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Background: Currently, there are few established pharmacogenetic predictors of response to treatment in multiple sclerosis (MS) patients. Commonly used second line treatments include natalizumab that has proven to be successful in slowing MS progression in a subset of patients. Our aim was to identify pharmacogenetic factor(s) associated with MS patients’ response to natalizumab. Methods: Ten MS patients not responding to natalizumab and 23 MS patients responsive to natalizumab were selected for exome sequencing. Exome sequences were analyzed and resultant variant was assessed in an additional cohort of 86 MS patients. Results: Exome analysis revealed a missense polymorphism (rs2304166) in glycoprotein VI (GP6) gene (19q13.42, c.940C > G, p.P314A) associated in homozygosity with MS poor response to natalizumab (p = 0.0012). An additional cohort of 86 MS patients of which 19 were natalizumab unresponsive and 67 responsive confirmed rs2304166 CC significant association with poor response to natalizumab (p = 0.0000027). In addition, rs2304166 CC MS patients had increased MS disability despite taking natalizumab (Odds ratio 22.18, 95% CI: 5.758–95.88, p = 0.00000001). Conclusion: Natalizumab is a commonly used second line treatment for MS, and poor response to natalizumab appears to be associated with rs2304166 CC genotype in MS patients. Our findings suggest the need to investigate GP6’s rs2304166 role as a potential pharmacogenetic predictor for MS patients’ response to natalizumab. Keywords: Multiple sclerosis, Natalizumab, Glycoprotein VI, Pharmacogenetics Background Environmental factors such as trauma, patient adherence Multiple sclerosis (MS) treatments are being developed or life style can influence drug response. Genetic factors at a rapid pace in tandem with increasing prevalence of whilst very few are known are thought to contribute to MS worldwide . MS worldwide prevalence is esti- MS co-morbidities, drug detoxification, adverse effects, mated to be 2500,000 cases, with a projected future in- and overall drug response. The disparity in patient re- crease in some countries . MS management regimens sponse to MS disease-modifying drugs have gravitated MS involve treating MS-related symptoms in conjunction research towards discovery of novel treatments and advo- with available targeted MS disease-modifying drugs that cacy for personalized MS treatment research [4, 5]. In can be broadly classified into anti-inflammatory and im- recent years, second-line treatments have been developed munosuppressive treatments. Despite the wide selection to target MS patients that do not respond to first-line of MS therapeutics available, disease progression and re- treatments such as beta-interferon derivatives and glatira- lapse are frequent. Several factors influence MS treatment mer acetate . Among the most effective second-line success that can either be environmental or genetic . treatments for MS is Natalizumab (commercial name Tysabri©) . Natalizumab (NTZ) is a monoclonal anti- body against alpha-4-integrins expressed on lymphocytes. * Correspondence: email@example.com Alpha-4 integrins facilitate the attachment of myelin-react- Human Genetics Unit, Department of Pathology, Faculty of Medicine, ive lymphocytes to endothelial cell walls and their Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Al-Mojel et al. Multiple Sclerosis and Demyelinating Disorders (2019) 4:2 Page 2 of 6 transmigration across the blood brain barrier into the MS of 86 MS patients on NTZ was collected after the com- brain. Lymphocyte migration to the brain initiates the mye- pletion of the exome sequencing part of the study as a lin targeted autoimmune inflammatory reaction character- validation cohort using the same exclusion/inclusion cri- istic of MS. NTZ’s successful treatment of MS relies on teria as above except for duration of NTZ adherence several factors including; adherence to treatment, starting which was adjusted to > 2 years to allow detection of in an active MS phase, having a relapsing-remitting MS sufficient physical evidence of MS disease activity. The course, and a mild to moderate expanded disability score validation cohort included 19 NTZ unresponsive pa- [8–10]. Natalizumab’s success is hampered by the adverse tients after an average of 4 years of NTZ treatment. effect associated with long-term use; as it associates with increased risk of progressive multifocal leukoencephalopa- Exome sequencing thy (PML) . Moreover, a small percent of MS patients