LETTER
LETTER
Genetic variant rs763361 regulates multiple sclerosis CD226 gene expression Guiyou Liua,1, Yang Hua,1, Shuilin Jinb, and Qinghua Jianga,2
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).
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 NKcell function.
Acknowledgments This work was supported by funding from the National Nature Science Foundation of China (Grants 61571152 and 81300945), and the Major State Research Development Program of China (2016YFC1202302).
a
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China; and bDepartment of Mathematics, School of Science, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China Author contributions: G.L., Y.H., S.J., and Q.J. designed research, performed research, contributed new reagents/analytic tools, analyzed data, and wrote the paper. The authors declare no conflict of interest. 1 G.L. and Y.H. contributed equally to this work. 2 To whom correspondence should be addressed. Email: [email protected].
E906–E907 | PNAS | February 7, 2017 | vol. 114 | no. 6
www.pnas.org/cgi/doi/10.1073/pnas.1618520114
Table 1. rs763361 T allele and CD226 expression in eight eQTLs datasets Datasets/source (3) (4) (5) (6) (7) (8) GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx Braineac Braineac Braineac
Samples
Effect allele
β
P value
Gene
Tissues
5,311 3,255 2,318 373 173 777 157 100 298 93 114 272 285 190 96 103 185 82 302 159 134 134 134
T T NA NA NA T T T T T T T T T T T T T T T T T T
< 0 (z = −14.92) −0.18 NA NA NA −0.0976 −0.5585 −0.3676 −0.2012 −0.2858 −0.2912 −0.2113 −0.1981 −0.2487 −0.3462 −0.3354 −0.1954 −0.3077 −0.1547 −0.2453 −0.1867 −0.0795 −0.0873
2.44E-50 1.40E-10 9.83E-10 5.31E-06 2.16E-04 1.70E-03 3.25E-09 1.86E-03 2.93E-03 5.52E-03 5.82E-03 7.72E-03 9.03E-03 1.11E-02 1.32E-02 1.42E-02 1.88E-02 1.90E-02 3.26E-02 3.29E-02 3.42E-02 3.99E-02 4.64E-02
CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226
Peripheral blood Blood Liver Lymphoblastoid cell lines Peripheral blood mononuclear cells Lymphoblastoid cell lines Testis Brain_Caudate_basal_ganglia Adipose_s.c. Brain_Nucleus_accumbens_basal_ganglia Cells_EBV-transformed_lymphocytes Cells_Transformed_fibroblasts Artery_Tibial Heart_Left_Ventricle Brain_Cortex Brain_Cerebellum Adipose_Visceral_Omentum Brain_Putamen_basal_ganglia Skin_Sun_Exposed_Lower_leg Heart_Atrial_Appendage Brain thalamus Brain medulla 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.
1 Gross CC, et al. (2016) Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation. Proc Natl Acad Sci USA 113(21):E2973–E2982. 2 Hafler JP, et al.; International Multiple Sclerosis Genetics Consortium (IMSGC) (2009) CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun 10(1):5–10. 3 Westra HJ, et al. (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45(10):1238–1243. 4 Fehrmann RS, et al. (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7(8):e1002197. 5 Greenawalt DM, et al. (2011) A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res 21(7): 1008–1016. 6 Lappalainen T, et al.; Geuvadis Consortium (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501(7468):506–511. 7 Heinzen EL, et al. (2008) Tissue-specific genetic control of splicing: Implications for the study of complex traits. PLoS Biol 6(12):e1. 8 Grundberg E, et al.; Multiple Tissue Human Expression Resource (MuTHER) Consortium (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44(10):1084–1089. 9 Anonymous; GTEx Consortium (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 348(6235):648–660. 10 Ramasamy A, et al.; UK Brain Expression Consortium; North American Brain Expression Consortium (2014) Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 17(10):1418–1428.
Liu et al.
