Exp Brain Res DOI 10.1007/s00221-014-3968-z
Genetic factors associated with pharmacotherapy and background sensitivity to postoperative and chemotherapy‑induced nausea and vomiting Piotr K. Janicki · Shigekazu Sugino
Received: 30 January 2014 / Accepted: 3 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Postoperative nausea and vomiting (PONV) continues to be a most common complication of surgery and anesthesia. It has been suggested that the inherited factors may play a significant role in the background sensitivity to both PONV and also chemotherapy-induced nausea and vomiting (CINV), including resistance to antiemetic prophylaxis and/or therapy. This notion could be best exemplified by occurrence of PONV in several generations of families and concordance of PONV in monozygotic twins. The most frequently addressed issue in the research on genomic background of PONV/CINV relates to the inherited resistance to the antiemetic treatment (pharmacogenomics), and in lesser degree to their genomic background. The most common group of antiemetics consists of 5HT3 receptor antagonists, and this group was an initial target of pharmacogenomic research. Most research approaches have been based on the investigation of polymorphic variations in the target for the antiemetic 5HT3 receptor antagonists, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). The other area of pharmacogenomic investigations includes metabolic pathways of 5HT3 antagonists, in particular polymorphic variants of the CYP450 2D6 isoform (CYP2D6) because most of them are metabolized in various degrees by the CYP2D6 system. The results of targeted genomic association studies indicate that other genes are also associated with PONV and CINV, including OPRM1, and ABCB1. In addition, genes such as DRD2 and CHRM3 genes have recently been associated with PONV. The new genome-wide association studies
P. K. Janicki (*) · S. Sugino Laboratory of Perioperative Genomics, Department of Anesthesiology, Penn State College of Medicine, 500 University Drive, H187, Hershey, PA 17033‑0850, USA e-mail: [email protected]
seem also to indicate that the background genomic sensitivity to PONV and CINV might be multifactorial and include several genomic pathways. Keywords Postoperative · Nausea · Vomiting · Chemotherapy-induced nausea and vomiting · Genomics · Genetic polymorphism · PONV · CINV · Genetic variants
Significance of PONV for patient care Postoperative nausea and vomiting (PONV) continues to be a most frequent complication of surgery performed under general anesthesia worldwide. It is a limiting factor in the early discharge after ambulatory surgery, as well a leading cause of unanticipated hospital admission (Gan et al. 2014). Unresolved PONV can lead to increased recovery room time, expanded nursing care, and potential hospital admission—all factors that may increase total health care costs. Equally important are the high levels of patient discomfort and dissatisfaction associated with PONV. Approximately 30 % of all patients continue to experience PONV, and in subset of high-risk patients, the PONV rate can be as high as 80 % (Gan et al. 2014). The most important risk factors for PONV in adults include female sex, previous history of PONV and motion sickness (including family history), nonsmoking, duration of anesthesia, postoperative opioids, use of general anesthesia with nitrous oxide, type of surgery, and younger age. Apfel et al. (1999) created a simplified risk factor chart identifying four primary risk factors for PONV in patients receiving balanced inhaled anesthesia: female sex, nonsmoking status, history of PONV, and opioid use. The incidence of PONV with the presence of none, one, two, three, or all four of these risk factors was approximately 10, 20, 40, 60, and 80 %, respectively. The
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Table 1 Known human genes and their polymorphisms (as referenced in the manuscript) associated with occurrence of PONV, CINV, and motion sickness Target protein
Type of observed polymorphism
Serotonin receptor type 3
Morphine opioid receptor Cytochrome P450 2D6 isoform
Muscarinic receptor type 3 Neurokinin 1 receptor Transporter adenosine triphosphate-binding cassette subfamily B member 1 Dopamine receptor type 2 Serotonin transporter gene
CHRM3 TACR1 ABCB1
