Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRB1*1501, CCR5 deletion mutation, apolipoprotein E)

Schreiber, Karen; Oturai, Annette Bang; Ryder, L. P.; Madsen, Hans O.; Jørgensen, Ole Steen; Svejgaard, A; Sørensen, Per Soelberg

doi:10.1191/1352458502ms816oa

Cited by 56 publications

(38 citation statements)

References 33 publications

(36 reference statements)

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“…Patients with the CCR5-∆32 allele showed a non-significant trend towards a small lesion burden (total lesion area/years duration), but the presence of this allele was not associated with a mild edSS/year duration. the data support the previous hypothesis of a modulation of severity in MS by the CCR5-∆32 genotype, which may result in less inflammation and tissue destruction (66). However, due the limited number of patients enrolled, weak associations between this polymorphism and disease variables cannot be excluded.…”

Section: Tnf-a Tnf-β and The Tnf Receptor Genessupporting

confidence: 87%

“…the association between the apoe and mS progression measured by clinical disability and mri parameters was evaluated in a population-based patient sample (n=70). carriers of the apoe-ε4 alleles did not show a more severe disease progression, neither by edSS/years of duration nor by the total lesion area/years duration (66). although the study was carried out on a genetically homogeneous danish population, the limited number of mS patients enrolled could interfere with the results obtained and the association between this gene and disease variables could not be excluded.…”

Section: Apolipoprotein E Gene (Apoe)mentioning

confidence: 94%

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Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (Review)

Kallaur

Kaimen-Maciel²,

Morimoto³

et al. 2011

Int J Mol Med

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Abstract. multiple sclerosis (mS) is an autoimmune disease characterized by areas of inflammation, demyelination and axonal damage. the etiology of mS is multifactorial with an interaction between genetic, environmental and geographical factors. the objective of this study was to review the physiopathology and the genetic polymorphisms associated with the development and clinical course of mS. Studies carried out in populations worldwide showed that polymorphisms in the genes of the major histocompatibility complex (mHc) class ii and class iii have been associated with susceptibility, resistance and clinical forms of mS. considerable attention has been focused on studies evaluating disease-modifying effects in MS that identified seven genes of probable importance such as the Hla class ii, apoe, il-1ra, il-1β, tnf-α, tnf-β and ccr5 genes. However, the results described in the literature about genetic biomarkers in mS are not consistent in the worldwide population. the detection of a single nucleotide polymorphism involved in the etiology and physiopathology of MS is very difficult and, it is likely that, several genetic polymorphisms are involved, each with a small contribution to the susceptibility or resistance to mS. taken together the results show the need for continued research in genetically heterogeneous populations to identify new biomarkers associated with mS that could be used as prognostic markers or as therapeutic targets to modulate the autoimmune response in mS patients. this information may contribute to a better understanding of the physiopathology and treatment of mS, with the possibility of developing different therapeutic strategies according to the genetic profile of each individual.

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Section: Tnf-a Tnf-β and The Tnf Receptor Genessupporting

confidence: 87%

Section: Apolipoprotein E Gene (Apoe)mentioning

confidence: 94%

Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (Review)

Kallaur

Kaimen-Maciel²,

Morimoto³

et al. 2011

Int J Mol Med

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mentioning

confidence: 99%

“…21 Genetic studies indicate MS is likely to be a polygenic disorder, due to multiple gene associations. [22][23][24] Some of the genes reported to be associated with MS include interleukin, 25,26 CTLA4, 27 HLA-DRB1*1501, and apolipoprotein E. 28 Early-published reports 29,30 of epidemiological studies of MS concluded that the disease was common in persons of Scandinavian descent: an ethnic group that exhibits a high prevalence of CCR5 ⌬32 mutation. Among the European white population there is a north to south gradient of prevalence of the CCR5 ⌬32 mutant allele, with the allelic frequencies highest in Scandinavia (16%) and lowest in Sardinia (4%), with a mean allelic frequency across the whole of Europe of 9.1%, where as this variant was found in only 1% in individuals of African origin, 0% in Asians, and 9.8% in Caucasians.…”

mentioning

confidence: 99%

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

Gade-Andavolu

Comings

MacMurray

et al. 2004

Genetics in Medicine

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Purpose: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 ⌬32 deletion in this disorder. Methods: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 ⌬32 deletion allele. Results: An increased frequency of 32-bp deletion allele was found to be associated with early death (P ϭ 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). Conclusion: A strong association of the CCR5⌬32 deletion with early death could serve as a prognostic marker for MS. Genet Med 2004:6(3):126 -131. Key Words: multiple sclerosis, polymerase chain reaction, chemokine receptor, experimental autoimmune encephalomyelitisMultiple sclerosis (MS) is a chronic demyelinating disorder pathologically characterized by an infiltration of monocytes and T-lymphocytes into the brain parenchyma, destruction of oligodendrocytes, and the loss of myelin. The role of chemokines and chemokine receptors is particularly important in MS, where myelin-destructive inflammation occurs inside the blood-brain barrier and is related to the influx of peripheral proinflammatory T cells into the CNS. Chemokines play a significant role in the migration of monocytes and T cells and also have been implicated in the onset or progression of MS and experimental autoimmune encephalomyelitis (EAE). 1,2 CCR5, a seven transmembrane spanning G protein-coupled receptor, is a specific binding site for the CC-chemokines and is expressed on T-helper cells. Several studies have ascribed to CCR5 surface expression levels an important role in HIV-1 entry and pathogenesis, 3 and a CCR5 ⌬32 mutation (homozygous deletion) almost invariably protects from HIV-1 infection. 4,5 The heterozygotes demonstrate a delay in progression of the disease 6 -8 lower viral loads and higher CD4 ϩ counts. 9Aberrant production of chemokines has been described in humans and experimental CNS demyelinating lesions. 10,11 ␤-Chemokine receptors were examined in postmortem MS CNS tissue by immunohistochemistry, and an elevated expression of CCR2, CCR3, and CCR5 was noted. 12-14 HHV6 virus was additionally found in the human brain specimens and a possible association with MS was suggested. [15][16][17] Chemokine receptor expression studies showed CCR5 and CXCR3 to have annualized increase in T2 lesion loads, suggesting these chemokines play an important role in the development of new lesions in MS than in the long-te...

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“…Although homozygous individuals for CCR5-Δ32 were not protected from MS, heterozygosity for this deletion has been associated to prolonged diseasefree intervals and a delay in MS onset and with a lower risk of recurrent clinical disease activity (12). Results obtained in another study also confirm that the genotype CCR5-Δ32 could modulate the severity in MS, resulting in less inflammation and tissue destruction (33).…”

Section: Ccr5-δ32 Genetic Polymorphism Associated With Benign Clinicamentioning

confidence: 86%

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

Kaimen-Maciel

Reiche²,

Souza³

et al. 2007

Int J Mol Med

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Abstract. The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Δ32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsingremitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Δ32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (±SD) age at disease onset among the carriers and non-carriers of the CCR5-Δ32 allele was 31.7 (±11.1) and 36.6 (±12.0) years, respectively (p=0.1312). The duration (±SD) of the disease was 11.2 (±12.9) and 7.7 (± 5.6) years among the CCR5-Δ32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (±SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Δ32 allele was 2.4±1.2 and 2.67±2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Δ32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Δ32, and CCR5-Δ32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Δ32 involvement in the specific process of MS pathology and pathogenesis.

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Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRB1*1501, CCR5 deletion mutation, apolipoprotein E)

Cited by 56 publications

References 33 publications

Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (Review)

Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (Review)

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

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