Whole blood was withdrawn in EDTA vacutainers and seemingly suitable for NTZ treatment fail to respond posi- centrifuged at 2500 rpm at room temperature for frac- tively with apparent relapses, additional disability and new tionation. Plasma fractions were retained and stored at lesions on magnetic resonance imaging (MRI) indicative of − 80 °C, and buffy coat fractions were collected for DNA disease activity [12, 13]. Here we show that a single nucleo- extraction. DNA extraction was performed using Qiagen tide polymorphism (rs2304166, c.940C > G, p.P314A) in DNA mini kit (Qiagen, Germany) according to manufac- exon 8 of glycoprotein VI gene located on chromosome turer’s standard protocol. DNA concentration and qual- 19q13.42 can predict poor response to NTZ. ity were assessed using spectrophotometry and agarose gel electrophoresis. Exome sequencing was performed Methods on an Illumina HiSeq2000 platform using SureSelectXT Sample collection v5 library preparation with target coverage of 50X (Illu- All MS patients included in this study were recruited at mina, CA, USA). Sequences were checked for quality Dasman Diabetes Institute while attending their routine using FASTQC software, and BWA software was used to monthly appointments. All study protocols were ap- map and align sequences to reference hg19 sequences. proved by Dasman diabetes institute ethical review com- Picard was used to remove duplicate reads, and SAM- mittee which adheres to the declaration of Helsinki’s tools was used to convert sequences from SAM format Ethical Principles for Medical Research Involving Hu- to sorted and indexed BAM files. GenomeAnalysisTK man Subjects. Information pertinent to study protocols (GATK) was used to analyze the sequences for genotype was explained to all participants prior to procurement of calling and SnpEff was used to annotate variants and their informed written consent. MS patients’ inclusion predict their effects. Resultant exomes were uploaded criteria were; a detailed clinical history (demographics, for comparative analysis using Tute Genomics applica- age of onset, disease duration, expanded disability status tion (Tute Genomics, Inc., UT, USA). Variants that have scale (EDSS) score, and treatment history), MS disease a Fisher exact test p-values of highest significance were duration of ≥2 years, currently on NTZ, being adherent prioritized and one was selected for further analysis in a to NTZ for at least 1 year, and the agreement to provide secondary MS cohort. a blood sample. Exclusion criteria included; having an EDSS score of 0, and MS disease duration of less than 2 Rs2304166 genotyping years. The first sample collection identified 33 MS pa- Blood samples of the validation MS cohort were processed tients on NTZ. Of the 33 MS patients, 23 were classified according to the same protocol mentioned above for DNA as NTZ responsive and 10 were unresponsive when their extraction. A genetic variant (rs2304166) in GP6 had the MS clinical characteristics at the end of this part of the most significant association with NTZ response as de- study’s duration of two years were compared to their tected by exome sequencing and was further investigated pre-NTZ treatment clinical characteristics. Criteria used in the validation cohort. Taqman genotyping assay for to categorize NTZ treated MS patients as responsive in- single nucleotide polymorphism (SNP) rs2304166 was used cluded; having a stable or reduced EDSS, no occurrence to genotype all samples. In summary, 50 ng of DNA from of relapse, and regression or lack of new MS-related every sample were used for genotyping using ABI7500 Fast CNS lesions on MRI. Whereas, NTZ unresponsive MS Real-time PCR system (Applied Biosystems, CA, USA). patients were identified based on the following; having Genotype allelic discrimination was determined by SDS an increased EDSS despite treatment, occurrence of a re- v1.4.1 software (Applied Biosystems, CA, USA). lapse during treatment course, and detection of new MS-related lesions on MRI compared to pre-treatment GP6 enzyme-linked immunosorbent assay MRI results. These patients were selected for exome se- Human GP6 sandwich enzyme-linked immunosorbent quencing to investigate the genetic factor affecting their assay was used (LifeSpan Biosciences, Inc., WA, USA) ac- response to NTZ. The second sample collection cohort cording to manufacturer’s protocol. In summary, plasma Al-Mojel et al. Multiple Sclerosis and Demyelinating Disorders (2019) 4:2 Page 3 of 6 samples were diluted in provided sample diluent at 1:10 