Genetic Association in the Pathophysiology of Degenerative Cervical Disc Disease: Defining Roles?

Abstract

Background

Degenerative cervical myelopathy (DCM), encompassing cervical spondylotic myelopathy and posterior longitudinal ligament ossification, is now being documented frequently and significantly burdening the health care systems. The pathogenesis of DCM remains somewhat obscure, and the focus is now on identifying the role of genetic risk factors. Identifying these risk factors is essential for formulating future studies for novel preventive and therapeutic measures.

Materials and Methods

In a cohort study, we evaluated the genetic association of two genes involved in the pathophysiology of DCM, that is, COL11A1 (single-nucleotide polymorphism [SNP] rs1337185) and ADAMTS5 (SNP rs162509).

Results

A total of 60 subjects (27 with DCM and 33 without DCM) were included. The primary and minor allelic frequencies were evaluated and compared between the cohorts. Significant association was found for SNP rs162509 of gene ADAMTS5 for DCM (odds ratio [OR] 2.5375, 95% confidence interval [CI] 0.655–9.89, p = 0.177), whereas no conclusive relation was found for SNP rs1337185 of the COL11A1 gene (OR 0.93, 95% CI 0.24–3.68, p = 0.91).

Conclusion

Preliminary data from our study identify a probable association of two candidate genes, which play a pivotal role in the matrix synthesis and degradation. The complex etiopathogenesis of DCM may be guided by alterations in these genes and mediated through the altered gene products. Further studies are needed to substantiate and validate this.

Keywords

degenerative cervical myelopathy - genetics - single-nucleotide polymorphism

Introduction

Degenerative cervical myelopathy (DCM) encompasses all degenerative cervical spine disorders, that is, degenerative disc disease (DDD), cervical spondylotic myelopathy, and ossification of the posterior longitudinal ligament.[1] The prevalence of nonspecific neck pain, radiculopathy, and myelopathy in the Indian population is reported to be around 21, 12, and 0.4% in the adult population, and the prevalence is reported to be higher among females.[2]

The fundamental reason for degeneration in the discs is the weakening of tissues resulting from aging, nutritional compromise, heredity, and loading history. An essential triggering factor is a structural disruption in response to an injury or fatigue failure.[3] Severe disease has many clinical implications for the young and socioeconomic importance, which can be estimated in terms of lost productivity.[3]

In the past two decades, studies have indicated that genetic predisposition, along with environmental/physical factors, play a chief role in the pathophysiology of DDD. Genes that encode for the major structural components of intervertebral discs (IVDs), extracellular matrix (ECM) turnover, and inflammatory mediators such as interleukin or their receptors have all been implicated in DDD.[1] [2] [3]

Individual genes involved with DDD include those for collagen type XI, collagen type IX, cartilage intermediate layer protein, aggrecan, matrix metalloproteinases (MMP3), and vitamin D receptor. The products of these genes possibly alter the mechanical strength of tissues, and thus, their systemic effects reflect why DDD is more frequent in those with osteoarthritis.[1] [2] [3]

As per the literature, various extensive center studies have shown gene involvement in disc structural changes. A study by Videman et al[4] found that genetic polymorphisms are responsible for interindividual differences in disc matrix synthesis and disc degeneration. Twelve of the 99 variants they studied showed corroboration of association with disc signal intensity in the lumbar disc regions, maximally seen with the allelic variants of AGC1, COL9A1, and COL11A2.

Rathod et al,[5] in their study, concluded that COL9A2 homozygosity in Indian candidates can be considered a genetic marker of disc disease. However, this does not correlate with the disease severity. Rajasekaran et al[6] reported specific single-nucleotide polymorphism (SNP) associations of 5 out of 35 candidate genes studied to have a significant association in young adults with severe degeneration in lumbar discs. These five genes identified were COL11A1, ADAMTS5, CALM1, IL1F5, and COX2. These genes were reported to have specific functions in the ECM metabolism, intracellular signaling, and inflammatory cascade. This gives enough evidence to conclude that DDD is a complex disease with an intricate interaction of multiple genetic polymorphisms.

