Pharmacogenetics of Glatiramer Acetate Therapy for Multiple Sclerosis: the Impact of Genome-Wide Association Studies identified disease risk loci

Abstract

We pinpointed the involvement of several GWAS-identified MS risk loci in GA therapy efficacy. These findings may be aggregated to predict the optimal GA response in MS patients.

Pharmacogenomics of Multiple Sclerosis: A Systematic Review

“…The authors also demonstrated that the presence of the DR15-DQ6 haplotype and the absence of the DR17-DQ2 haplotype is significantly associated with positive treatment response (52). Furthermore, in a cohort of 296 Russian patients, the nominally significant association of HLA-DRB1 * 4 allele with a positive response to GA was detected comparing responders to nonresponders and intermediate responders, P f = 0.015, OR = 2.02 [95% CI, 1.11–3.67] (53).…”

“…In the most recent study examining association between GWAS identified MS susceptibility loci and efficacy of GA therapy in a Russian population of 296 RRMS patients, five SNPs were associated by themselves with event-free phenotype: EOMES rs2371108 T allele, CLEC16 A rs6498169 A allele, IL22RA2 rs202573 GG genotype, PVT1 rs2114358 A allele, and HLA-DBR1 * 4 ( P f = 0.032-0.00092). Authors demonstrated increased significance levels when taking into account biallelic and triallelic combinations of these genes with additionally included polymorphic variants of TYK2, CD6, IL7RA and IRF8 genes (53).…”

“…Furthermore, we suppose that the phenotype of the response to an immunomodulatory pleiotropic therapy, such as IFN-beta and GA, is a sum of numerous contributing genetic factors that were not sufficiently simultaneously and combinatorially assessed by current study designs and methodologies. More studies investigating cumulative effects of polymorphisms in multiple genes (additive effects or epistatic interactions), such as studies of Kulakova et al (34, 53), are needed to gain a more comprehensive insight into genetic variability in association to the efficacy of treatment.…”

Involvement of Genetic Factors in Multiple Sclerosis

“…More interesting were the results of GWAS on response to IFNβ (Byun et al, 2008;Comabella et al, 2009;Esposito et al, 2015;Clarelli et al, 2017;Mahurkar et al, 2017); these investigations not only confirmed the role of genes implicated in the IFNβ pathway, such as IFNAR2, but also identified genes involved in neuronal functions like GPC5 (Byun et al, 2008), the glutamate receptors GRIA3 (Comabella et al, 2009), GRM3 and GRIK2 (Clarelli et al, 2017) and SLC9A9 (Esposito et al, 2015), which has been linked to neuronal excitability (Gu et al, 2001), pointing to a possible role for glutamate metabolism and excitotoxicity in modulating drug response. Similarly, candidate gene studies on response to glatiramer acetate (GA) (Fusco et al, 2001;Grossman et al, 2007;Tsareva et al, 2012;Kulakova et al, 2017) focused mainly on immunerelated genes and found that the clinical outcome during GA treatment is associated with HLA class II genes (Fusco et al, 2001;Gross et al, 2011) and other genes involved in T cell activation (TCRB, Grossman et al, 2007), antigen presentation (CD86) or proinflammatory signaling [(IL1R1 and IL12RB2, Grossman et al, 2007), (CCR5, Tsareva et al, 2012)]. Additionally, a recent GWAS on more than 2,500 GAtreated MS patients (Ross et al, 2017) selected a set of 4 SNPs mapping to HLA-DQB2, MBP, UVRAG, and ZAK, which distinguished signature-positive or negative patients, signaturepositive subjects displaying a better outcome over signaturenegative individuals.…”

Pharmacogenetics in multiple sclerosis: the long and winding road ahead of us

“…There are few studies on the pharmacogenetics of MS 3,4,5,6,7,8,9 . The specific response of an individual patient to any of the DMDs remains largely unpredictable, and a trial-and-error approach is the rule when deciding on treatment regimens.…”