scholarly journals Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions

2019 ◽  
Author(s):  
DS Goodin ◽  
P Khankhanian ◽  
PA Gourraud ◽  
N Vince
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Susceptibility ◽  
Disease Risk ◽  
Additive Model ◽  
Life Time ◽  
Necessary Condition ◽  
Specific Gene ◽  
Susceptible Individual ◽  
Probability Models ◽  
Extended Haplotypes

AbstractOBJECTIVETo study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes of the MHC and three non-MHC risk-loci nearby genes EOMES, ZFP36L1, CLEC16A.BACKGROUNDDefining “genetic-susceptibility” as having a non-zero probability of developing MS, both theoretical considerations and epidemiological observations indicate that only 2.2–4.5% of northern-populations can possibly be “genetically-susceptible” to MS. Nevertheless, many haplotypes (both within the MHC and elsewhere) are unequivocally MS-associated and, yet, have population-frequencies of >20%. Such frequency-disparities underscore the complex-interactions that must occur between these “risk-haplotypes” and MS-susceptibility.DESIGN/MEHTODSThe WTCCC dataset was statistically-phased at the MHC and at three other susceptibility-regions. Haplotypes were stratified by their impact on “MS-risk”. MS-associations for different combinations of “risk-haplotypes” were assessed. The appropriateness of both additive and multiplicative risk-accumulation models was determined.RESULTSCombinations of different “risk-haplotypes” produced an MS-risk that was considerably closer to an additive model than a multiplicative model. Nevertheless, neither of these simple probability-models adequately accounted for the accumulation of disease-risk in MS at these four loci.CONCLUSIONS“Genetic-susceptibility” to MS seems to depend upon the exact state at each “risk-locus” and upon specific gene-gene combinations across loci. Moreover, “genetic-susceptibility” is both rare in the population and, yet, is a necessary condition for MS to develop in any individual. In this sense, MS is a “genetic” disease. Nevertheless although, “genetic-susceptibility” is a necessary condition for MS to develop, environmental factors (whatever these may be) and stochastic processes are also necessary determinants of whether a “genetically-susceptible” individual will actually get MS.Author SummaryDefining a “genetically-susceptible” individual to be any person in the population who has any chance of developing multiple sclerosis (MS), we demonstrate that, at a theoretical level and using widely-accepted epidemiological observations, only 2.2-4.5% of individuals in northern populations can possibly be “genetically susceptible” to MS. Thus, more than 95.5% of individuals in these populations have no chance of getting MS, regardless of the environmental circumstances that they may experience.Nevertheless, certain “susceptibility-haplotypes” (e.g., HLA-DRB1*15:01~DQB1*06:02) have a far greater carrier-frequency than 2.2-4.5%. Consequently, most carriers of these “susceptibility-haplotypes” have no chance of getting MS and, therefore, their “susceptibility” must arise from some combination of these haplotypes with other “susceptibility-haplotypes”. By analyzing such combinatorial impacts at four susceptibility-loci, we found significant interactions both within and between the different “susceptibility-haplotypes”, thereby confirming the relationship between “genetic-susceptibility” and specific gene-gene combinations.The nature of “genetic-susceptibility” developed here is applicable to other complex genetic disorders. Indeed, any disease for which the MZ-twin concordance rate is substantially greater than the life-time risk in the general population, only a small fraction of the population can possibly be in the “genetically-susceptible” subset (i.e., have any chance of developing the disease).

scholarly journals Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions

2020 ◽  
Author(s):  
Douglas S Goodin ◽  
Pouya Khankhanian ◽  
Pierre-Antoine Gourraud ◽  
Nicolas Vince
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Susceptibility ◽  
Risk Models ◽  
Snp Data ◽  
Extended Haplotypes ◽  
Multiplicative Risk

Abstract BACKGROUNDTo study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. MEHTODSWTCCC SNP-data was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01~DQB1*06:02~a1)-containing (H+); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different “risk-combinations” at the MHC and other non-MHC “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed.RESULTSDifferent combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H+)-haplotypes had greater impact when combined with (0)-haplotypes than with (H+)-haplotypes, whereas, (H+)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H+), (c1,H+), (H+,H+) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H+) and (AP,c1) were unaffected.CONCLUSIONSGenetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.

scholarly journals Genetic and Environmental Susceptibility to Multiple Sclerosis

2021 ◽  
Vol 9 (6) ◽  
Author(s):  
Douglas Goodin
Keyword(s):  
Multiple Sclerosis ◽  
Sex Ratio ◽  
Genetic Susceptibility ◽  
Environmental Exposure ◽  
Viral Infections ◽  
Life Time ◽  
Environmental Response ◽  
Response Curves ◽  
Male Sex ◽  
General Populations

