Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.
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ABSTRACT:
SUBMITTER: Oksenberg JR
PROVIDER: S-EPMC1181903 | biostudies-literature | 2004 Jan
REPOSITORIES: biostudies-literature
Publications
Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.
Oksenberg Jorge R JR Barcellos Lisa F LF Cree Bruce A C BA Baranzini Sergio E SE Bugawan Teodorica L TL Khan Omar O Lincoln Robin R RR Swerdlin Amy A Mignot Emmanuel E Lin Ling L Goodin Douglas D Erlich Henry A HA Schmidt Silke S Thomson Glenys G Reich David E DE Pericak-Vance Margaret A MA Haines Jonathan L JL Hauser Stephen L SL
American journal of human genetics 20031210 1
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 wit ...[more]
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Project description:Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.
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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.
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Project description:Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene-gene interactions and disease susceptibility in a well-characterized African-American case-control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75-76% accuracy (P<0.01). These results demonstrate the importance of exploring both main effects and gene-gene interactions in the study of complex diseases.
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Project description:To evaluate whether vitamin D is associated with multiple sclerosis (MS) status and disease severity in African Americans.Serum 25-hydroxyvitamin D was compared in a cross-sectional sample of 339 African Americans with MS and 342 African American controls. Correlations between disease severity (Multiple Sclerosis Severity Score [MSSS]) and 25-hydroxyvitamin D levels were sought.A total of 71% of controls and 77% of patients with MS were vitamin D deficient (<50 nmol/L; <20 ng/mL), and 93% of controls and 94% of patients with MS were vitamin D insufficient (<75 nmol/L; <30 ng/mL). Median unadjusted (29.7 vs 36.6 nmol/L, p = 0.0001) and deseasonalized (p = 0.0013) 25-hydroxyvitamin D levels were lower in the MS group. Multivariable analysis revealed that differences in latitude and ultraviolet index accounted for much of this association. The median (interquartile range) MSSS was 6.1 (4.8-8.1). There was no apparent association between the MSSS and vitamin D status. A greater proportion of European genetic ancestry, a measure of genetic admixture, was positively correlated with 25-hydroxyvitamin D (p = 0.007).Levels of 25-hydroxyvitamin D were lower in African Americans with MS than controls, an observation primarily explained by differences in climate and geography. There was no apparent association between vitamin D status and disease severity. These results are consistent with observations in other populations that lower 25-hydroxyvitamin D is associated with having MS, but also highlight the importance of climate and ancestry in determining vitamin D status.
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