Comment; Complex; …”the gene of interest that influences both drug concentrations and toxin removal from tissues in the body is the ABCB1 gene that encodes for a set of P-glycoprotein (P-gp) efflux pumps. P-gp pumps are known to influence the absorption and excretion of a large group of substrates in the body including medications and bacterial toxins as well as interfere with optimal medication concentrations in some patients.” Sounds like a good target to understand!
JoannaLyonaHyunukSeungbShow morehttps://doi.org/10.1016/j.mgene.2019.100589Get rights and contentUnder a Creative Commons licenseopen access
Abstract
Post Treatment Lyme Disease Syndrome (PTLDS) poses a difficult to understand health issue. This multi-centered, randomized control trial studied the possible correlation between ABCB1 (MDR1) gene variants and the incidence of PTLDS in affected patients. Genomic DNA was isolated and analyzed for four ABCB1 gene SNPs (rs1128503, rs1045642, rs2235067, and rs4148740). Significant findings include the association of rs1128503 TC variant with PTLDS status. Additionally, the rs1128503+ rs1045642+ rs2235067 SNP combination increased rs1128503 genotype TC significance to 3.83 times the rs1128503 genotype CC. The TT variant of rs4148740 in conjunction with rs1128503 reduced the odds ratio and appeared to convey a PTLDS protective status to the rs1128503 TC variant.
Background
Lyme disease, caused by the organism Borrelia burgdorferi, continues to pose a significant public health risk, particularly in the Eastern United States. The Centers for Disease Control (CDC) document a yearly increase in reported cases, with 16 states listed as high incidence locations in 2017.(Why Is CDC Concerned About Lyme Disease? | Lyme Disease | CDC [Internet], 2017; Lyme Disease Maps: Most Recent Year | Lyme Disease | CDC [Internet], 2018; Lyme Disease Charts and Figures: Most Recent Year | Lyme Disease | CDC [Internet], 2018; Lyme Disease Data Tables: Most Recent Year | Lyme Disease | CDC [Internet], 2018) Of particular interest and concern with this disease state is the observation of lasting or chronic health related issues in a subset of patients who have been treated for a diagnosed Lyme disease infection. Although many patients return to baseline health after a standard antibiotic treatment regimen, there has been the perplexing phenomenon that occurs in some patients where this pre-infection baseline is not regained. Although no sign of active infection is apparent, the patients continue to self-report a variety of symptoms that include musculoskeletal or neurologic complications.(Rebman et al., 2017; Melanie et al., 2016; Marques, 2008; Touradji et al., 2019; Kathy et al., 2018). These lingering symptoms in some patients have been termed Post-Treatment Lyme Disease Syndrome (PTLDS) and have varying rates of incidence depending on the reference source. For example, the CDC identifies the syndrome, yet only states that ‘some’ patients experience these symptoms, while other researchers cite an incidence rate ranging from 5% to 17% of post-treatment Lyme patients. (Aucott et al., 2012; Ścieszka et al., 2015; Chronic Lyme Disease [Internet], 2019)
Although opinions differ about the actual cause of PTLDS, several gene analysis studies have begun to indicate a possible correlation between genetics and the prevalence of chronic symptoms in Lyme patients. For example, Strle et al. demonstrated a possible correlation between the TLR1-1805GG polymorphism and lingering arthritic symptoms in treated Lyme patients.(Strle et al., 2012) The TLR1 gene is involved in the body’s immune response to pathogens, with the rs5743618 GG polymorphism occurring in 50% of Caucasians and appearing to have a possible significance in the inflammatory response generated in patient Lyme infection responses.(Johnson et al., 2007) In addition, Schroder et al. demonstrated a possible significance of the TLR-2 polymorphism rs5743708 in producing a reduced occurrence of PTLDS in the treated patient population.(Schroder et al., 2006)