Literature suggests that cytokines, namely MMPs and “a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS),” retard ECM formation and promote the synthesis of degradative/destructive enzymes that break down the matrix of the IVDs. Increased MMPs and ADAMTS enzyme activity, especially that of MMP7, MMP13, ADAMTS4, and ADAMTS5, is a characteristic of the degenerative process in IVDs.[7]

Chen et al[8] in 2013 analyzed the gene expression profile of various genes at different stages of disc degeneration using bioinformatics and found that Rho and MAP family genes, RHOBTB2 and MAP2K6, respectively, play a crucial role in the progression of degeneration of grades III and IV discs.[8]

The prime advantage of any genetic study is that the effect between a disease and a genetic marker can only be in one direction. Since only a few studies have been conducted specifically on cervical disc degeneration and its genetic association, this study will provide us with the platform for future studies regarding the genetic workup of cervical disc degeneration.

Different researchers worldwide have studied some genes in lumbar disc degeneration.[3] [4] [5] [6] [7] [8] [9] Recognizing disc degeneration at a later or irreversible stage is of limited use and often alleviates symptoms. Picking up the degenerative changes early, planning treatment, and adopting preventive measures, particularly in the young, is the prime intent behind the study. Therefore, in our present study, we attempted to evaluate the role of specific genes (rs1337185 of COL11A1 and rs162509 of ADAMTS5) involved in the pathogenesis of cervical disc degeneration. Our goal was to find whether the same genes have some involvement in cervical disc degeneration and to what extent by studying gene profiling. We attempted to evaluate whether these can be recognized early from where a therapeutic or preventive intervention is possible.

Materials and Methods

This study was conducted in the Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, after registering with Clinical Trials Registry-India (CTRI/2021/02/031078) and institutional ethical clearance. We recruited 60 subjects and segregated them into two groups: a case cohort of 27 subjects and a control cohort of 33 subjects. Patients older than 18 years with chronic neck pain and signs/symptoms of degenerative cervical disease (confirmed with magnetic resonance imaging) were included as cases, whereas controls comprised a similar age group and presented with acute traumatic cervical spine injury with no clinical or radiological evidence of DCM.

After informed consent, a 3-mL blood sample in an EDTA vial was collected and stored at −80°C for genetic study.

Quantification of Disc Degeneration

Grading of disc degeneration in the lumbar disc has been known since the start of the 21st century. Various researchers have attempted to grade the cervical discs in the past two decades. In our study, we adopted a grading system developed by Suzuki et al.[9]

Isolation of DNA

The DNA extraction was done with a commercially available DNA extraction kit (Gsure, GCC Biotech G4625) as per the manufacturer's protocol. The frozen human blood sample quality and quantity of DNA were checked by agarose gel electrophoresis and spectrophotometry.

PCR Amplification and Sequencing

For polymerase chain reaction (PCR) amplification of the DNA, two oligonucleotide primers flanking the target SNP were used. Genomic DNA was amplified in a final reaction volume of 25 µL containing 10 mM Tris chloride pH 8.3, 50 mM KCl, 1.5 mM MgCl₂, 200 µM each of the four dNTPs, 1 µM each of the primers, and 2 U Taq DNA polymerase.

The PCR machine used was Applied Biosystems Veriti 96 Well Thermal Cycler.

Genotyping

After PCR amplification, quality checks (QC) for the samples were performed by gel electrophoresis (2% agarose gel). QC passed samples proceeded for purification using QIAGEN QIAquick PCR Purification Kit (cat. no. 28104). Purified samples were taken for sequencing. The sequencing PCR reaction was set up in Applied Biosystems MiniAmp Plus Thermal Cycler using Big Dye Terminator V3.1 kit.

After PCR amplification, the primer-extended products were purified and subjected to capillary electrophoresis and analysis in a Genetic Analyzer.

Interpretation of Results

Once the sequencing was done, the data were provided in the Name.AB1 format (where name denotes the patient's CR no.). These data were then analyzed using software. The analysis software used was MEGA 11.0.10 for Windows. The brief steps of analysis were:

1. First, sequence reads were checked for quality base calls; only high-quality ones were kept for reading.

2. Read alignment or mapping to the reference genome was performed.

3. Variant calling to determine the nucleotide difference versus the reference genome.

The following flowchart demonstrates the whole analysis process ([Fig. 1]):

Fig. 1 Flowchart demonstrates the whole analysis process.

