Genetic determinants of risk and progression in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune disease that represents a primary cause of neurological disability in the young adult population. Converging evidence support the importance of genetic determinants for MS etiology. However, with the exception of the major histocompatibility complex, their nature has been elusive for more than 20 years. In the last decade, the advent of large genome-wide association studies has significantly improved our understanding of the disease, leading to the golden era of MS genetic research. To date more than 110 genetic variants have been firmly associated to an increased risk of developing MS. A large part of these variants tag genes involved in the regulation of immune response and several of them are shared with other autoimmune diseases, suggesting a common etiological root for this class of disorders. Despite the impressive body of data obtained in the last years, we are still far from fully decoding MS genetic complexity. For example, we ignore how these genetic factors interact with each other and with the environment. Thus, the biggest challenge for the next era of MS research will consist in identifying and characterizing the molecular mechanisms and the cellular pathways in which these risk variants play a role.

SPG5 and multiple sclerosis: clinical and genetic overlap?

“…A number of studies have been yet conducted either to explore the genetic basis of MS or to highlight possible correlations between drug responses and genetic profile (16)(17)(18)(19). Remarkably, the majority of the variants associated to an increased risk of MS tag genes involved in the regulation of immune response, and several of them are shared with other autoimmune diseases, suggesting a common etiological root for this class of disorders (20).…”

Vitamin D role in multiple sclerosis etiology and therapy

“…Patološku osnovu oštećenja centralnog nervnog sistema karakteriše dobro demarkirana inflamacija, oštećenje mijelinskog omotača (demijelinizacija), aktivacija mikroglije, proliferacija astrocita sa posledičnom gliozom i različitim stepenima aksonalne degeneracije. Postepena akumulacija fokalnih plakova demijelinizacije prisutna je naročito u periventrikularnim regijama mozga (12)(13)(14). Demijelinizacione lezije se diseminiraju kroz centralni nervni sistem, uključujući belu, i sivu masu, uzrokujući aksonalne i neuronalne gubitke i, posledično, brojne kliničke deficite kao što su slabost u jednom ili više ekstremiteta, senzorna oštećenja, optički neuritis, ataksija, disfunkcija mokraćne bešike i debelog creva, slabost, kognitivna oštećenja i emocionalni problemi (5,12,15,16).…”

“…Postepena akumulacija fokalnih plakova demijelinizacije prisutna je naročito u periventrikularnim regijama mozga (12)(13)(14). Demijelinizacione lezije se diseminiraju kroz centralni nervni sistem, uključujući belu, i sivu masu, uzrokujući aksonalne i neuronalne gubitke i, posledično, brojne kliničke deficite kao što su slabost u jednom ili više ekstremiteta, senzorna oštećenja, optički neuritis, ataksija, disfunkcija mokraćne bešike i debelog creva, slabost, kognitivna oštećenja i emocionalni problemi (5,12,15,16). Multipla skleroza počinje kao epizodna, relapsnoremitentna bolest, sa kompletnim ili parcijalnim oporavkom između relapsa.…”

The Genetics of Multiple Sclerosis

“…According to this model, the overall MS risk is the result of the contributions of multiple polymorphic genes with risk alleles common in the population, each one determining a moderate portion of the risk (10,11). This non-Mendelian pattern of transmission is not exclusive of MS but is shared with other autoimmune diseases and chronic disorders such as type II diabetes and obesity.…”