SNP in HTR3A: 1377A>G SNP in HTR3B: rs1176744, rs1672717, rs3782025, rs3758987, Tyr129Ser, Ala223Thr, Y129S; -100_-102delAAG deletion, c5+201_+202delCA, c6-137C>T SNP in HTR3C: K163 N, A405G SNP in HTR3D: rs6443930 SNP: rs1799971, haplotypes SNP: rs16947 (CYP2D6*2), rs35742686 (CYP2D6*3A), rs1135824 or rs35742686 (CYP2D6*3B), rs3892097 (CYP2D6*4), rs5030655 (CYP2D6*6), rs5030867 (CYP2D6*7), rs5030865 (CYP2D6*8), rs5030656 (CYP2D6*9), rs1065852 (CYP2D6*10), rs5030863 (CYP2D6*11) further genotypes listed at http://snpedia.com/ index.php/CYP2D6 SNP: rs685550, rs10802789, rs2165870 SNP: rs3755468, haplotypes SNP: rs1045642, rs2032582 and rs1128503, 3435C>T, 2677G>T/A Taq IA SNP: rs1176713 LA/SA polymorphism
effect of inherited factors for the incidence of PONV (i.e., history of PONV in mother, father of siblings) has also been acknowledged in pediatric PONV risk score by Eberhart et al. (2004). The identification of individuals at high risk for PONV (through medical history and/or molecular testing when available) can narrow the pool of potential candidates for specific type of the prophylactic antiemetic therapy, indicating those most likely to benefit and reducing antiemetic side effects and costs for patients unlikely to benefit.
Neurobiology of nausea and vomiting The so-called vomiting center lies in the medulla oblongata and comprises the reticular formation and the nucleus of the vestibular nuclei (Vnu), tractus solitaries (NTS), and area postrema (AP) (Horn et al. 2014). When activated, motor pathways descend from this center and trigger vomiting. These efferent pathways travel within the 5th, 7th, 9th, 10th, and 12th cranial nerves to the upper gastrointestinal tract, within vagal and sympathetic nerves to the lower tract, and within spinal nerves to the diaphragm and abdominal muscles. The vomiting center can be activated directly by irritants or indirectly following input from 4 principal areas: gastrointestinal tract, cerebral cortex and thalamus, vestibular region, and chemoreceptor trigger zone (CRTZ). The CRTZ is closest in proximity, lying
SNP: rs4680, rs4633, rs165722
between the medulla and the floor of the fourth ventricle. Unlike other brain centers, it is not protected by the blood– brain barrier. This is to say that the endothelium of its capillaries is not tightly joined or surrounded by glial cells and is permeated easily by irritants regardless of their lipid solubility or molecular size. The principal receptors, ligands, and their associate polymorphisms linked to nausea and/ or vomiting sensitivity or pharmacology are provided in Table 1. Antiemetic targets for drug interventions are predicated on their ability to block the referenced receptor sites (Gan 2007). Receptors along with their conventional ligands are as follows: H1 histamine, M1–3 acetylcholine, 5-HT3 serotonin, D2 dopamine, NK1 (neurokinin or substance P), and μ-type opioid receptor (MOR). Transmitter mediators in the cerebral cortex and thalamus are poorly understood, although cortical cannabinoid (CB1) pathways have been characterized.
Patient‑related factors in sensitivity to PONV and CINV PONV is multifactorial in its origin. In addition to wellestablished emetogenic agents used during anesthesia such as opioids and inhalation anesthetics, a large number of factors appear to render patients more susceptible including female gender, nonsmoking history, anxiety and prior history of PONV, motion sickness, and migraine. No
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explanation has been offered for the increased incidence in female patients, but this increased risk persists throughout life, even following menopause, which obviates any role for estrogen as a factor. It is speculated that smokers may have developed some tolerance because of the chronic emetogenic influence of nicotine, which is lacking in the nonsmoker. A history of motion sickness suggests a more susceptible vestibular component. Nevertheless, it is surprising that none of these factors is a reliable predictor independently. It has been suggested that the inherited factors can play significant role in the background sensitivity to PONV and CINV, and/or resistance to antiemetic prophylaxis and/ or therapy. This notion is exemplified by multiple observations of increased frequency of PONV in the several generation of the same family (up to three generations in some cases) and almost 100 % concordance of PONV in monozygotic twins (Janicki, observation unpublished), as well as established increased risk of PONV in children with the history of PONV in family (Eberhart et al. 2004). This seems to be particularly true for intractable PONV, which is either resistant to conventional antiemetic medication and/ or have severe and protracted duration.