therefore ignored, and two were missense. The mis- and 1:20 dilutions and run in duplicates to ensure all sam- sense variants were rs2304166 in glycoprotein VI (GP6) ples’ readings fall within standard curve concentrations. (p = 0.0012) and rs3748229 in phosphoinositide 3-kinase Standards were prepared and 100 μl of blank, standards adapter protein 1 (OIK3AP1) (p = 0.0049). We prioritized and samples were added to a 96-well plate in duplicates. the variant rs2304166 in GP6 as it was homozygous CC in Plates were sealed and incubated at 37 °C for 1 h followed 100% of NTZ unresponsive MS patients, and 41% hetero- by standard and sample aspiration from each well. Detec- zygous (CG) and 59% homozygous wild-type (GG) in MS tion reagent A was added to each well and mixed thor- patients responsive to NTZ (Table 1). This variant’sminor oughly followed by incubation at 37 °C for 1 h. Following allele C occurs at a frequency of 38% in the 1000 genomes incubation, detection reagent was aspirated and wells were project, and is considered to be benign in ClinVar data- washed three times with kit supplied wash buffer and base. In our Kuwaiti population, rs2304166 allelic distribu- dried on absorbent paper. Detection reagent B was added tion was investigated in 319 healthy control exomes and to each well and plates were incubated for 30 min at 37 °C. found to be 63.47% for allele G and 36.53% for the minor After incubation, reagent B was aspirated and wells were allele C. Prediction program tools gave contradicting pre- washed five times with wash buffer, dried, and TMB solu- dictions for this variant. Polyphen2 predicted it to be tion was added into each well. Plates were incubated in probably damaging, and polyphen2 HDIV prediction was the dark for 20 min at 37 °C and upon optimal color devel- probably damaging as well. SIFT predicted rs2304166 to opment incubation was terminated by adding kit provided be deleterious with low confidence, mutation taster and stop solution. Optical density (OD) readings were imme- FATHMM both predicted it to be tolerable. Whereas, diately recorded on a microplate reader set at 450 nm genome evolutionary rate profile (GERP++) prediction wavelength. A standard curve was generated using a gave a moderate score of 2.65 suggesting a moderately four-parameter logistic curve-fit and samples’ GP6 deleterious prediction, and cross species prediction pro- concentrations were corrected for dilution factors and gram SiPhy29way had a score of 8.956 suggestive of high recorded accordingly. conservation and a probably deleterious rs2304166 effect. Rs2304166 is a nonsynonymous conserved amino acid Data analysis substitution (p.P314A) which may alter protein function. To assess the impact of our resultant variant we chose the This variant was assessed further in a replicate cohort lon- following prediction program tools; Polyphen2 both HDIV gitudinally followed for an average of 4 years after patient’s and HVAR (a score of > = 0.957 is probably damaging), SIFT first NTZ drug administration and adherence to treat- (deleterious if score is <=0.05), Mutation Taster, FATHMM, ment. The replicate cohort composed of 19 MS patients Genome Evolutionary Rate Profiling++ (GERP++) for which poorly responding to NTZ based on disease progression higher scores are probably deleterious, and SiPhy log Odds assessments, and 67 patients responding to NTZ. Repli- which is a probabilistic framework that uses data from cate cohort rs2304166 genotyping results show that allele 29 species and higher scores are more deleterious. For C significantly associated with poor response to NTZ exome and genotype analysis Fisher’s exact-test, chi- (Odds ratio 22.18, 95%CI: 5.758–95.88, p = 0.000000011). square test, and linear regression analyses were used. Homozygous CC patients were at greatest risk of disease For ELISA data D’Agostino and Pearson normality progression while taking NTZ as assessed by worse tests were performed prior and non-parametric data EDSS, occurrence of relapse, and new CNS lesion de- Mann-Whitney U-test, and Kruskall-Wallis test were used tection on MRI (p = 0.0000027). Analysis of both exome if data was non-normally distributed, whereas t-test and and replicate MS cohorts collectively demonstrated NTZ one-way ANOVA tests were used when variables analyzed unresponsive MS patients had significantly worse EDSS were normally distributed. All statistical analyses were after the completion of follow-up assessment (p <0.001), performed using SPSS v.25 (IBM, NY, USA). whereas NTZ responsive patients had