PNAS | February 7, 2017 | vol. 114 | no. 6 | E907
LETTER
Genetic variant rs763361 regulates multiple sclerosis CD226 gene expression Guiyou Liua,1, Yang Hua,1, Shuilin Jinb, and Qinghua Jianga,2
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).
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 NKcell function.
Acknowledgments This work was supported by funding from the National Nature Science Foundation of China (Grants 61571152 and 81300945), and the Major State Research Development Program of China (2016YFC1202302).
a
School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China; and bDepartment of Mathematics, School of Science, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China Author contributions: G.L., Y.H., S.J., and Q.J. designed research, performed research, contributed new reagents/analytic tools, analyzed data, and wrote the paper. The authors declare no conflict of interest. 1 G.L. and Y.H. contributed equally to this work. 2 To whom correspondence should be addressed. Email: [email protected].
E906–E907 | PNAS | February 7, 2017 | vol. 114 | no. 6
www.pnas.org/cgi/doi/10.1073/pnas.1618520114
Table 1. rs763361 T allele and CD226 expression in eight eQTLs datasets Datasets/source (3) (4) (5) (6) (7) (8) GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx GTEx Braineac Braineac Braineac
Samples
Effect allele
β
P value
Gene
Tissues
5,311 3,255 2,318 373 173 777 157 100 298 93 114 272 285 190 96 103 185 82 302 159 134 134 134
T T NA NA NA T T T T T T T T T T T T T T T T T T
< 0 (z = −14.92) −0.18 NA NA NA −0.0976 −0.5585 −0.3676 −0.2012 −0.2858 −0.2912 −0.2113 −0.1981 −0.2487 −0.3462 −0.3354 −0.1954 −0.3077 −0.1547 −0.2453 −0.1867 −0.0795 −0.0873
2.44E-50 1.40E-10 9.83E-10 5.31E-06 2.16E-04 1.70E-03 3.25E-09 1.86E-03 2.93E-03 5.52E-03 5.82E-03 7.72E-03 9.03E-03 1.11E-02 1.32E-02 1.42E-02 1.88E-02 1.90E-02 3.26E-02 3.29E-02 3.42E-02 3.99E-02 4.64E-02
CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226 CD226
Peripheral blood Blood Liver Lymphoblastoid cell lines Peripheral blood mononuclear cells Lymphoblastoid cell lines Testis Brain_Caudate_basal_ganglia Adipose_s.c. Brain_Nucleus_accumbens_basal_ganglia Cells_EBV-transformed_lymphocytes Cells_Transformed_fibroblasts Artery_Tibial Heart_Left_Ventricle Brain_Cortex Brain_Cerebellum Adipose_Visceral_Omentum Brain_Putamen_basal_ganglia Skin_Sun_Exposed_Lower_leg Heart_Atrial_Appendage Brain thalamus Brain medulla 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.
1 Gross CC, et al. (2016) Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation. Proc Natl Acad Sci USA 113(21):E2973–E2982. 2 Hafler JP, et al.; International Multiple Sclerosis Genetics Consortium (IMSGC) (2009) CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun 10(1):5–10. 3 Westra HJ, et al. (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45(10):1238–1243. 4 Fehrmann RS, et al. (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7(8):e1002197. 5 Greenawalt DM, et al. (2011) A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res 21(7): 1008–1016. 6 Lappalainen T, et al.; Geuvadis Consortium (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501(7468):506–511. 7 Heinzen EL, et al. (2008) Tissue-specific genetic control of splicing: Implications for the study of complex traits. PLoS Biol 6(12):e1. 8 Grundberg E, et al.; Multiple Tissue Human Expression Resource (MuTHER) Consortium (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44(10):1084–1089. 9 Anonymous; GTEx Consortium (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 348(6235):648–660. 10 Ramasamy A, et al.; UK Brain Expression Consortium; North American Brain Expression Consortium (2014) Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 17(10):1418–1428.
Liu et al.
PNAS | February 7, 2017 | vol. 114 | no. 6 | E907
