Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill A.; Cree, Bruce A.C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

doi:10.1001/jamaneurol.2016.0980

Cited by 69 publications

(74 citation statements)

References 33 publications

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“…Individuals who are HLA-DRB1*15:01 homozygotes carry a high-risk genotype with ORs exceeding 7.0, compared to a range between 3.5 and 5.0 for heterozygotes HLA-DRB1*15:01 / X . In addition to risk, HLA-DRB1*15:01 has been associated with phenotypic markers of disease severity [89]. A decade long effort of genomic screens provided statistical evidence for over 30 independent allelic and genetic associations within the extended MHC region.…”

Section: Mhc Boxmentioning

confidence: 99%

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

2017

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Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple GWAS in the last 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk to MS is driven by multiple common variants whose biological effects are not immediately clear. This review will present a historical perspective on the progress made on MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes.

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Section: Mhc Boxmentioning

confidence: 99%

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

2017

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“…Given previous reports of greater risk effects of DR15 in female patients with multiple sclerosis (MS) [44] and the stronger effect of APOE ɛ4 in females [45], we assessed whether men versus women showed similar or different HLA haplotype associations with AD risk. When split by sex, two of the three most significant five-allele haplotypes from the combined sex analysis were significant in an individual sex.…”

Section: Resultsmentioning

confidence: 99%

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

et al. 2017

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BackgroundAlzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.Methods and findingsBuilding on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10−4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also asso...

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“…We calculated the cumulative HLA genetic burden (HLAGB) resulting from carrying different alleles in different HLA genes in 652 MS patients who had comprehensive phenotypic information and 455 controls of European descent. As suggested by previous studies, we found that higher HLAGB scores are associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with RR-MS. Conversely, HLA-B*44:02 showed a nominally protective effect for subcortical gray matter atrophy (37).…”

Section: Genotype-phenotype Correlations In Msmentioning

confidence: 96%

The Genetics of Multiple Sclerosis

Didonna

Oksenberg

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by focal inflammation, demyelination, and axonal injury. The etiology of MS is still uncertain, but the most updated working model for disease pathogenesis proposes the interplay between genetic and environmental factors as necessary for MS manifestation. With the notable exception of the major histocompatibility complex (MHC), the identity of MS genetic determinants has been elusive for decades. In recent years, the advent of genome-wide association studies (GWAS) and collaborative efforts among international centers have fueled the characterization of several non-MHC loci associated with MS susceptibility. To date, after a number of GWAS screenings, 110 MS risk variants have been discovered outside the MHC locus in European populations. In the future, functional studies will be required to define the biological pathways and cellular activities connected to these variants.

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Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

Cited by 69 publications

References 33 publications

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

The Genetics of Multiple Sclerosis

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