susceptibility and the ethnic barriers can be a useful biomedical tool. Increasingly, the born region and the ethnic admixture (the apparent ethnic phenotypes based on physical characteristics) are considered an element that helps the diagnosis of diseases. Such is the case of neuromyelitis optica and multiple sclerosis, which may be clinically similar but have well-established genetic susceptibility and ethnic differences. In Mexico, the susceptibility to neuromyelitis optica is given by HLA-DRB1^∗16:02, and it usually occurs in individuals with a high Mexican Native American ancestry (Gorodezky et al., 1986; Romero-Hidalgo et al., 2020) (and usually, the physical characteristics indicate it). But in multiple sclerosis, the susceptibility is mainly given by HLA-DRB1^∗15, and it occurs in individuals with higher Caucasian ancestry (Ordoñez et al., 2015). Another good example includes Multifocal Epithelial Hyperplasia, which depends on genetic susceptibility and is expressed in specific populations with high Mexican Native American components.

On the other hand, the technical aspect of this type of study is important. HLA sequencing study has helped to describe the ethnic admixture load in the patient and control populations. It deepens susceptibility and protection alleles and haplotypes due to high-fidelity performance. Finally, non-HLA variants in the MHC area contribute to the risk through linkage disequilibrium with HLA genes. Therefore, the CEHs help to explain better the susceptibility and protection in groups with known ethnic composition. However, the linkage of these variants with HLA requires a more in-depth analysis to understand how they add risk to CEH and the specific variants conserved in the Mexican population.

The datasets presented in this study can be found in the online repository: Allele frequency net database (AFND) with the accession Mexico Mexico City Mestizo population (n = 143) (SLE). African: Burkina Faso Mossi (n = 53), Cameroon Yaounde (n = 92), Ghana Ga-Adangbe (n = 141), Kenya (n = 144), Uganda Kampala pop 2 (n = 175), Kenya Nandi (n = 240), Zimbabwe Harare Shona (n = 230). European: England Blood Donors of Mixed Ethnicity (n = 519), France Lyon (n = 4813), Germany Essen (n = 174), Ireland Northern (n = 1000), Italy Lombardy (n = 674), Italy Sardinia pop 3 (n = 100), Netherlands UMCU (n = 64), Spain Catalunya, Navarra, Extremadura, Aragon, Cantabria (n = 4335). Mestizo Mexican populations from Northern Mexico: Mexico Baja California, Mexicali (n = 100), Mexico Chihuahua Chihuahua City (n = 119), Mexico Colima, Colima city (n = 61), Mexico Durango, Durango city (n = 153), Mexico Nuevo Leon, Monterrey city (n = 266), Mexico Sinaloa Rural (n = 183), Mexico Sonora Rural (n = 197). Mestizo Mexican populations from the Center of Mexico: Mexico Aguascalientes State (n = 95), Mexico Guanajuato Rural (n = 162), Mexico Guerrero state (n = 144), Mexico Jalisco, Guadalajara city (n = 1189), Mexico Mexico City Center (n = 152), Mexico Mexico City West (n = 33), Mexico Mexico City East (n = 79), Mexico Mexico City South (n = 52), Mexico Mexico City North (n = 751), Mexico Michoacan Rural (n = 348), Mexico Nayarit, Tepic (n = 97), Mexico Queretaro, Queretaro city (n = 45), Mexico San Luis Potosi Rural (n = 87), Mexico Mexico City Mestizo pop 2 (n = 234) (Controls). Mestizo Mexican populations from Southern Mexico: Mexico Chiapas Rural (n = 121), Mexico Oaxaca, Oaxaca city (n = 151), Mexico Quintana Roo Rural (n = 50), Mexico Tabasco Rural (n = 142), Native American Mexican populations: Mexico Nahuas (n = 72), Mexico Oaxaca Mixe (n = 55), Mexico Mixtec (n = 97), Mexico Chihuahua Tarahumara (n = 97), Mexico Oaxaca Mixe (n = 55), Mexico Oaxaca Mixtecs (n = 103), Mexico Oaxaca Zapotec (n = 90), Mexico Sonora Seri (n = 34), Mexico Chiapas Lacandon Mayans (n = 218). Non-Mexican Latin-American populations: Argentina Gran Chaco Eastern Toba (n = 125), Bolivia La Paz Aymaras (n = 88), Colombia Barranquilla (n = 188), Costa Rica African-Caribbean (n = 102), Costa Rica Amerindians (n = 125), Ecuador Andes Mixed Ancestry (n = 824), Nicaragua Managua (n = 339), Panama (n = 462). Asian: China Han (n = 314) http://www.allelefrequencies.net/ (Gonzalez-Galarza et al., 2020).

The studies involving human participants were reviewed and approved by The Ethics Committee from the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Reference No. 1738. The patients/participants provided their written informed consent to participate in this study.

SH-D, JG, GV-A, and JZ performed the conceptualization of the study. SH-D and JM-G performed the methodology. SH-D, JJ-O, LL, and GL investigated the study. JZ, JG, DR, VT-M, LL, and GL did the contribution with resources. SH-D, JM-G, and VA-A carried out the data curation. SH-D wrote the original draft and visualized the data. SH-D, JG, GV-A, and LL wrote, reviewed, and edited the draft of the manuscript. JZ, GV-A, and JG supervised the project. JG carried out the project administration. JG and JZ carried out the funding acquisition. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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