In addition, there has been some speculation that PTLDS might be partially caused by the inability of the medication regimen to completely eradicate the Borrelia burgdorferi organism due to a variety of theorized mechanisms.(Caskey et al., 2019) This incomplete removal of the organism or possibly toxin components of the bacterium may either perpetuate the initial infection or allow the body to create an autoimmune response related to the lengthened exposure to the Borrelia burgdorferi organism. One gene of interest that influences both drug concentrations and toxin removal from tissues in the body is the ABCB1 gene that encodes for a set of P-glycoprotein (P-gp) efflux pumps. P-gp pumps are known to influence the absorption and excretion of a large group of substrates in the body including medications and bacterial toxins as well as interfere with optimal medication concentrations in some patients.(Hodges et al., 2011) In addition, P-gp coded by the ABCB1 gene has been recently implicated in several autoimmune type disorders. García-Carrasco et al. correlated an over expression of P-gp in patients exhibiting both systemic lupus and rheumatoid arthritis chronic disease states.(García-Carrasco et al., 2015) Similarly, Mijac et al. correlated the TT genotype of the rs1128503 ABCB1 polymorphism with a greater frequency of ulcerative colitis in patients.(Mijac et al., 2018) Finally, Miyake and Nocera have shown an association between high P-gp expression and greater tissue inflammation in chronic rhinosinusitis patients.(Miyake et al., 2018) It is currently uncertain why this overexpression and genetic variation in P-gp is related with autoimmune conditions and whether the varying regulation of either toxins or medications is part of this disease mechanism. Since the ABCB1 gene seems to affect both drug and toxin concentrations in patients and autoimmune disease states and since there are currently no studies investigating the possible correlation between P-gp polymorphisms and the chronic symptoms exhibited by PTLDS patients, the ABCB1 gene was selected for analysis in this study.
A number of ABCB1 SNPs have been studied in relation to disease states and medication response in patients. This study chose two SNPs that were shown to affect medication and toxin transport in genetically variant patients (rs2235067 and rs4148740). In addition, two synonymous or ‘silent’ SNPs with no known change in amino acid encoding were selected (rs1128503 and rs1045642) since these had been correlated with a possible change in P-gp expression in several studies.(Fung and Gottesman, 2009) In this way, the study could examine both the premise of medication concentration fluctuation as well as P-gp expression as it related to the PTLDS disease state.
To further investigate the possible association between the ABCB1 gene including rs1128503, rs1045642, rs2235067, and rs4148740 and PTLDS symptoms, this study sought to determine whether there was an increased frequency of allele variants in patients exhibiting symptoms of the PTLDS disease state.
To further investigate the possible association between the ABCB1 gene including rs1128503, rs1045642, rs2235067, and rs4148740 and PTLDS symptoms, this study sought to determine whether there was an increased frequency of allele variants in patients exhibiting symptoms of the PTLDS disease state.
Discussion
This study found a significant association with PTLDS and patients with the rs1128503 variant allele TC on the ABCB1 gene. There were no individual associations found with variants on rs1045642, rs2235067, or rs4148740 alleles and PTLDS symptoms in patients. Only the TC variant of the rs1128503 allele was correlated with an increased incident of the disease state. The TT and the combination of TT and TC alleles did not yield a more significant disease incidence correlation with the rs1128503 allele. When the study SNPs were analyzed in combination for a potential amplified clinical effect, it was determined that rs1128503 + rs2235067 TC variant demonstrated an increased odds ratio, but the combination of rs1128503+ rs1045642+ rs2235067 TC variant showed the greatest correlation with the PTLDS disease state.
In addition, it was observed that the only time the PTLDS disease state had an increased correlation with the TT variant of an allele was with rs4148740. When the TC and TT variants of rs4148740 were combined in conjunction with rs1128503, the odds ratio for this disease state increased (OR = 3.13, 95% CI = (1.28, 7.65)) when compared to the TC variants of this allele combination (OR = 2.85, 95% CI = (1.17, 6.94)).
