The genetics of multiple sclerosis: review of current and emerging candidates

Figures & data

Table 1 Non-HLA candidate genes found to be associated with multiple sclerosis

Chr	rsID	Putative gene of interest	Risk allele
1	rs4648356	MMEL1	C Previously identified
1	rs11810217	EVI5	A Previously identified
1	rs1335532	CD58	A Previously identified
1	rs1323292	RGS1	A Previously identified
1	rs7522462	KIF21B	G Previously identified
3	rs2028597	CBLB	G Previously identified
3	rs2293370	TMEM39A	G Previously identified
3	rs2243123	IL12A	G Previously identified
5	rs6897932	IL7R	G Previously identified
5	rs4613763	PTGER4	G Previously identified
6	rs13192841	OLIG3	A Previously identified
8	rs1520333	IL7	G Previously identified
10	rs3118470	IL2RA	G Previously identified
10	rs1250550	ZMIZ1	A Previously identified
11	rs650258	CD6	G Previously identified
12	rs1800693	TNFRSF1A	G Previously identified
12	rs12368653	CYP27B1	A Previously identified
12	rs949143	MPHOSPH9	G Previously identified
16	rs7200786	CLEC16A	A Previously identified
16	rs13333054	IRF8	A Previously identified
17	rs9891119	STAT3	C Previously identified
19	rs8112449	TYK2	G Previously identified
20	rs2425752	CD40	A Previously identified
1	rs11581062	VCAM1	G Novel independent
2	rs12466022	No gene	C Novel independent
2	rs7595037	PLEK	A Novel independent
2	rs17174870	MERTK	G Novel independent
2	rs10201872	SP140	A Novel independent
3	rs11129295a	EOMES	A Novel independent
3	rs669607	No gene	C Novel independent
3	rs9282641	CD86	G Novel independent
5	rs2546890	IL12B	A Novel independent
6	rs12212193	BACH2	G Novel independent
6	rs802734	THEMIS	A Novel independent
6	rs11154801	MYB	A Novel independent
6	rs17066096	IL22RA2	G Novel independent
6	rs1738074	TAGAP	G Novel independent
7	rs354033	ZNF746	G Novel independent
8	rs4410871	MYC	G Novel independent
8	rs2019960b	PVT1	G Novel independent
10	rs7923837	HHEX	G Novel independent
12	rs10466829	CLECL1	A Novel independent
14	rs4902647	ZFP36L1	G Novel independent
14	rs2300603	BATF	A Novel independent
14	rs2119704	GALC	C Novel independent
18	rs7238078	MALT1	A Novel independent
19	rs1077667	TNFSF14	G Novel independent
19	rs874628	MPV17L2	A Novel independent
19	rs2303759	DKKL1	C Novel independent
20	rs2248359	CYP24A1	G Novel independent
22	rs2283792	MAPK1	C Novel independent
22	rs140522	SCO2	A Novel independent
4	rs228614	NFKB1	G Novel independent
11	rs630923	CXCR5	C Novel independent
16	rs2744148	SOX8	G Novel independent
17	rs180515	RPS6KB1	G Novel independent
20	rs6062314	TNFRSF6B	A Novel independent

Adapted with permission from Macmillan Publishers Ltd: wellcome Trust Case Control Consortium, Sawcer S, Hellenthal G, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219.9⁹

Table 2 Summary of microRNA (miRNA)-expression studies carried out both in patients and in an experimental autoimmune encephalomyelitis (EAE) model

