IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients.
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ABSTRACT:
SUBMITTER: Couturier N
PROVIDER: S-EPMC2947096 | biostudies-literature | 2009 Jun
REPOSITORIES: biostudies-literature
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IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients.
Couturier Nicolas N Gourraud Pierre-Antoine PA Cournu-Rebeix Isabelle I Gout Claire C Bucciarelli Florence F Edan Gilles G Babron Marie-Claude MC Clerget-Darpoux Françoise F Clanet Michel M Fontaine Bertrand B Brassat David D
European journal of human genetics : EJHG 20090121 6
A recent investigation reported, for the first time, an association between variants in the IFIH1-GCA-KCNH7 locus and multiple sclerosis (MS). We sought to replicate this genetic association in MS with a new independent MS cohort composed of French Caucasian MS trio families. The two most significant IFIH1 single nucleotide polymorphisms, rs1990760 and rs2068330, reported as involved in MS susceptibility, were genotyped in 591 French Caucasian MS trio families, and analyzed using the transmissio ...[more]
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Project description:ObjectiveVariation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.MethodsUsing a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.ResultsScreening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).InterpretationVariation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.
| S-EPMC2737610 | biostudies-literature
Project description:ObjectiveTo explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.BackgroundRecently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort.Design/methodsThe African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms.ResultsOf the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)-similar to that observed in the WTCCC (OR = 3.25; p<10-168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)-again, similar to the WTCCC (OR = 2.2; p<10-38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs.ConclusionsThe common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"-perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.
| S-EPMC8352072 | biostudies-literature
Project description:An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.
| S-EPMC1181903 | biostudies-literature
Project description:Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.
| S-EPMC5391720 | biostudies-literature
Project description:CONTEXT:A recent large-scale analysis of nonsynonymous coding polymorphisms showed strong evidence that an alanine to threonine amino acid change at codon 946 of the interferon-induced helicase (IFIH1) gene (SNP ID rs1990760) was associated with type 1 diabetes. Previous investigations have also demonstrated that an intronic polymorphism (termed PD1.3; SNP ID rs11568821) in the programmed cell death (PDCD1) gene was associated with systemic lupus erythematosus and rheumatoid arthritis. OBJECTIVE:We sought to replicate these genetic associations in Graves' disease and autoimmune Addison's disease patient cohorts. PATIENTS AND METHODS:A total of 602 Graves' disease subjects, 214 Addison's disease subjects, and 446 healthy controls were genotyped for the IFIH1 and PDCD1 single-nucleotide polymorphisms using mass spectrometer analysis of primer extension products (Sequenom). RESULTS:The alanine-carrying allele at the IFIH1 codon 946 polymorphism was present in 796 of 1204 (66%) Graves' disease patient alleles compared with 508 of 892 (57%) control subject alleles [odds ratio 1.47 (5-95% confidence interval, 1.23-1.76); P = 1.9 x 10(-5)]. In contrast, there was no association of alleles at this marker in autoimmune Addison's disease. Neither was there evidence for association in either patient cohort at the PD1.3 polymorphism. CONCLUSIONS:We confirm a significant contribution of the Ala946Thr IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves' disease. This polymorphism may also contribute to several other autoimmune disorders.
| S-EPMC6952273 | biostudies-literature
Project description:ObjectiveTo understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases.BackgroundCertain 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/methodsWe 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.ResultsWe 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.ConclusionsThe 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.
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Project description:Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS.We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls.Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set.The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease.
| S-EPMC3661208 | biostudies-literature
Project description:To apply quantitative susceptibility mapping (QSM) in the basal ganglia of patients with multiple sclerosis (MS) and relate the findings to R2* mapping with regard to the sensitivity for clinical and morphologic measures of disease severity.The local ethics committee approved this study, and all subjects gave written informed consent. Sixty-eight patients (26 with clinically isolated syndrome, 42 with relapsing-remitting MS) and 23 control subjects underwent 3-T magnetic resonance (MR) imaging. Susceptibility and R2* maps were reconstructed from the same three-dimensional multiecho spoiled gradient-echo sequence. Mean susceptibilities and R2* rates were measured in the basal ganglia and were compared between different phenotypes of the disease (clinically isolated syndrome, MS) and the control subjects by using analysis of variance, and regressing analysis was used to identify independent predictors.Compared with control subjects, patients with MS and clinically isolated syndrome had increased (more paramagnetic) magnetic susceptibilities in the basal ganglia. R2* mapping proved less sensitive than QSM regarding group differences. The strongest predictor of magnetic susceptibility was age. Susceptibilities were higher with increasing neurologic deficits (r = 0.34, P < .01) and lower with normalized volumes of gray matter (r = -0.35, P < .005) and the cortex (r = -0.35, P < .005).QSM provides superior sensitivity over R2* mapping in the detection of MS-related tissue changes in the basal ganglia. With QSM but not with R2* mapping, changes were already observed in patients with clinically isolated syndrome, which suggests that QSM can serve as a sensitive measure at the earliest stage of the disease.
| S-EPMC3632806 | biostudies-other
Project description:Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large data sets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. in Nat Genet 39(9):1083-1091, 2007; International Multiple Sclerosis Genetics Consortium in N Engl J Med 357(9):851-862, 2007; Lundmark in Nat Genet 39(9):1108-1113, 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. in Nat Genet 39(9):1083-1091, 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control data sets, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control data set (4,831 samples) with joint p values as high as 8.29 x 10(-6) and 3.48 x 10(-7), respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p values reaching 3.47 x 10(-4), and BCL2 with p values reaching 4.32 x 10(-4). The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.
| S-EPMC2854871 | biostudies-literature
Project description:BACKGROUND: MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors. METHODS: A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America. RESULTS: For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ? 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely. CONCLUSIONS: The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (? 5.2%) are even susceptible to getting MS.
| S-EPMC2994805 | biostudies-literature