Genetic background of PONV: animal models of genetic background of PONV Susceptibility to motion sickness is an important predictor of PONV, and studies in humans suggest that genetic factors determine sensitivity to motion sickness. The focus of the recently performed studies has been to selectively breed an animal model of motion-induced emesis that could be applied to future molecular-genetic studies. In this respect, laboratory shrews and ferrets have recently been used for these experiments because, unlike mice and rats, they are capable of vomiting and are a well-characterized species for motion-induced emesis using standardized behavioral test conditions (Horn et al. 2012). Further analysis of the inhalation anesthetics-induced PONV in these animal species indicates that ferrets are probably not useful for delineating mechanisms responsible for isoflurane-induced emesis. In contrast to ferrets, musk shrews have been very sensitive to isoflurane-induced emesis (0.5–3 %, 10-min exposure; up to 11.8 ± 2.4 emetic episodes), whereas ferrets failed to induce vomiting (Horn et al. 2012). Musk shrews may therefore become a model animal for the investigations of vomiting after inhalation of volatile agents. In the most recent paper, Horn et al. (2013) showed that highresponse strain musk shrews demonstrated significantly more emetic episodes to motion exposure compared to low-response strain animals in the F1 and F2 generations. In F2 animals, there were no significant differences in total
emetic responses or emetic latency between strains after nicotine injection or CuSO4 gavage. However, isoflurane exposure stimulated more emesis in F1 and F2 high versus low strain animals, which suggests a relationship between vestibular- and inhalational anesthesia-induced emesis. Overall, these results indicate genetic determinants of motion sickness in a preclinical model and a potential common mechanism for motion sickness and inhalational anesthesia-induced emesis. Future work may include genetic mapping of potential “emetic sensitivity genes” to develop novel therapies or diagnostics for patients with high risk of nausea and vomiting.
Genetic background of PONV and CINV in humans: clinical studies History of clinical research on inherited factors involved in the pathogenesis of PONV and related chemotherapyinduced nausea and vomiting (CINV) or motion sickness is relatively new, with oldest papers in this area published G was associated with a significantly higher risk (odds ratio [OR] 2.972 and the HTR3B variants c5+201_+202delCA (OR 0.421) and c6-137C>T (OR 0.034) were associated with a lower risk for PONV). All significant genetic variants were located in noncoding regions of the investigated genes. The authors concluded that genetic variations in the HTR3A and
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HTR3B gene seem to be associated with the individual risk of developing PONV. In addition, Sugai et al. (2006) investigated the effect HTR3A and HTR3B gene polymorphisms on nausea induced by paroxetine in 78 Japanese psychiatric patients. They demonstrated that Tyr129Ser polymorphism of the HTR3B gene had a significant effect on the incidence of nausea. Logistic regression analysis also showed that patients with the Tyr/Tyr genotype had a 3.95-fold higher risk of developing nausea than patients with the Ser allele. They also reported that HTR3A gene polymorphisms and the CYP2D6 gene polymorphisms had no significant effect on the incidence of nausea in this group of patients. The effect of yet another commonly occurring singlenucleotide polymorphisms (SNP) in HTR3 was reported by Fasching et al. (2008) [nonsynonymous SNPs: Y129S (HTR3B), K163N (HTR3C) and A405G (HTR3C)]. All patients received epirubicin, with or without cyclophosphamide, and preventive medication with ondansetron and dexamethasone. The patients documented every vomiting event on an hourly basis. The overall proportion of patients (total n = 110) who reported vomiting in the first 24 h after chemotherapy was 31.8 %. The variant genotype of K163N (HTR3C) was associated with vomiting, which occurred in 50.0 %. The authors concluded that polymorphisms in the HTR3C gene could serve as a predictive factor for CINV in patients undergoing moderately emetogenic chemotherapy. In the subsequent paper, the same group (Hammer et al. 2010) reported results of an investigation in 110 previously characterized chemotherapy-naive women with