significantly better EDSS (p < 0.001) (Table 2). In addition, linear regression Results analysis adjusted for sex, age, MS type, and disease dur- Exome sequencing data coverage shows an average of ation result shows initiating NTZ treatment in MS pa- 99.82% 1x coverage rate and an average depth of 57.63 tients at mild or intermediate EDSS scores affects positive reads per probe. Fisher’s exact test analysis of exome se- response to NTZ (β = 0.089, 95% CI: 0.164 - 0.036, p = quences of the two cohorts showed nine variants with a 0.003) as previously reported. However, rs2304166 CC p-value < 0.005, which is less than the accepted p-value for had a strong predictive potential of negative response to − 6 exome sequencing association results (p-value ≤2.5 × 10 ) NTZ when adjusted for the above mentioned variables in- (Additional file 1: Table S1). However, given the small sam- cluding EDSS (β = 0.274, 95% CI: 0.166–0.379, p < 0.0001). plesizewepursued the top hitfor possibleassociation with We next investigated whether rs2304166 influences GP6 response to NTZ. Of the nine variants seven were silent levels in our cohort. Genotype CC patients’ GP6 levels Al-Mojel et al. Multiple Sclerosis and Demyelinating Disorders (2019) 4:2 Page 4 of 6 Table 1 Cohorts’ clinical characteristics and rs2304166 genotypes’ distribution Criteria Natalizumab Responsive Natalizumab Unresponsive Exome cohort n =23 n =10 Sex (Female/male) 14 / 9 9 / 1 MS type (RRMS/SPMS) 19 / 4 6 / 4 Age at natalizumab treatment (Average years) 32.3 32.5 Duration of natalizumab treatment (Average years) 2.95 3 a b EDSS before/after natalizumab [Median (IQR )] 3 (2–4.5) / 3 (2–4) 3.5 (2.5–6) / 6 (4.5–6.5) GP6 rs2304166 genotypes GG 7 0 GC 12 3 CC 4 7 Replicate cohort n =67 n =19 p-value Sex (Female/male) 36 / 31 16 / 3 0.018 MS type (RRMS/SPMS) 56 / 11 13 / 6 0.19 Age at natalizumab treatment (Average years) 32.8 34.5 0.09 Duration of natalizumab treatment (Average years) 3.17 3.25 0.66 a b EDSS before/after natalizumab [Median (IQR )] 2.5 (2–4) / 2 (1.5–3) 4.25 (2–6) / 6.5 (5.5–7) < 0.001 GP6 rs2304166 genotypes GG 20 1 0.0000027 GC 37 4 CC 10 14 a b EDSS Expanded disability status scale, IQR Interquartile range were normally distributed, whereas genotype GG and GC adhesion molecules’ interactions in the endothelium . patients’ GP6 levels were non-normally distributed. Log Here we have shown that a variant in GP6 appears to transformed GP6 levels were used to assess the effect of reduce the efficacy of NTZ’s therapeutic potential in MS rs2304166 genotypes and we found no significant effect of patients homozygous CC for rs2304166. GP6 is composed rs2304166 on plasma GP6 levels (p = 0.46, Fig. 1). of two extracellular immunoglobulin (Ig)–homology domains, a transmembrane domain, and a 51-amino Discussion acid cytoplasmic domain. GP6 shares ~ 44.1% amino NTZ targets alpha-4 integrin subunits on lymphocytes. acid similarities with leukocyte immunoglobulin-like Leukocytes require alpha-4 integrins for trafficking to sites receptors. GP6 is a collagen receptor found on the sur- of inflammation. The alpha-4 integrins and their receptors face of platelets that dimerizes to activate thrombotic are widely involved in fetal and adult lymphopoiesis and signaling pathways, and its ectodomain can be found in hematopoiesis in addition to leukocyte activation and sur- soluble form during platelet shedding . Upon GP6 vival [14, 15]. Treatment with NTZ has been shown to binding to exposed collagen at injured vascular sites it increase leukocyte counts, nucleated red blood cell counts induces platelet activation and aggregation leading to and spleen weight as it limits leukocytes to the circulation thrombus formation at site of injury . In hemostasis inhibiting extravasation through alpha-4 integrin and and thrombosis, GP6 is pivotal for the maintenance of vessel wall integrity during inflammation by inhibiting Table 2 The clinical characteristics of the replicate cohort MS neutrophil-induced vascular damage. Mutations in GP6 patients at the end of the study categorized by rs2304166 that result in loss of GP6 protein, or an abnormally genotypes short or nonfunctional GP6 are associated with an Rs2304166 Pre-NTZ treatment Post 2-year NTZ treatment autosomal recessive hereditary bleeding disorder due to genotype EDSS EDSS New CNS Relapse (n) the inability to produce clots (OMIM ID 614201). Al- (N = 86) a [Median (IQR )] [Median (IQR)] lesion (n) though our reported variant (rs2304166) in the GP6 gene GG 3.5 (2.5–4.5) 3 (2–4.75) 0 0 is a missense variant, this