Genetic variation in the gene<i>LRP2</i>increases relapse risk in multiple sclerosis

Zhou, Yuan; Graves, Jennifer; Simpson, Steve; Charlesworth, Jac; Mei, Ingrid van der; Waubant, Emmanuelle; Barcellos, Lisa F.; Belman, Anita; Krupp, Lauren; Lucas, Robyn; Ponsonby, Anne–Louise; Taylor, Bruce

doi:10.1136/jnnp-2017-315971

Cited by 22 publications

(28 citation statements)

References 32 publications

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“…The MS susceptibility polymorphism within the Abelson Helper Integration site 1 gene ( AHI1 ) has been associated with higher relapse rate in two separate cohorts (one of children and another of adults), with similar effect size . In a genome wide search for alleles associated with relapse rate, a SNP within the gene LRP2 was associated with a twofold increase in the hazard to relapse in three independent MS cohorts, including adults and children . LRP2 is located on the cell surface of neurons and oligodendrocytes and participates in axon guidance.…”

Section: Cause Versus Course – Are the Risk Factors Different?mentioning

confidence: 99%

Environmental and genetic risk factors for MS: an integrated review

Waubant

Lucas

Mowry

et al. 2019

Ann Clin Transl Neurol

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184

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Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

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Section: Cause Versus Course – Are the Risk Factors Different?mentioning

confidence: 99%

Environmental and genetic risk factors for MS: an integrated review

Waubant

Lucas

Mowry

et al. 2019

Ann Clin Transl Neurol

Self Cite

219

184

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“…In this way, VD internalization can be mediated by LRP2, with or without the participation of CUBN and the DAB2 adaptor protein, although vitamin D also accesses some cells freely. Zhou et al () describe an association between MS relapses and LRP2 variant rs12988804. The study was based on data from three cohorts of patients with MS, including one series of paediatric patients.…”

Section: Discussionmentioning

confidence: 99%

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

et al. 2019

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Introduction Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS. The evaluation of gene variants in all the members of families could contribute to an additional knowledge on the information obtained from case‐control studies that use nonrelated healthy people. Material and Methods We studied 94 individuals from 15 families including at least two patients with MS. We performed whole‐exome next generation sequencing on all individuals and analyzed variants of the DHCR7, CYP2R1, CYP3A4, CYP27A1, GC, CYP27B1, LRP2, CUBN, DAB2, FCGR, RXR, VDR, CYP24A1, and PDIA3 genes. We also studied PTH, FGF23, METTL1, METTL21B, and the role of the linkage disequilibrium block on the long arm of chromosome 12, through analysis of the CDK4, TSFM, AGAP2, and AVIL genes. We compared patients with MS, other AIDs and unaffected members from different family types. Results The study described the variants in the VD signaling pathway that appear in families with at least two patients with MS. Some infrequent variants were detected in these families, but no significant difference was observed between patients with MS and/or other AIDs and unaffected family members in the frequency of these variants. Variants previously associated with MS in the literature were not observed in these families or were distributed similarly in patients and unaffected family members. Conclusion The study of genes involved in the VD signaling pathway in families that include more than one patient with MS did not identify any variants that could explain the presence of the disease, suggesting that VD metabolism could probably play a role in MS more as an environmental factor rather than as a genetic factor. Our study also supports the analysis of cases and unaffected individuals within families in order to determine the influence of genetic factors.

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“…Genes influence everything in humans, including susceptibility to diseases such as MS. Genetic variations affect susceptibility to MS and MSR. Family studies have shown that MSR prevalence is ~15%, and that MSR risk may be higher among first-degree relatives compared with other family members, an effect that tends to decrease with “genetic distance.”[56] Several researchers have shown that there is a genetic contribution to MSR that varies among different populations. These efforts have led to the identification of >110 genes that have critical roles in the development and relapse of MS.[57]…”

Section: Effects Of Genes and The Environmentmentioning

confidence: 99%

“…Due to a lack of reliable longitudinal data and shortage of prospective studies on MSR, several investigations on the link between genetics and MSR have thus far failed to identify the factors that can reliably predict the risk of MSR at the genomic level. Zhou et al [56] undertook genome-wide association analyses in an attempt to identify different genetic variants that may influence and predict MSR. In total, they analyzed 449 DNA samples and clinical histories from various populations to determine the genetic differences that may influence MSR.…”

Section: Effects Of Genes and The Environmentmentioning

confidence: 99%

Factors involved in relapse of multiple sclerosis

Kamel

2019

J Microsc Ultrastruct

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Multiple sclerosis (MS), a chronic autoimmune disorder, affects the central nervous system (CNS). It affects the brain, spinal cord, and optic nerve, leading to problems with vision, balance, muscle control, and other basic bodily functions. MS relapse (MSR) involves an acute inflammatory demyelinating reaction within the CNS. This review focuses on the main factors involved in MSR based on a detailed literature search. Evidence suggests that MSR is influenced by age, sex, pregnancy, serum levels of Vitamin D, interactions between genetic and environmental factors, and infectious diseases. Many of these factors are modifiable and require the attention of patients and health-care providers if favorable outcomes are to be realized. Identification of MSR risk factors can help in the development of therapies that could be used to manage MS and MSR.

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Genetic variation in the geneLRP2increases relapse risk in multiple sclerosis

Abstract: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course.

Cited by 22 publications

References 32 publications

Environmental and genetic risk factors for MS: an integrated review

Environmental and genetic risk factors for MS: an integrated review

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole‐exome next generation sequencing

Factors involved in relapse of multiple sclerosis

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