Sreeram Ramagopalan - Academia.edu (original) (raw)
Uploads
Papers by Sreeram Ramagopalan
Epidemiology, 2009
ABSTRACT An abstract is unavailable. This article is available as HTML full text and PDF.
Journal of Neuroimmunology, 2008
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the clinical course of which varies considerably between patients. Genetic complexity and interactions with as yet unknown environmental factors have hindered researchers from fully elucidating the aetiology of the disease. In addition to influencing disease susceptibility, epidemiological evidence suggests that genetic factors may affect phenotypic expression of the disease. Genes that affect clinical outcome may be more effective therapeutic targets than those which determine susceptibility. We present in this review a comprehensive survey of the genes (both MHC- and non-MHC-related) that have been investigated for their role in disease outcome in MS. Recent studies implicating the role of the genotype and epistatic interactions in the MHC in determining outcome are highlighted.
Current Opinion in Neurology, 2009
Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause... more Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause is unknown, but detailed epidemiological and genetic studies have shown a clear inherited component. We review here some of the recent findings of MS genetics with a particular focus on genes of the major histocompatibility complex (MHC). Recent studies add further complexity to the role of the MHC in MS. Reported MHC associations are complex, involving haplotypes rather than single alleles and may involve epigenetic mechanisms and other modulators of gene expression. MHC class II haplotypes display a hierarchy of risks, including protective effects and epistatic interactions, which together dwarf any non-MHC genetic effect. Genes in the MHC region have been shown to influence disease severity, display parent-of-origin effects and interact with a major environmental candidate for MS, vitamin D. The MHC class II association with MS is not as straightforward as previously thought. A complete understanding of the epistatic interactions and epigenetic features of this region will be important to understand disease pathogenesis and likely aid the discovery of new therapeutics.
Journal of Neuroimmunology, 2008
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Given a possible role for dysregulation of iron metabolism in MS disease pathogenesis, we investigated whether or not mutations in the HFE gene influence the prognosis of the disease. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of HFE on MS disease severity. This approach increases the effective sample size by some 40-fold. Genotyping the two sets of MS patients (112 benign and 51 malignant) provided no evidence to suggest that mutations in HFE have any outcome modifying activity, although small effects cannot be ruled out. The frequency of HFE mutations was not different in MS compared to the general population.
Trends in Neurosciences, 2008
Proceedings of The National Academy of Sciences, 2008
Nature Reviews Neurology, 2010
Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate... more Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.
Neurologic Clinics, 2011
Multiple sclerosis (MS) is the most common disease of the central nervous system that causes perm... more Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This article discusses the epidemiology of MS.
Annals of Neurology, 2010
Journal of Neurology, 2010
... Colleen Guimond • David A. Dyment • Sreeram V. Ramagopalan • Gavin Giovannoni • Maria Criscuo... more ... Colleen Guimond • David A. Dyment • Sreeram V. Ramagopalan • Gavin Giovannoni • Maria Criscuoli • Irene M. Yee • George C. Ebers • A. Dessa ... Smestad C, Sandvik L, Holmoy T, Harbo HF, Celius EG (2008) Marked differences in prevalence of multiple sclerosis between ...
BMC Medical Genetics, 2009
Background Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region e... more Background Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear HLA-DRB1*15. However, several other HLA-DRB1 alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk. Methods In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of HLA-DRB1 for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions. Results We found that amino acid 60 of the HLA-DRB1 peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13. Conclusion Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the HLA-DRB1 sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered.
Trends in Molecular Medicine, 2010
Epidemiology, 2009
ABSTRACT An abstract is unavailable. This article is available as HTML full text and PDF.
Journal of Neuroimmunology, 2008
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system (CNS), the clinical course of which varies considerably between patients. Genetic complexity and interactions with as yet unknown environmental factors have hindered researchers from fully elucidating the aetiology of the disease. In addition to influencing disease susceptibility, epidemiological evidence suggests that genetic factors may affect phenotypic expression of the disease. Genes that affect clinical outcome may be more effective therapeutic targets than those which determine susceptibility. We present in this review a comprehensive survey of the genes (both MHC- and non-MHC-related) that have been investigated for their role in disease outcome in MS. Recent studies implicating the role of the genotype and epistatic interactions in the MHC in determining outcome are highlighted.
Current Opinion in Neurology, 2009
Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause... more Multiple sclerosis (MS) is the most common neurological disease affecting young adults. The cause is unknown, but detailed epidemiological and genetic studies have shown a clear inherited component. We review here some of the recent findings of MS genetics with a particular focus on genes of the major histocompatibility complex (MHC). Recent studies add further complexity to the role of the MHC in MS. Reported MHC associations are complex, involving haplotypes rather than single alleles and may involve epigenetic mechanisms and other modulators of gene expression. MHC class II haplotypes display a hierarchy of risks, including protective effects and epistatic interactions, which together dwarf any non-MHC genetic effect. Genes in the MHC region have been shown to influence disease severity, display parent-of-origin effects and interact with a major environmental candidate for MS, vitamin D. The MHC class II association with MS is not as straightforward as previously thought. A complete understanding of the epistatic interactions and epigenetic features of this region will be important to understand disease pathogenesis and likely aid the discovery of new therapeutics.
Journal of Neuroimmunology, 2008
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpasse... more Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Given a possible role for dysregulation of iron metabolism in MS disease pathogenesis, we investigated whether or not mutations in the HFE gene influence the prognosis of the disease. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of HFE on MS disease severity. This approach increases the effective sample size by some 40-fold. Genotyping the two sets of MS patients (112 benign and 51 malignant) provided no evidence to suggest that mutations in HFE have any outcome modifying activity, although small effects cannot be ruled out. The frequency of HFE mutations was not different in MS compared to the general population.
Trends in Neurosciences, 2008
Proceedings of The National Academy of Sciences, 2008
Nature Reviews Neurology, 2010
Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate... more Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.
Neurologic Clinics, 2011
Multiple sclerosis (MS) is the most common disease of the central nervous system that causes perm... more Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This article discusses the epidemiology of MS.
Annals of Neurology, 2010
Journal of Neurology, 2010
... Colleen Guimond • David A. Dyment • Sreeram V. Ramagopalan • Gavin Giovannoni • Maria Criscuo... more ... Colleen Guimond • David A. Dyment • Sreeram V. Ramagopalan • Gavin Giovannoni • Maria Criscuoli • Irene M. Yee • George C. Ebers • A. Dessa ... Smestad C, Sandvik L, Holmoy T, Harbo HF, Celius EG (2008) Marked differences in prevalence of multiple sclerosis between ...
BMC Medical Genetics, 2009
Background Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region e... more Background Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear HLA-DRB1*15. However, several other HLA-DRB1 alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk. Methods In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of HLA-DRB1 for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions. Results We found that amino acid 60 of the HLA-DRB1 peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13. Conclusion Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the HLA-DRB1 sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered.
Trends in Molecular Medicine, 2010