primary breast cancer treated with anthracycline-containing chemotherapy which served as a study group for mutational analysis by direct sequencing. Eight common SNPs in HTR3 genes (HTR3A, HTR3B, HTR3D, and HTR3E) were selected for association analysis. A nonsynonymous variant in HTR3D, G36A (rs6443930), was found to be over-represented in nonresponders. In addition, Cox proportional regression analysis resulted in a hazards ratio of 0.36 for homozygous carriers of the C allele to vomit within 24 h after first chemotherapy administration. These data support again hypothesis that 5-HT3 receptors play an important role in the pathogenesis of CINV. Along with previously identified HTR3 polymorphisms, the HTR3D G36A variant could also contribute to facilitating individual risk predictions. Finally, in the most recent multicenter study in cancer patients receiving opioids, Laugsand et al. (2011) included patients from 17 centers in 11 European countries. Intensities of nausea and vomiting were reported by 1,579 patients on four-point categorical scales. In stratified regression models including demographical and disease-related factors as covariates, 96 SNPs in 16 candidate genes related to opioid- or nausea/vomiting signaling pathways (ABCB1,
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OPRM1, OPRK1, ARRB2, STAT6, COMT, CHRM3, CHRM5, HRH1, DRD2, DRD3, TACR1, HTR3A, HTR3B, HTR3C, CNR1) were analyzed for association with nausea and vomiting. Eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids (P 0.8 and minor allele frequency >10 %. One of these (rs3758987 in HTR3B) was statistically associated with vomiting, after adjusting for body weight, body mass index, and duration of general anesthesia in dominant and additive models. It was therefore concluded that the HTR3B rs3758987 SNP might serve as a predictor of postoperative vomiting in Chinese Han patients undergoing gynecological laparoscopic surgery. CYP450 2D6 system Other area of pharmacogenomic investigations includes metabolic pathways of clinically used 5HT3RA, in particular polymorphic variants of the Cyp450 2D6 isoform (CYP2D6). Most of the 5-HT3RA, so-called setrons, are metabolized in various degrees by the CYP2D6 system (with notable exception of granisetron) (Janicki 2005). Early in 2002, Kaiser et al. sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on CYP2D6 genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated. They included in the study 270 cancer patients receiving their first day of chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 h after drug administration was analyzed in a subgroup of 42 patients. Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients. Approximately 30 % of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined
ultrarapid metabolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 h (P T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT3RA, particularly in
granisetron-treated patients, during the short-term phase of chemotherapy. The previously described involvement of the polymorphic CYP2D6 system in 5-HT3RA pharmacology was subsequently validated in surgical patients experiencing PONV and using ondansetron, dolasetron, or granisetron (as negative control) as primary prophylactic antiemetic regimen. Candiotti et al. (2005) examined two hundred and fifty female patients undergoing standardized general anesthesia who were given 4 mg ondansetron 30 min before extubation. Patients were observed for symptoms of nausea and vomiting and blood DNA analyzed for CYP2D6 polymorphism. In patients with one, two, or three CYP2D6 copies, the incidences of vomiting were 3 in 33 (27 %), 27 in 198 (14 %), and 7 in 23 (30 %), respectively. The incidence of vomiting in subjects with three CYP2D6 copies was significantly different from those with two copies, but not from those with one copy. When analyzed by genotype, the incidences of vomiting in poor, intermediate, extensive, and ultrarapid metabolizers were 1 in 12 (8 %), 5 in 30 (17 %), 26 in 176 (15 %), and 5 in 11 (45 %), respectively (P T/A, and 3435C>T polymorphisms of ABCB1. The incidence of PONV was lower in patients with the 2677TT during the first 2 h after surgery. There were no significant differences in the incidence of PONV between the different genotype groupings during period between 2 and 24 h after surgery. In conclusion, the authors concluded ABCB1 genotypes may be a clinical predictor of responsiveness for ondansetron.
