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

D S Goodin1, P Khankhanian2, P A Gourraud3,4,5

  • 1Department of Neurology, University of California, UCSF MS Center, San Francisco 675 Nelson Rising Lane, Suite #221D, CA, 94158, San Francisco, USA. douglas.goodin@ucsf.edu.

BMC Medical Genomics
|July 11, 2021
PubMed
Abstract

Insights

Genetic susceptibility to multiple sclerosis (MS) risk is influenced by combinations of human leukocyte antigen (HLA) and non-HLA risk-haplotypes. Risk accumulation appears closer to additive, but interactions between specific haplotype combinations are crucial for MS development.

Area of Science:

  • Genetics
  • Immunology
  • Epidemiology

Background:

  • Multiple sclerosis (MS) risk is associated with specific human leukocyte antigen (HLA) conserved-extended-haplotypes (CEHs) and non-HLA risk-haplotypes near EOMES, ZFP36L1, and CLEC16A.
  • The high frequency of some MS-associated haplotypes in the general population necessitates understanding their risk accumulation patterns.

Purpose of the Study:

  • To investigate how combinations of MHC-CEHs and three non-MHC risk-haplotypes influence the accumulation of MS risk.
  • To assess the appropriateness of additive and multiplicative models for risk accumulation based on these genetic combinations.

Main Methods:

  • Phasing of single nucleotide polymorphism (SNP) data from the WTCCC cohort at the MHC and three non-MHC regions.
  • Classification of MHC CEHs into five groups: (HLA-DRB1*15:01~DQB1*06:02~a1)-containing (H+), extended-risk (ER), all-protective (AP), neutral (0), and single-CEH (c1).
  • Analysis of MS associations for various risk-haplotype combinations at the MHC and non-MHC loci.

Main Results:

  • Risk accumulation from combined "risk-haplotypes" more closely approximated additive than multiplicative models, though neither model perfectly fit the data.
  • The impact of (H+) haplotypes varied depending on co-occurring haplotypes; they had a greater effect with (0) than (H+) haplotypes, and with (c1) than (0) haplotypes.
  • Specific genotype combinations like (0,H+), (c1,H+), (H+,H+), and (0,c1) showed additive risk with non-MHC loci, while (ER,H+) and (AP,c1) genotypes were unaffected.

Conclusions:

  • Genetic susceptibility is necessary but not sufficient for MS development.
  • The specific combination of risk-haplotypes an individual carries, and their interactions, significantly determine the actual development of MS.
Keywords:
AdditiveCombinationEpidemiologyGeneticMultiple sclerosisMultiplicativeRiskSusceptibility

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