Paper	Sample	Tissue	Technique	Number of analyzed miRNA	Dysregulated miRNA†	Experimentally validated target	Function
Blood
Otaegui et al^Citation60	DC: 4 relapsing MS, 9 remitting MS, 8 HC. VC: 4 relapsing MS, 3 remitting MS, 7 HC	PBMCs	qPCR (TLDA)	364	miR-18b, miR-599, miR-96
Keller et al^Citation61	20 RRMS, 19 HC	Whole blood	Microarrays	866	miR-145, miR-186, miR-664, miR-20b, miR-422a, miR-142–3p, miR-584, miR-223, miR-1275, miR-491-5p
Du et al^Citation55	25 relapsing MS, 18 remitting MS, 42 HC, 11 NMO	Peripheral blood leucocytes	qPCR	7	miR-326	Ets-1	Promote TH-17 differentiation
Lindberg et al^Citation62	DC: 8 RRMS, 10 HC. VC: 15 RRMS, 10 HC	CD4^+ T cells, CD8^+ T cells, B cells	qPCR (TLDA)	365	CD4^+: miR-485-3p, miR-376a, miR-497, miR-193a, miR-126, miR-17-5p, miR-34a. CD8^+¥: miR-629, miR-30a-3p, miR-149, miR-497. B cells¥: miR-497, miR-92, miR-135b, miR-153, miR-189, miR-422a
Cox et al^Citation63	59 RRMS, 37 HC	Whole blood	Microarrays and qPCR	733	miR-17, miR-20a
De Santis et al^Citation64	DC: 12 MS, 14 HC. VC: 10 MS, 10 HC	CD4^+CD25^+ T cells	Microarrays	723	miR-29c, miR-107, miR-210, let-7i, miR-15a, miR-19a, miR-19b, miR-138-2*, miR-324-3p, miR-301a, miR-338-5p, miR-22, miR-512-3p, miR-564, miR-886-3p, miR-106b, miR-29a, miR-93, miR-489, miR-148a, miR-590-5p, miR-223, miR-221
Guerau-de-Arellano et al^Citation65	5 PPMS, 12 RRMS, 5 SPMS, 16 HC	CD4^+ T cells	qPCR (TLDA)	667	miR-128, miR-27b, miR-340	miR-128 and miR-27b → BMI, miR-340 → IL-4	Inhibit TH2 cell differentiation and contribute to proinflammatory TH1 response
Fenoglio et al^Citation66	16 relapsing MS, 6 SPMS, 7 PPMS, 19 HC	PBMCs	qPCR	5	miR-21, miR-146a, miR-146b
Boneschi et al^Citation67	DC: 7 RRMS, 6 SPMS, 6 PPMS, 14 HC. VC: 5 RRMS, 2 SPMS, 3 PPMS, 10 HC	PBMCs	Microarrays and qPCR	1145	let-7g, miR-150
Siegel et al^Citation68	4 MS, 4 HC	Plasma	Microarrays	>900	miR-614, miR-572, miR-1979, miR-648, miR-422a, miR-1826, miR-22
Paraboschi et al^Citation69	10 MS, 10 HC	PBMCs	Microbead-based technology	22	miR-155
Sievers et al^Citation70	DC: 10 untreated RRMS, 10 NTZ treated RRMS, 10 HC. VC: 30 RRMS, 7 HC	B cells	Microarrays and qPCR	1059	miR-106b, miR-19b, miR-181a
Brain
Junker et al^Citation57	20 MS, 9 HC	Active and inactive white matter MS brain lesions	qPCR	365	miR-155, miR-130a, miR-30a-3p, miR-23a, miR-199a*, miR-152, miR-l46b, miR-650, miR-326	miR-155, miR-326 and miR-34a → CD47	Downregulation of CD47 in brain resident cells promotes macrophage phagocytosis of myelin
CSF
Haghikia et al^Citation71	17 RRMS, 30 SPMS, 6 PPMS, 39 OND	CSF	qPCR	760	miR-922, miR-633, miR-181c
EAE
Ponomarev et al^Citation72	4–5 mice	Peripheral macrophages and microglia	qPCR	31	miR-124	C/EBP-α	Transform macrophages from an activated into a quiescent phenotype. Administration of miR-124 during preclinical stage prevented disease symptoms
Murugaiyan et al^Citation58	8 mice	CD4^+ T cells (spleen, lymph node, CNS)	qPCR		miR-155		Induce expression of cytokines needed for TH1 and TH 17 cell response
Zhu et al^Citation56	2 mice	Inflammatory lesions	qPCR	641	miR-23b, miR-30a, miR-146a, miR-214	miR-23b → TAB2, TAB3, IKK	Repress autoimmune inflammation
Lescher et al^Citation73	20 EAE, 10 WT mice	Spinal cord	qPCR (TLDA)	586	miR-155, miR-326, miR-142-3p, miR-146a, miR-146b, miR-21, miR-184, miR-19a
Guan et al^Citation59	WT, CD44 KO mice	CD4^+ T cells	Microarrays and qPCR	609	let-7e	IL-10	Modulation of TH differentiation and development of EAE

Notes:

† Only validated miRNAs or the most remarkable ones in each study have been listed.

¥ Not validated

Abbreviations: DC, discovery cohort; VC, validation cohort; OND, other neurological diseases; PPMS, primary progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; HC, healthy controls; EAE, experimental autoimmune encephalomyelitis; WT, wild-type; KO, knockout; CNS, central nervous system; CSF, cerebrospinal fluid; NTZ, Natalizumab; PBMC, peripheral blood mononuclear cells; qPCR, quantitative polymerase chain reaction; TLDA, TaqMan Low Density Arrays.

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