Statistical analysis was conducted using IBM SPSS Statistics for Windows, version 22.0. Armonk, New York, United States: IBM Corp. All data were entered into Microsoft Excel to make a master sheet, which was imported into SPSS software for final analysis. All the data were tested for normal distribution using the Shapiro–Wilk's normality test. After assessing the normality of the data, nonnormally distributed data were analyzed using nonparametric tests, that is, chi-square test with Yates's correction for SNP association using odds ratio (OR) and proportionate of the outcome. To examine the association between radiological severity (total degenerative disc score [TDDS] < 10 vs. ≥ 10) and genetic polymorphisms in COL11A1 and ADAMTS5 genes, we applied Fisher's exact test, due to the presence of small and zero cell counts. Results were reported as the standard error of the mean or as a percentage for demographic data, and p-values were reported in the table with confidence interval (CI), with p-value < 0.05 (95% CI) considered to be statistically significant.

Observations and Analysis

The mean age of the patients was 45.49 ± 15.76 years (range 18–80). The mean age of female subjects was 47.07 ± 12.01 years (range 20–65), and that of male subjects was 45.22 ± 16.23 years (range 18–80); 8% of the subjects had hypertension, 4% had diabetes, and 2% had other conditions (chronic lung disease and chronic kidney disease). As per the number of cervical IVD level involvement, around 12% of patients had single-level involvement, 57% had two-level involvement, 22% had three-level involvement, and the remaining 9% had four- or more-level involvement.

Radiological Findings (Based on the Number of Cervical Intervertebral Disc Levels Involved)

In the case group (A), 10 out of 27 patients (37%) had two-level involvement, 11 (40.7%) had three-level involvement, and 6 (22.3%) had four- or more-level involvement. In the control group (B), on the other hand, out of 33 subjects, one, two, three, and four or more levels of cervical IVDs were involved in 7 (21.3%), 24 (72.7%), 2 (6%), and 0 (0%) participants, respectively. When compared between the groups, both groups were comparable. There was a statistically significant difference observed between the groups ([Table 1]). The comparison of the grading of disc degeneration at individual levels between the groups is shown in [Table 2].

Table 1 Number of cervical disc levels involved

Number of cervical intervertebral disc levels involved	Case, n (%)	Control, n (%)	p-Value
Single-level involvement	0 (0)	7 (21.3)	0.004692
Two-level involvement	10 (37)	24 (72.7)	0.002039
Three-level involvement	11 (40.7)	2 (6)	0.0001429
More than three-level involvement	6 (22.3)	0 (0)	0.002008

Table 2 Comparison of individual degenerative disc scores at various levels

Degenerative score at individual disc level (0–3)	Case (mean ± SD)	Control (mean ± SD)	p-Value
C2–C3	1.34 ± 0.70	0.256 ± 0.50	0.004
C3–C4	2.09 ± 0.69	0.69 ± 0.70	0.317
C4–C5	2.75 ± 0.44	0.974 ± 0.70	0.190
C5–C6	2.88 ± 0.34	1.28 ± 0.92	0.001
C6–C7	2.37 ± 0.55	0.95 ± 0.89	0.099
C7–T1	1.47 ± 0.58	0.36 ± 0.67	0.932

Abbreviation: SD, standard deviation.

Comparison of the Grading of Degeneration between the Groups

After scoring the disc at the individual level, a total score was calculated by adding all individual scores. Thus, the maximum score possible is 18 (6 levels from C2–T1), and the minimum is 0. The comparison of TDDS among cases and controls is depicted in [Table 3]:

Table 3 Comparison of total degenerative disc score

	Case (mean ± SD)	Control (mean ± SD)	p-Value
Total degenerative disc score (0–18)	12.91 ± 1.84	4.51 ± 2.09	0.541

Abbreviation: SD, standard deviation.

Thus, it is clear that we found no statistically significant difference in TDDSs between cases and controls. Still, the individual disc degenerative score at C5–C6 and C2–C3 significantly differs among cases and controls. Moreover, the C5–C6 is the most common level with severe degenerative changes (mean 2.88).

Genetic Association Analysis

In our present study, we studied the SNPs of two genes. The details of the SNP, its position, and its location are summarized in [Table 4].

Table 4 The pertinent SNPs in the candidate genes with their location in the respective chromosomes

Chromosome	SNP	Position	Gene
1	rs1337185	103079209	COL11A1
2	rs162509	26953456	ADAMTS5

Abbreviation: SNP, single-nucleotide polymorphism.