variant changes an amino acid GC 2 (2.5–4.25) 2 (1.5–4.25) 0 0 (Proline) that is evolutionarily conserved across primates. CC 3.5 (2–5.87) 5.25 (2–6.5) 2 2 Proline change into alanine occurs in a peptide palin- IQR Interquartile range drome (PPAPP) that might be critical for the protein’s Al-Mojel et al. Multiple Sclerosis and Demyelinating Disorders (2019) 4:2 Page 5 of 6 4.5 4.0 3.5 3.0 Rs2304166 Genotype Fig. 1 Circulating GP6 levels were variably distributed when plotted according to GP6 rs2304166 genotypes secondary structure. Alanine is a non-polar amino acid GP6 rs2304166 CC MS patients limits their response to with a methyl side chain, whereas proline is also NTZ remains to be investigated. non-polar but has a pyrrolidine side chain characteristic of transmembrane domains. It is plausible that this variant Conclusions produces a less stable GP6 monomer or dimer on the sur- A variant (rs2304166) in GP6 gene is associated with face of platelets that alters its shedding potential which is poor response to NTZ in homozygous CC genotype MS considered a thrombus growth limiting event . patients. Rs2304166 CC associated with progressive MS While the mechanism by which this GP6 variant disability. Our findings support the need to investigate lessens the efficacy of NTZ treatment of MS is currently rs2304166 as a potential pharmacogenetic predictor of unknown, it should be noted that only 10.5% NTZ unre- MS patients’ response to NTZ, and exploration of alter- sponsive MS patients had new MRI activity, while 89.5% native therapeutics for this subset of MS patients. showed significant disease progression assessed by wors- ening EDSS. Based on what is known about GP6 and Additional file NTZ it is possible that the efficiency of platelet response to vascular injury is reduced due to GP6 reduced surface Additional file 1: Table S1. Exome sequencing significant (p < 0.005) stability resulting in poor vascular homeostasis causing results generated by comparing MS patients responding to NTZ (n = 23) and those unresponsive to NTZ (n = 10). (DOCX 14 kb) accumulation of cerebral vascular injury and reductions in cerebrovascular reactivity shown to cause additional neurodegeneration in MS [20, 21]. Moreover, moder- Funding This work was funded by Kuwait University Research Sector Grant MG04/15. ately low GP6 levels in rs2304166 CC MS patients re- flect this possibility pointing towards the occurrence of Availability of data and materials thrombocytopenia. Sporadic case reports have docu- The datasets analysed during the current study are available from the mented immune thrombocytopenia development sec- corresponding author on reasonable request. ondary to NTZ treatment in MS patients [22–24]. It is Authors’ contributions possible that NTZ induced thrombocytopenia in con- MA performed the genotyping experiment, RAR facilitated sample collection junction with GP6 reduced functionality inflicts a clot- and provided patients demographics and clinical data, TK performed ELISA ting disorder that counteracts the beneficial impact of experiments, MD performed the bioinformatics analysis and provided population frequency data, and RAT performed the exome sequencing, NTZ on MS related disability. GP6 is not the only fac- authored the manuscript and is the project’s principal investigator. All tor involved in initiating thrombosis, integrin alpha-IIb authors read and approved the final manuscript. beta3 is another factor that has similar functions and share similar pathways. Our reported GP6 variant’sef- Ethics approval and consent to participate All study protocols were approved by Dasman diabetes institute ethical fects might not be substantial under normal conditions, review committee which adheres to the declaration of Helsinki’s Ethical but come into effect when NTZ hematological changes Principles for Medical Research Involving Human Subjects. Informed written take place. Whether thrombocytopenia development in consent was secured from each participant prior to sample collection. CC GC GG Log10 (GP6) Al-Mojel et al. Multiple Sclerosis and Demyelinating Disorders (2019) 4:2 Page 6 of 6 Consent for publication 14. Arroyo AG, Yang JT, Rayburn H, Hynes RO. Differential requirements for Not applicable. alpha4 integrins during fetal and adult hematopoiesis. Cell. 1996;85(7): 997–1008. 15. Rose DM. The role of the alpha4 integrin-paxillin interaction in regulating Competing interests leukocyte trafficking. Exp Mol Med. 2006;38(3):191–5. https://doi.org/10. 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