High Resolution HLA Analysis Reveals Independent Class I Haplotypes and Amino-acid Motifs Protective for Multiple Sclerosis

Overview

Journal Genes Immun

Date 2018 Jan 9

PMID 29307888

Citations 9

Authors

Steven J Mack

Julia Udell

Franziska Cohen

Kazutoyo Osoegawa

Sharon K Hawbecker

David A Noonan

Martha B Ladner

Damian Goodridge

Elizabeth A Trachtenberg

Jorge R Oksenberg

Henry A Erlich

Affiliations

Soon will be listed here.

Abstract

We investigated association between HLA class I and class II alleles and haplotypes, and KIR loci and their HLA class I ligands, with multiple sclerosis (MS) in 412 European American MS patients and 419 ethnically matched controls, using next-generation sequencing. The DRB1*15:01~DQB1*06:02 haplotype was highly predisposing (odds ratio (OR) = 3.98; 95% confidence interval (CI) = 3-5.31; p-value (p) = 2.22E-16), as was DRB1*03:01~DQB1*02:01 (OR = 1.63; CI = 1.19-2.24; p = 1.41E-03). Hardy-Weinberg (HW) analysis in MS patients revealed a significant DRB1*03:01~DQB1*02:01 homozyote excess (15 observed; 8.6 expected; p = 0.016). The OR for this genotype (5.27; CI = 1.47-28.52; p = 0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C*03:04~B*40:01 haplotype (OR = 0.27; CI = 0.14-0.51; p = 6.76E-06) was highly protective for MS, especially in haplotypes with A*02:01 (OR = 0.15; CI = 0.04-0.45; p = 6.51E-05). By itself, A*02:01 is moderately protective, (OR = 0.69; CI = 0.54-0.87; p = 1.46E-03), and haplotypes of A*02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (OR = 0.53; CI = 0.35-0.78; p = 7.55E-04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB1*15:01, but the Bw4T variant was protective (OR = 0.64; CI = 0.49-0.82; p = 3.37-04) independent of LD with DRB1*15:01. The Bw4I variant was not associated with MS. Overall, we find specific class I HLA polymorphisms to be protective for MS, independent of the strong predisposition conferred by DRB1*15:01.

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References

Brassat D, Salemi G, Barcellos L, McNeill G, Proia P, Hauser S . The HLA locus and multiple sclerosis in Sicily. Neurology. 2005; 64(2):361-3. DOI: 10.1212/01.WNL.0000149765.71212.0A. View

Hansasuta P, Dong T, Thananchai H, Weekes M, Willberg C, Aldemir H . Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur J Immunol. 2004; 34(6):1673-9. DOI: 10.1002/eji.200425089. View

Jelcic I, Hsu K, Kakalacheva K, Breiden P, Dupont B, Uhrberg M . Killer immunoglobulin-like receptor locus polymorphisms in multiple sclerosis. Mult Scler. 2011; 18(7):951-8. DOI: 10.1177/1352458511431726. View

Andersson G . Evolution of the human HLA-DR region. Front Biosci. 1998; 3:d739-45. DOI: 10.2741/a317. View

Fusco C, Guerini F, Nocera G, Ventrella G, Caputo D, Valentino M . KIRs and their HLA ligands in remitting-relapsing multiple sclerosis. J Neuroimmunol. 2010; 229(1-2):232-7. DOI: 10.1016/j.jneuroim.2010.08.004. View

Yeo T, De Jager P, Gregory S, Barcellos L, Walton A, Goris A . A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol. 2007; 61(3):228-36. PMC: 2737610. DOI: 10.1002/ana.21063. View

Shi F, Takeda K, Akira S, Sarvetnick N, Ljunggren H . IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-gamma by NK cells. J Immunol. 2000; 165(6):3099-104. DOI: 10.4049/jimmunol.165.6.3099. View

Dyment D, Herrera B, Cader M, Willer C, Lincoln M, Sadovnick A . Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet. 2005; 14(14):2019-26. DOI: 10.1093/hmg/ddi206. View

Bergamaschi L, Leone M, Fasano M, Guerini F, Ferrante D, Bolognesi E . HLA-class I markers and multiple sclerosis susceptibility in the Italian population. Genes Immun. 2009; 11(2):173-80. PMC: 2834350. DOI: 10.1038/gene.2009.101. View

10.

Trachtenberg E, Holcomb C . Next-generation HLA sequencing using the 454 GS FLX system. Methods Mol Biol. 2013; 1034:197-219. PMC: 4196724. DOI: 10.1007/978-1-62703-493-7_10. View

11.

Raychaudhuri S, Sandor C, Stahl E, Freudenberg J, Lee H, Jia X . Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012; 44(3):291-6. PMC: 3288335. DOI: 10.1038/ng.1076. View

12.

Brynedal B, Duvefelt K, Jonasdottir G, Roos I, Akesson E, Palmgren J . HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One. 2007; 2(7):e664. PMC: 1919434. DOI: 10.1371/journal.pone.0000664. View

13.

Mayo L, Quintana F, Weiner H . The innate immune system in demyelinating disease. Immunol Rev. 2012; 248(1):170-87. PMC: 3383669. DOI: 10.1111/j.1600-065X.2012.01135.x. View

14.

Chen J, Hollenbach J, Trachtenberg E, JUST J, Carrington M, Ronningen K . Hardy-Weinberg testing for HLA class II (DRB1, DQA1, DQB1, and DPB1) loci in 26 human ethnic groups. Tissue Antigens. 2000; 54(6):533-42. DOI: 10.1034/j.1399-0039.1999.540601.x. View

15.

Backstrom E, Chambers B, Kristensson K, Ljunggren H . Direct NK cell-mediated lysis of syngenic dorsal root ganglia neurons in vitro. J Immunol. 2000; 165(9):4895-900. DOI: 10.4049/jimmunol.165.9.4895. View

16.

WINTER C, Gumperz J, Parham P, Long E, Wagtmann N . Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol. 1998; 161(2):571-7. View

17.

Goris A, van Setten J, Diekstra F, Ripke S, Patsopoulos N, Sawcer S . No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis. Hum Mol Genet. 2013; 23(7):1916-22. PMC: 3943520. DOI: 10.1093/hmg/ddt574. View

18.

Thomson G, Single R . Conditional asymmetric linkage disequilibrium (ALD): extending the biallelic r2 measure. Genetics. 2014; 198(1):321-31. PMC: 4174944. DOI: 10.1534/genetics.114.165266. View

19.

Barcellos L, Sawcer S, Ramsay P, Baranzini S, Thomson G, Briggs F . Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet. 2006; 15(18):2813-24. DOI: 10.1093/hmg/ddl223. View

20.

Cocco E, Sardu C, Pieroni E, Valentini M, Murru R, Costa G . HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia. PLoS One. 2012; 7(4):e33972. PMC: 3324467. DOI: 10.1371/journal.pone.0033972. View