Profile of COL11A1

In group A, 4 (6.7%) subjects had a minor allele genotype, that is, GC, whereas 21 (35%) subjects expressed the GG major allelic genotype on evaluation. Similarly, in group B, 6 (10%) subjects had a minor allele genotype (GC), whereas 29 (48.3%) subjects expressed GG major allelic genotype ([Table 5]).

Table 5 Frequency of distribution of allelic variants between two groups for the COL11A1 gene

Allelic variant	Case, n (%)	Control, n (%)
Minor allele genotype (GC)	4 (6.7)	6 (10)
Major allele genotype (GG)	21 (35)	29 (48.3)

Profile of ADAMTS5

In group A, 7 (11.7%) subjects had a minor allele genotype, that is, GC, whereas 20 (33.3%) subjects expressed the GG major allelic genotype on evaluation. Similarly, in group B, 4 (6.7%) subjects had a minor allele genotype (GC), whereas 29 (48.3%) subjects expressed the GG major allelic genotype ([Table 6]).

Table 6 Frequency of distribution of allelic variants between the two groups for the ADAMTS5 gene

Allelic variant	Case, n (%)	Control, n (%)
Minor allele genotype (GC)	7 (11.7)	4 (6.7)
Major allele genotype (CC)	20 (33.3)	29 (48.3)

Association of Radiological Parameters with Genetic Polymorphism

To study the association of radiological parameters with genetic polymorphism, we further divided our groups into two subdivisions with TDDS < 10 and ≥ 10 and evaluated the association of these with the genetic polymorphism of two genes, that is, COL11A1 and ADAMTS5. There were only 3 cases with TDDS < 10, and 24 cases with scores > 10, while, on the other hand, all the controls had TDDS scores < 10. The results are summarized in [Table 7], along with their significance.

Table 7 Association of radiological degenerative disc scores with two candidate genes, that is, COL11A1 and ADAMTS5

Total degenerative disc score	Association with COL11A1 gene, p-Value	Association with ADAMTS5 gene, p-Value
≥ 10	< 0.001	< 0.001

Notes: The bold values denote a highly statistically significant difference between the two groups.

Correlation of Clinical Parameters with Genetic Polymorphism

We attempted to find a correlation between various clinical blood parameters studied with the specific genetic polymorphism in the two genes studied among cases and controls. The results were statistically insignificant. The summary of each parameter, its association with the respective gene, and its significance are tabulated in [Table 8].

Table 8 Correlation of blood parameters with two candidate genes

Clinical blood parameters vs. gene polymorphism	Correlation with COL11A1 gene, p-Value	Correlation with ADAMTS5 gene, p-Value
Serum sodium (mmol/dL)	0.358	0.353
Serum potassium (mmol/dL)	0.953	0.458
Serum chloride(mmol/dL)	0.929	0.093
Serum calcium (mg/dL)	0.222	0.737
Serum urea (mg/dL)	0.681	0.916
Serum creatinine (mg/dL)	0.062	0.116
Hemoglobin (gm/dl)	0.498	0.901
Total leucocyte count (per mm3)	0.270	0.354
Platelet count (per mm3)	0.150	0.624

Summary of Results and Inferences

After a thorough statistical analysis, the following inferences are drawn:

1. Association of TDDS with genetic polymorphisms of the two genes (COL11A1 and ADAMTS5) showed statistical significance (p = 0.00) within the two groups, indicating that a TDDS more than ≥ 10 is highly suggestive of presence of polymorphism in the specific variants of these two genes, that is, SNP rs1337185 of COL11A1 and SNP rs162509 of ADAMTS5 ([Table 7]). However, the clinical relevance of this correlation needs to be addressed by further focused studies.

2. The risk of DDD in people with the GC genotype does not show a statistically significant difference from those of the GG genotype in the studied population (p = 0.9068) for the allelic variants of gene COL11A1 (rs1337185).

3. Similarly, the risk of DDD in people with the GC genotype does not show a statistically significant difference from those of the CC genotype in the studied population (p = 0.1777) for the allelic variants of the gene ADAMTS5 (rs162509). The summary of these findings is tabulated in [Table 9].

