Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis

Güher Saruhan-Direskeneli; Travis Hughes; Vuslat Yilmaz; Hacer Durmus; Adam Adler; Mahdi Alahgholi-Hajibehzad; Fikret Aysal; Sibel P Yentür; Mehmet Ali Akalin; Oner Dogan; Alexander Marx; Yesim Gülsen-Parman; Piraye Oflazer; Feza Deymeer; Amr H Sawalha

doi:10.1016/j.clim.2016.05.003

Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis

Clin Immunol. 2016 May:166-167:81-8. doi: 10.1016/j.clim.2016.05.003. Epub 2016 May 12.

Authors

Affiliations

¹ Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey. Electronic address: gsaruhan@istanbul.edu.tr.
² Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Division of Health Science and Technology, Harvard Medical School, Boston, MA, USA.
³ Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
⁴ Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
⁵ Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁶ Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.
⁷ Department of Neurology, Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey.
⁸ Department of Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
⁹ Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁰ Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

PMID: 27181991
DOI: 10.1016/j.clim.2016.05.003

Abstract

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR=5.71 [3.77-8.66], P=2.24×10(-16)), HLA-B*08:01 (OR=7.04 [3.95-12.52], P=3.34×10(-11)) and HLA-C*07:01 (OR=2.74 [1.97-3.81], P=2.07(-9)), in LOMG, rs111256513 in the HLA class II region (OR=2.22 [1.59-3.09], P=2.48×10(-6)) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR=5.86, P=2.25×10(-14)) and HLA-DQB1*05:02 (OR=8.56, P=6.88×10(-13)) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.

Keywords: EOMG; Genome-wide association; LOMG; MuSK-MG; Myasthenia gravis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age of Onset
Alleles
Female
Gene Frequency
Genetic Heterogeneity*
Genetic Predisposition to Disease / genetics
Genome, Human / genetics
Genome-Wide Association Study / methods
Genotype
HLA-B Antigens / genetics
HLA-B Antigens / immunology*
HLA-C Antigens / genetics
HLA-C Antigens / immunology*
HLA-DQ beta-Chains / genetics
HLA-DQ beta-Chains / immunology*
Humans
Linkage Disequilibrium
Male
Myasthenia Gravis / epidemiology
Myasthenia Gravis / genetics
Myasthenia Gravis / immunology*
Polymorphism, Single Nucleotide
Receptor Protein-Tyrosine Kinases / immunology
Receptors, Cholinergic / immunology
Turkey / epidemiology

Substances

HLA-B Antigens
HLA-C Antigens
HLA-DQ beta-Chains
HLA-DQB1 antigen
Receptors, Cholinergic
MUSK protein, human
Receptor Protein-Tyrosine Kinases