Coulbault et al. (2006) performed an investigation of several genomic factors, including ABCB1 polymorphism, involved in PONV. Seventy-four patients who planned to undergo colorectal surgery were included in this pilot study. The cumulative 24-h postoperative dose of morphine and PONV requiring the antiemetic ondansetron was the 2 clinical end points. The association of patient characteristics, A118G mu-opioid receptor (OPRM1) SNP; T802C uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) SNP; and ABCB1 (also known under alternative names as multidrug resistance 1 [MDR1] gene) exonic SNPs (G2677T/A, and C3435T) with study end points, was investigated. The homozygous ABCB1 diplotype (GG-CC) conferred an odds ratio of 0.12 with regard to the use of ondansetron for PONV. Multivariate analysis identified that the ABCB1 GG-CC diplotype was the only borderline predictive factor of morphine side effects. Another study that examined the association of the ABCB1 and µ-opioid genes and adverse opioid drug reactions focused on oxycodone. In this study, Zwisler et al. (2009) recruited 33 healthy volunteers who were exposed to experimental pain. In this small sample, there were no significant differences between the genotypes for the µ-opioid A118G; however, they observed a significant difference in adverse reactions (nausea and vomiting) based on the ABCB1 genotype. Morphine (μ) opioid receptor gene Because of the direct association of opioid analgesic with the incidence and severity of PONV in surgical patients, a significant number of previous pharmacogenomic investigations have focused on the polymorphism in the mu-opioid receptor gene (OPRM1) which serves as the main target of all clinically used opioid agonists. The major target of these investigations was focused on the common, nonsynonymous polymorphism in OPRM1– A118G (rs179991). The results and conclusions from the studies published so far remain controversial. Several studies reported the association of the µ-opioid receptor gene (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty and after total abdominal hysterectomy (e.g., Chou et al. 2006a, b. In both studies, they reported a higher incidence of PONV in patients who were the homozygous (AA) variants. The strong trend reported was based on observing 22 % of subjects in the AA group with PONV, as compared to 12 and 7 % in the heterozygous (AG) and homozygous variant (GG) groups, respectively. This trend was confirmed by the work of Sia et al. (2008). In their study of women post-cesarean section, they report that genetic variation at A118G of the µ-opioid receptor is associated with individual differences in pain score, amount of
self-administered morphine, and the incidence of postoperative nausea. Specifically, results showed that those subjects who carried the AA (wild type) for A118G had significantly more PONV, despite a lower consumption of PCA morphine postoperatively. They concluded that a greater sensitivity to morphine may be attributed to the AA allele and thus lead to the increased PONV that was observed in the wild-type group. As far as Caucasian population is concerned, several studies did not confirm any association between A118G polymorphism and the incidence of PONV (Janicki et al. 2006a, b; Wesmiller 2013-unpublished). In fact, association of A118 SNP was recently questioned in the study Chen et al. (2013) who directly investigated whether this polymorphism prevents PONV associated with patient controlled intravenous opioid analgesia (IV-PCA) in 179 Taiwanese patients. They observed no significant difference between the severity and incidence of IV-PCA morphine-induced side effects and SNP A118G genotype or between the associations between morphine consumption versus genotype. The genetic analysis for the severity and incidence of IVPCA morphine-induced nausea or vomiting showed no association between phenotype and genotype. They concluded that SNP A118G does not protect against IVPCA morphine-induced nausea or vomiting. In the recent meta-analysis performed by Song et al. (2013), six clinical studies were included with a total 838 women who received epidural analgesia with fentanyl during labor. The meta-analysis results indicated that there were no statistically significant differences between an AA homozygote and a G carrier (AG + GG) in the incidence of nausea and vomiting. In addition, it was recently postulated that the altered sensitivity for PONV in relation to the OPRM1 polymorphism might be related not so much to the presence of single OPRM1 SNP variant