When examining the ABCB1 gene, it has been noted that both rs1128503 and rs1045642 are both considered synonymous or ‘silent’ SNPs with no known change in amino acid encoding, yet despite this synonymous status, there has been speculation that both of these variants might affect co-translational folding of other nearby amino acids, especially because there might be unknown linkages with non-synonymous SNPs that might alter the transcription and/or function.(Hodges et al., 2011; Fung and Gottesman, 2009) This hypothesis of a clinical effect of a synonymous ABCB1 SNP appears to be supported by the correlation of the rs1128503 TC variant and PTLDS in this study. This becomes a more interesting finding when it is observed that rs2235067, a non-synonymous intron variant SNP appears to amplify the correlation of rs1128503 with PTLDS in this study and another non-synonymous intron variant rs4148740 seems to decrease the correlation with the rs1128503 SNP and PTLDS.(rs2235067 RefSNP Report – dbSNP – NCBI [Internet], 2018; rs4148740 RefSNP Report – dbSNP – NCBI [Internet], 2018)
Several studies have observed that rs1128503 and rs1045642 are related in a linkage disequilibrium (LD) and influence the clinical correlation of each other.(Salama et al., 2006; Rychlik-Sych et al., 2018; Öztaş et al., 2018) For example, Salama et al. demonstrated that rs112850 and rs1045642 variants can significantly reduce P-gp activity across epithelial tissue.(Salama et al., 2006) Rychlik-Sych et al. found that rs1045642TT variant resulted in a two-fold reduction of P-gp in duodenal epithelium tissue.(Rychlik-Sych et al., 2018) While Oztas et al. noted a significant decrease in fexofenadine plasma concentrations in correlation with the rs1045642 TT variant. (Öztaş et al., 2018)
This study also confirms that there is an associated clinical effect with these two SNPs. In addition, this study has also correlated both rs2235067 and rs4148740, which are inherited in a separate LD block with both an increased and decreased effect of the rs1128503 respectively.(Uhr et al., 2008)
The respective amplification and reduction of the rs1128503 SNP with rs2235067 and rs4148740 appear to indicate that these two non-synonymous SNPs are in some way helping to regulate the function of the synonymous rs1128503 SNP. Generally, when variants are analyzed, a heterozygous variant (TC) combination only partially changes the function of an allele, while a homozygous variant (TT) tends to have a more disabling effect on the allele. Since the only time the TT homozygous variant increased the odds ratio correlation with PTLDS is when the non-synonymous rs4148740 allele was combined with the synonymous rs1128503 allele, it is possible that the TT variant of rs4148740 causes this intron variant SNP to lose function and no longer interfere with the function of rs1128503 SNP. This lack of interference now allows for a greater rs1128503 impact on the disease state.
For completeness, it is important to mention that this study found a slight age-related increase in disease state incidence with rs1128503 and rs1045642 individually. This may represent a significant finding based on the 2017 CDC reported data that two age groups (5–14 years old and 50 to 69 years old) have a higher number of confirmed cases of Lyme disease than the rest of the population.(Lyme Disease Charts and Figures: Most Recent Year | Lyme Disease | CDC [Internet], 2018) Further investigation is needed to correlate this data with PTLDS.
In conclusion, PTLDS has remained a perplexing disease state. There has been an unresolved debate in the literature about whether afflicted patients have an ongoing infection, an autoimmune reaction to the Borrelia burgdorferi organism, or a psychosomatic condition. The correlation of PTLDS patients and the ABCB1 allele rs1128503 seems to indicate an association between PTLDS symptoms and a set of patients with the TC genetic variant.
- COVID UPDATE: What is the truth? - 2022-11-08
- Pathologist Speaks Out About COVID Jab Effects - 2022-07-04
- A Massive Spike in Disability is Most Likely Due to a Wave of Vaccine Injuries - 2022-06-30