Table 9 Summary of association analysis of SNPs between cases and controls

S no.	Chromosome	Gene	SNP	p-Value	Odds ratio	95% CI
1	1	COL11A1	rs1337185	0.9068	0.9206	0.2306–3.6749
2	21	ADAMTS5	rs162509	0.1777	2.5375	0.6551–9.8290

Abbreviation: CI, confidence interval; SNP, single-nucleotide polymorphism.

Discussion

Disc degeneration involves multiple complex pathological mechanisms, and patient, environmental, occupational, and genetic factors contribute to its risk; degeneration in the cervical disc is no exception. It is a process that has been reported to start as early as the second decade of life.[10] Around 20% of people in their teenage years have mild signs of degenerative changes, and these changes increase as age progresses.[10]

The landmark study, which documented the critical role of inheritance in disc degeneration, performed in twin subjects, opened the path and interest of various researchers toward the genetic linkage and association of disc degeneration.[11] But, the question is, why do we need this knowledge and understanding of the genetic basis? The answer is straightforward and crucial. As the incidence and prevalence of DDD are on the rise, with the world heading toward a population with the majority made up of the elderly, DDD will considerably add to the disability-adjusted life years. Also, we know that the IVD degenerates much earlier than other musculoskeletal tissues; understanding the genetic risk factors well will help formulate and implement preventive strategies.

Most of the studies have been performed in the Western population, and there is limited data about the disease dynamics in the Asian population, with most studies done exclusively on the lumbar disc. This present study focused on cervical disc degeneration and evaluated the genetic association of polymorphism in two genes, that is, rs1337185 of COL11A1 and rs162509 of ADAMTS5.

Collagen XI (COL11A1)

This type XI collagen is a significant constituent of nucleus pulposus and annulus fibrosus. It is a cartilage-specific matrix protein crucial for cartilage–collagen fibril interaction, formation, and organization. It is made up of three chains, namely chain 1 (XI), chain 2 (XI), and chain 3 (II), which are encoded by three different genes, that is, COL11A1, COL11A2, and COL11A3, respectively. These three chains now fold into trihelical heteromers to form procollagen, which exudes into the matrix. In the ECM, it then forms fibrils along with other collagens (cartilage-specific type II and IX collagens) and modulates the overall diameter of fibrils. These interactions of proteins have been picked up as probable contributors to DDD.[6]

Mio et al (2007)[12] found a strong correlation between susceptible SNP (rs1676486) of the COL11A1 gene and lumbar disc herniation (LDH) in Japanese patients. They reported that the customarily expressed COL11A1 mRNA in healthy IVDs is markedly decreased in LDH patients, and this fall in mRNA expression is proportional to the severity of disc degeneration. These point toward the sensitivity of genetic polymorphism producing unstable gene transcripts.[12] Genetic association studies by Videman et al (2009)[4] identified a positive association in two collagen-encoding genes. It concluded that specific allelic variants of COL11A1 were associated with severe disc bulges, mainly in the upper lumbar spine, and allelic variations in COL1A2 with disc bulges in the lower lumbar spine.[4]

Solovieva et al[13] identified a correlation between a G nucleotide to A nucleotide substitution—SNP in the intron 9 of the gene COL11A2 and lumbar disc bulge or herniation. They further concluded that the patients who carry this polymorphism have a 2.1-fold increased risk of developing disc bulges in the lumbar spine compared with those who do not. This study also reported a 1.6-fold increase in the risk of signs specific to DDD, but the results were not statistically significant.[13] Nonetheless, despite statistically insignificant results, this study made us aware that G to A SNP of the COL11A2 gene could be linked with disc degenerative disease.

Raine et al[14] worked on allelic expression imbalance (AEI) and evaluated the AEI of the COL11A1 gene by studying three different probable polymorphic loci: rs2615977, rs1676486, and rs9659030. They found that a reduction in the genetic expression of the COL11A1 gene, which was due to the appearance of a rare “T” allele at the genetic locus rs1676486 (p.Ser1419Thr), was found to be in linkage disequilibrium with rs9659030, concluding that AEI at rs1676486 polymorphic locus is a potential genetic risk factor for LDH.[14]

In our study, the genetic association of SNP (rs1337185) of the COL11A1 gene with cervical disc degeneration in Indian patients reported an OR of 0.9206 (95% CI 0.2306–3.6749, p = 0.906).