but rather combination of several variants (haplotypes). In this respect, Sugino et al. (2013) examined the incidence and severity of PONV during 24 h after surgery in 85 Japanese patients who received IV- PCA fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene were genotyped for haplotype analysis and its association with postoperative pain and PONV outcome data. The four most common haplotypes with a frequency of >10 % which were observed in the investigated groups included GGGAACAC (33 %), AGGGACAC (19 %), GGGAACGC (12 %), and AGAGACAC (10 %). The severity of PONV in carriers of GGGAACGC haplotype was significantly lower than in the carriers of other haplotypes (P G (rs1176713) showed a trend toward PONV. Higher anxiety and higher pain clustered with PONV, yet the PONV group consumed less opioids. Both SLC6A4 variable number (L/S alleles) tandem repeats (VNTR) LL and the wildtype A genotype of the SNP 14396A>G represent higher serotonin activity and are associated with increased PONV
in this sample. Common hepatic organic cation transporter 1 (OCT1; SLC22A1) loss-of-function polymorphisms may also affect pharmacokinetics and efficacy of 5HT3RA. Tzvetkov et al. (2012) demonstrated in vitro that both tropisetron and ondansetron inhibited aspartate uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations and higher clinical efficacy compared with carriers of fully active OCT1. This work may indicate that in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake. Opioids are commonly used in the perioperative period (and for cancer analgesia) to control pain. Opioids are well known to induce nausea and vomiting as an independent stimulus (i.e., opioid-induced nausea and vomiting—OINV). UDP-glucuronosyltransferase (UGT2B7) plays a role in the metabolism of morphine to its main metabolites. Fujita et al. (2010) examined the relation of morphine-related adverse events to polymorphisms in UGT2B7, ABCB1, and OPRM1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. The UGT2B7*2 genotype was associated with the frequency of nausea (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2,677 and 3,435 in ABCB1 was associated with the frequency of vomiting (grades 1–3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2,677 and 3,435 suffered from vomiting. The newly employed approach of next-generation sequencing of the whole exome was recently performed in patients suffering from hyperemesis gravidarum (HG). HG is severe nausea and vomiting of pregnancy that often results in dehydration and undernutrition and is the second leading cause of hospitalization in pregnancy after preterm birth. In the study of Fejzo et al. 2013, saliva samples and surveys have been collected on 716 HG cases, 643 unaffected controls, and 29 families with 3 or more affected individuals. Exome sequencing was performed on 5 families and included 15 affected and 3 unaffected individuals. An average of 125 rare nonsynonymous damaging variants shared by affected relatives was identified in each family using a series of filtering steps. Four variants were identified in the PKD1 gene in two of five families. Three variants in the related genes PKHD1, LAMA5, and HOXD9 were identified in the remaining families. Variants were confirmed to segregate with the disease in the families by Sanger sequencing. The authors concluded that all 5 HG families carry biologically related rare damaging variants in genes known to cause polycystic kidney disease. Thus, a common pathway may be responsible for the majority of
cases of familial HG. Screening of variants in additional families and in sporadic HG cases and controls will determine whether this pathway represents a major cause of HG. This novel discovery is the first step in understanding the biology of HG, may be relevant to understanding genetic susceptibility to nausea. Another rare syndrome associated with nausea and vomiting is called cyclic vomiting syndrome (CVC) and represents a chronic disorder that is characterized by episodic nausea and vomiting. It occurs mostly in pediatric population but is being recognized with increased frequency in adults. The pathophysiology of CVS is largely unknown, but extensive pedigree analysis of children with CVS has revealed a clustering of functional disorders in maternal side relatives. It was suggested recently by Venkatesan (2013) and Malik et al. (2013) that mitochondrial DNA polymorphism may confer significantly higher odds of developing CVS in comparison with controls.
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