Novel genetic markers, associated with first remission duration in multiple sclerosis, as predictor of the following disease severity in Russian patients

Abstract

Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of polygenic etiology. Relapsing–remitting MS (RRMS) is the most prevalent form of MS, which is characterized with high interindividual clinical variability, probably due to individual genetic status. It is known that first remission duration (FRD) correlates with rate of further disease progression, where short FRD is associated with relatively rapid progression of MS. Assuming the genetic control of FRD, the aim of present investigation was the association analysis of the immune response genes polymorphisms with FRD, which may provide predictive value for earliest MS severity prognosis. Initial study group included 227 RRMS patients; validation group included 331 RRMS patients (all of Russian ethnicity). Functional polymorphisms in 13 candidate genes were studied: TNFRSF1A (rs4149584, rs1800693), IL2RA (rs2104286), СD58 (rs2300747), CD6 (rs17824933), CLEC16A (rs6498169), IFNB1 (rs1051922), TNF (rs1800629), IL7RA (rs6897932), CCR5 (rs333), MIR146 (rs2910164), STAT3 (rs744166), SOCS1 (rs243324) and DRB1 HLA class II. Carriage of allele/genotype/allelic combinations associated with the short FRD (s-FRD, ≤ 1 year) or long FRD (1-FRD, >1 year) was analyzed with APSampler algorithm with subsequent validation by means of the Fisher's exact test. Carriage of TNF*A was significantly associated with l-FRD both in initial and validation groups (p b 0.01). All FRD-associated biallelic sets included TNF*A or TNF*G/G in combination with the allele of CD6 or IFNB1 or STAT3 genes and were found in both initial and validation groups with increased level of significance. The latter reached values of p = 5 × 10 – 5 × 10 in the joint group. Such cumulative contribution may reflect the additive effect of independent allelic variants. Upon gender stratification significant difference for allelic combinations differing in carriage between s-FRD and l-FRD groups was found in women's subgroup only. Allelic variants associated with FRD may be considered as MS severity markers, with a major contribution of TNF gene and modulating effects of some other immune-response genes. This provides a possibility to use an individual genetic status of a patient for the earliest prognosis of MS severity.