Genetic variant rs763361 regulates multiple sclerosis CD226 gene expression

In a recent study, Gross et al. investigate the presence, distribution, and function of natural killer (NK) cells in three different compartments to characterize the role of NK cells in multiple sclerosis (MS) (1). Their results indicate that NK cells played an important role in controlling T-cell activity in vivo. In addition, Gross et al. found reduced expression of the activating NK-cell receptor DNAM-1 (CD226) in MS. Gross et al. compare their findings to those from human genetic-association studies. Interestingly, a nonsynonymous variant, Gly307Ser (rs763361), in the CD226 gene was identified to be significantly associated with several autoimmune diseases, including MS, which further supported Gross et al.’s findings as described in their discussion (1, 2). The authors conclude that the higher threshold for NK-cell activation is attributable to the reduced CD226 expression and rs763361 variant (1). However, it is still unclear whether rs763361 could affect CD226 signaling and further affect NK-cell function, as Gross et al. describe in their discussion (1). Thus, this question above prompts us to investigate their findings further.

In human genetic studies, evidence shows that genetic variants could modify gene expression and cause disease risk. Gross et al. report the reduced CD226 expression in MS (1). We thus investigated whether rs763361 could affect CD226 expression. Here, we evaluate the potential association between rs763361 variant and CD226 expression using six large-scale expression quantitative trait loci (eQTLs) datasets (3–8), which are included in the human genotype–phenotype association database PhenoScanner. Interestingly, we found that rs763361 could significantly regulate CD226 expression in blood, liver, lymphoblastoid cell lines, and peripheral blood mononuclear cells, as described in Table 1 (P < 0.05).

Table 1.

rs763361 T allele and CD226 expression in eight eQTLs datasets

Datasets/source	Samples	Effect allele	β	P value	Gene	Tissues
(3)	5,311	T	< 0 (z = −14.92)	2.44E-50	CD226	Peripheral blood
(4)	3,255	T	−0.18	1.40E-10	CD226	Blood
(5)	2,318	NA	NA	9.83E-10	CD226	Liver
(6)	373	NA	NA	5.31E-06	CD226	Lymphoblastoid cell lines
(7)	173	NA	NA	2.16E-04	CD226	Peripheral blood mononuclear cells
(8)	777	T	−0.0976	1.70E-03	CD226	Lymphoblastoid cell lines
GTEx	157	T	−0.5585	3.25E-09	CD226	Testis
GTEx	100	T	−0.3676	1.86E-03	CD226	Brain_Caudate_basal_ganglia
GTEx	298	T	−0.2012	2.93E-03	CD226	Adipose_s.c.
GTEx	93	T	−0.2858	5.52E-03	CD226	Brain_Nucleus_accumbens_basal_ganglia
GTEx	114	T	−0.2912	5.82E-03	CD226	Cells_EBV-transformed_lymphocytes
GTEx	272	T	−0.2113	7.72E-03	CD226	Cells_Transformed_fibroblasts
GTEx	285	T	−0.1981	9.03E-03	CD226	Artery_Tibial
GTEx	190	T	−0.2487	1.11E-02	CD226	Heart_Left_Ventricle
GTEx	96	T	−0.3462	1.32E-02	CD226	Brain_Cortex
GTEx	103	T	−0.3354	1.42E-02	CD226	Brain_Cerebellum
GTEx	185	T	−0.1954	1.88E-02	CD226	Adipose_Visceral_Omentum
GTEx	82	T	−0.3077	1.90E-02	CD226	Brain_Putamen_basal_ganglia
GTEx	302	T	−0.1547	3.26E-02	CD226	Skin_Sun_Exposed_Lower_leg
GTEx	159	T	−0.2453	3.29E-02	CD226	Heart_Atrial_Appendage
Braineac	134	T	−0.1867	3.42E-02	CD226	Brain thalamus
Braineac	134	T	−0.0795	3.99E-02	CD226	Brain medulla
Braineac	134	T	−0.0873	4.64E-02	CD226	Brain intralobular white matter

NA, not available; rs763361 position (hg19), 18_67531642_T_C; significance level for a potential association is 0.05; β Is the regression coefficient based on the effect allele. β > 0 and β < 0 means that this effect allele regulates increased and reduced gene expression, respectively. z score = effect (β)/SE.

In the original study, Hafler et al. (2) identified the rs763361 T allele to be associated with increased risk for multiple autoimmune diseases, including type 1 diabetes [odds ratio (OR) = 1.13, and P = 1.32E-08], MS (OR = 1.14, P = 4.20E-04), and rheumatoid arthritis (OR = 1.09, and P = 1.70E-02). However, the effect allele and the direction of this association (β) between rs763361 and CD226 expression are not available in the PhenoScanner database. We further selected another two eQTL datasets from the Genotype-Tissue Expression (GTEx) project (v6) (9), and the Brain eQTLs Almanac (Braineac) from the United Kingdom Brain Expression Consortium (10). Interestingly, we identified that the rs763361 T allele could significantly regulate and only regulate reduced CD226 expression in 14 tissues in the GTEx dataset, and 3 brain tissues in the Braineac dataset with β > 0 and P < 0.05, as described in Table 1.

Taking these data together, we find that Gross et al. highlight the decreased expression of activating NK-cell receptor CD226 in MS, and further support their findings using the evidence from human genetic-association studies (1). Here, following these findings, we show that the rs763361 T allele could reduce CD226 expression and contribute to the increased autoimmune disease risk. We believe that our findings provide important supplementary information about the potential mechanisms that rs763361 affects CD226 signaling, as well as NK-cell function.