A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5

ADAMTS5 is one of the critical members of ADAMTS protein family. This ADAMTS5 enzyme functions like an aggrecanase to break down the macromolecule aggrecan, and therefore, it is expected to play a crucial role in ECM degradation and metabolism. Notably, ADAMTS4 and ADAMTS5 are usually present at the degeneration site. As per a study done in the early 21st century, the role of ADAMTS5 on mouse cartilage suggested that ADAMTS5 was mainly responsible for the entire aggrecan turnover in the murine system.[15] This highlighted that exaggerated destruction of the matrix of the IVDs could subsequently result in early and advanced disc degeneration.

Following this, genetic association/linkage studies were performed to evaluate the risk associated with polymorphism in the genes of the ADAMTS family and IVD degeneration. Liu et al[16] investigated a genetic polymorphism in the gene ADAMTS4 (SNP rs4233367). The authors concluded that the 1877C/T substitution conferred a shallow risk of degeneration in a lumbar disc with an OR of 0.69. Similarly, cases with the TT genotype compared with the CC genotype were at one-fifth risk of developing disc degeneration in the lumbar region. This provided us with enough evidence that ADAMTS4 and ADAMTS5 play a crucial part in the degradation of matrix proteins.[16]

Rajasekaran et al,[6] in a study, enrolled 308 Indian subjects with mild degeneration in lumbar discs with a total score less than 10 (in the Pfirrmann grading system for lumbar disc degeneration) and 387 other Indian participants with severe disc degeneration with a total score of more than 10. They studied genetic analysis for the polymorphism of 58 SNPs of 35 probable candidate genes. The study identified a correlation between severe degeneration in the lumbar disc and six SNPs in five candidate genes, namely, rs1337185 of COL11A1, rs5275 and rs5277 of COX2, rs7575934 of IL1F5, rs3213718 of CALM1, and rs162509 of ADAMTS5. Young adults with the risk allele SNP rs162509 in ADAMTS5 were found to be associated with a 1.28-fold higher risk of developing severe disc degeneration compared with their peer groups.[6]

In a study in the Chinese Han population by Jiang et al (2017),[17] the genetic susceptibility for two candidate genes was analyzed, that is, COL11A1 (rs1337185) and ADAMTS5 (rs162509). Furthermore, subjects were subdivided into four mutually exclusive groups with shared characteristics such as herniated/bulging disc, spinal stenosis or spondylolisthesis, and degenerative scoliosis. The author interpreted that the allelic variant of the COL11A1 gene (SNP rs13371895) was a potential risk factor for developing various lumbar pathologies such as stenosis, spondylolisthesis, and disc herniation. The G allele of the ADAMTS5 gene (SNP rs16250) conferred an increased risk for the development of disc herniation.[17]

Our study found an association of the SNP of the ADAMTS5 gene (OR 2.5375, 95% CI 0.655–9.89, p = 0.177) with disc degeneration.

Strengths and Limitations

This is India's first genetic association study in disc degeneration, evaluating specifically cervical disc. All previous studies were performed in lumbar discs. This study assessed the data from the Indian population and the distribution of allelic variants with their frequency; this is the first step toward determining the genetic basis of cervical disc degeneration and, therefore, can guide future studies. Limitations being a single-center study, results were not statistically significant, probably due to low sample size availability. Our study suggested a positive association of polymorphism leading to or exaggerating the process of degeneration. Still, it does not specify how, when, and where this pathological process will happen.

Conclusion

Degeneration in the disc is a continuous process and involves the interplay of multiple factors, and the role of genetic factors is noteworthy. We found an association of both the genes, that is, SNPs of rs1337185 of COL11A1 gene (OR 0.9206, 95%CI 0.2306–3.6749, p = 0.906) and rs162509 of ADAMTS5 (OR 2.5375, 95%CI 0.655–9.89, p = 0.177) with disc degeneration, and there is no statistically significant association of these genes with the disease process. Despite an association, no genetic trend can be concluded in our study, probably due to the low sample size. However, this study shall guide other research scholars and stress the need for future large-scale multicentric trials focusing on genetic polymorphism and their respective genetic expressions.

Conflict of Interest

None declared.

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Publication History

Article published online:
23 June 2025