OBJECTIVE: To explore the nature and basis of environmental and genetic susceptibility to multiple sclerosis (MS). BACKGROUND Susceptibility to multiple sclerosis (MS) is complex but clearly involves both environmental events and genetic factors. Certain epidemiological observations regarding MS (e.g., proportion of women among MS patients, population-prevalence of MS, impact of birth-month and migration patterns on the likelihood of MS, recurrence-risks for MS in siblings and twins, and time-dependent changes in MS-prevalence and the female to male sex-ratio) are well-established. DESIGN/METHODS: We define the “genetically-susceptible” subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive “non-susceptible” subset (G–). We consider the implications that these well-established epidemiological observations have regarding the genetic and environmental basis of susceptibility to MS. In addition, we use the change in the female to male sex ratio, observed over a 35-year interval in Canada, to construct the response curves relating an increasing likelihood of MS to an increasing probability of a susceptible individual experiencing an environmental exposure sufficient to cause MS. RESULTS: Environmental susceptibility to MS requires at least three different events – one occurring during the intrauterine or early post-natal period, another during childhood or adolescence, and a third (or more) many years later. Vitamin D deficiency and Epstein-Barr viral infections are likely involved. Moreover, we demonstrate that only a very small fraction of the general populations throughout Europe and North America is susceptible to MS. The vast majority of individuals in these populations has no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, only a small minority can possibly be members the (G) subset. Also, despite the preponderance of women among MS patients, compared to men, women are less likely to be susceptible and have a higher environmental threshold for developing MS. Nevertheless, the penetrance of MS in susceptible women is substantially greater than it is in men. Moreover, MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these response-curves plateau at under 50% for women and at a significantly lower level for men. CONCLUSIONS: The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population and requires specific combinations of non-additive genetic risk-factors. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the environmental response-curves (especially in men) plateau well below 50%, which indicates that disease pathogenesis is partially stochastic.

scholarly journals The nature of genetic and environmental susceptibility to multiple sclerosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0246157
Author(s):  
Douglas S. Goodin ◽  
Pouya Khankhanian ◽  
Pierre-Antoine Gourraud ◽  
Nicolas Vince
Keyword(s):  
Multiple Sclerosis ◽  
Sex Ratio ◽  
Genetic Susceptibility ◽  
Environmental Exposure ◽  
Life Time ◽  
Monozygotic Twin ◽  
Environmental Response ◽  
Genetic Associations ◽  
Response Curves ◽  
Epidemiological Parameters

Objective To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Background Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades. Design/Methods We define the “genetically-susceptible” subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive “non-susceptible” subset (G–). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure. Results We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men. Conclusions The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.

scholarly journals Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
D. S. Goodin ◽  
P. Khankhanian ◽  
P. A. Gourraud ◽  
N. Vince
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Susceptibility ◽  
Risk Models ◽  
Extended Haplotypes ◽  
Multiplicative Risk

Abstract Background To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. Methods The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different “risk-combinations” at the MHC and other non-MHC “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed. Results Different combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. Conclusions Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.

COX-2 promoter region polymorphisms in multiple sclerosis: lack of association of ?765G>C with disease risk

2007 ◽  
Vol 34 (2) ◽  
pp. 71-74 ◽  
Author(s):  
S. Mazzola ◽  
M. Gomez Lira ◽  
M. D. Benedetti ◽  
A. Salviati ◽  
S. Ottaviani ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Promoter Region ◽  
Disease Risk ◽  
Cox 2

scholarly journals Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

2020 ◽  
Author(s):  
James D. Hocker ◽  
Olivier B. Poirion ◽  
Fugui Zhu ◽  
Justin Buchanan ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Dependent Manner ◽  
Cardiac Cell ◽  
Risk Variants ◽  
Gene Regulatory

ABSTRACTBackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined.MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants.ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population

2015 ◽  
Vol 37 (12) ◽  
pp. 1060-1067 ◽  
Author(s):  
Jozef Michalik ◽  
Daniel Čierny ◽  
Ema Kantorová ◽  
Daniela Kantárová ◽  
Javor Juraj ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Susceptibility ◽  
Slovak Population

scholarly journals Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition

2020 ◽  
Vol 26 (14) ◽  
pp. 1816-1821 ◽  
Author(s):  
Clare Walton ◽  
Rachel King ◽  
Lindsay Rechtman ◽  
Wendy Kaye ◽  
Emmanuelle Leray ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Risk ◽  
Multiple Stakeholders ◽  
High Quality ◽  
World Region ◽  
Epidemiologic Data ◽  
Prevalence Estimates ◽  
Age Of Diagnosis ◽  
The Mean ◽  
Regional Analyses

Background: High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts. Objectives: The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels. Methods: Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis. Regional analyses and comparisons with 2013 data were conducted. Results: A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population). MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist. The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years. Females are twice as likely to live with MS as males. Conclusions: The global prevalence of MS has risen since 2013, but good surveillance data is not universal. Action is needed by multiple stakeholders to close knowledge gaps.

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