LETTER

Autoimmune disease variants regulate GSDMB expression in human immune cells and LETTER whole blood Yang Hua, Shuilin Jinb, Liang Chengc, Guiyou Liua,1, and Qinghua Jianga,1

+ + There are four gasdermin (GSDM) , including in two immune cells, including the CD4 and CD8 GSDMA, GSDMB, GSDMC, and GSDMD, in the T cells, from 313 healthy European individuals in the (1). Genome-wide association studies Estonian Biobank (10). In all of these datasets, a linear have reported genetic variants at 17q12.2.1 loci, in- regression analysis or Spearman correlation coeffi- cluding GSDMA, GSDMB, and ORDML3 , to be cient is used to detect the potential association be- associated with kinds of autoimmune diseases, includ- tween GSDMB variants (rs2305479 and rs2305480) ing asthma, type 1 diabetes, inflammatory bowel dis- and the expression of neighboring genes, especially ease (IBD), and rheumatoid arthritis (1). However, the GSDMB (5–10). potential genetic mechanisms are unknown (1). In a Interestingly, both the rs2305479 A allele and recent study in PNAS, Chao et al. (1) identified that the rs2305480 T allele could significantly regulate GSDMB GSDMB gene SNPs (rs2305479 G > A and rs2305480 gene expression, and only regulated reduced GSDMB C > T), which are associated with an increased susceptibility gene expression in all of these eQTL datasets (5–10). In to asthma and IBD, could alter the structure of GSDMB, a addition to the GSDMB gene, both variants could signif- sulfatide and phosphoinositide binding . In their icantly regulate the expression of other neighboring discussion, Chao et al. (1) describe that GSDMB may func- genes such as GSDMA and ORDML3. More detailed tion in sulfatide cellular transport. The overexpression of results are described in Table 1 (significance level of 0.05). GSDMB might cause higher sulfatide levels (1). If the ex- Taken together, Chao et al. (1) identified that both pression of the GSDMB rs2305479 A:rs2305480 T leads to rs2305479 and rs2305480 variants could alter the aberrant sulfatide transport, this perturbation might com- structure of GSDMB. GSDMB may function in sulfatide promise the integrity of the epithelial cell barrier and/or cellular transport, and the overexpression of GSDMB promote inflammatory processes (1). Although these are might cause higher sulfatide levels (1). Here, we show interesting results, there is still one concern to be men- that both the rs2305479 A allele and rs2305480 T GSDMB tioned. Chao et al. (1) did not directly investigate allele could significantly regulate reduced whether the rs2305479 A allele and rs2305480 T allele gene expression in the human immune cells and GSDMB could regulate GSDMB gene expression, which has whole blood. The reduced gene expression prompted us to investigate their findings further. may lead to aberrant sulfatide transport, and further Evidence shows that some expression quantitative compromise the integrity of the epithelial cell barrier trait loci (eQTLs) have more ubiquitous effects and and/or promote inflammatory processes (1). We be- others may need cell- or tissue-specific factors to exert lieve that these findings provide important supple- their influences on gene expression (2–4). Here, we mentary information about the potential mechanisms by which both variants affect autoimmune disease risk. selected four large-scale eQTLs datasets in whole blood, including 5,311 individuals (5); 2,765 individ- Acknowledgments uals (6); 2,116 individuals (7); 5,257 individuals (8); one This work was supported by the Major State Research Development eQTL dataset in whole blood from 377 individuals Program of China (Grant 2016YFC1202302), and the National with rheumatoid arthritis (9); and two eQTL datasets Natural Science Foundation of China (Grant 61571152).

aSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China; bDepartment of Mathematics, Harbin Institute of Technology, Harbin 150080, China; and cCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150080, China Author contributions: Y.H., G.L., and Q.J. designed research; Y.H., L.C., G.L., and Q.J. performed research; Y.H., S.J., L.C., G.L., and Q.J. contributed new reagents/analytic tools; S.J., L.C., G.L., and Q.J. analyzed data; and Y.H., S.J., L.C., G.L., and Q.J. wrote the paper. The authors declare no conflict of interest. 1To whom correspondence may be addressed. Email: [email protected] or [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1712127114 PNAS Early Edition | 1of3 Downloaded by guest on September 29, 2021 Table 1. GSDMB variants and the expression of nearby genes Dataset (ref.) SNP Effect allele Samples Gene Beta Z-score P value ID Cell

(5) rs2305479 A 5,311 ORMDL3 NA −36.32 9.81E-198 1500112 Blood (5) rs2305479 A 5,311 GSDMB NA −35.9 9.81E-198 5390608 Blood (5) rs2305479 A 5,311 IKZF3 NA 4.27 1.99E-05 6900091 Blood (5) rs2305480 T 5,311 ORMDL3 NA −36.57 9.81E-198 1500112 Blood (5) rs2305480 T 5,311 GSDMB NA −32.92 9.81E-198 5390608 Blood (5) rs2305480 T 5,311 THRAP4 NA 2.95 3.15E-03 1980382 Blood (6) rs2305479 A 2,765 ORMDL3 −0.75 NA 1.50E-163 ILMN_1662174 Blood (6) rs2305479 A 2,765 GSDMB −0.89 NA 3.20E-238 ILMN_1666206 Blood (6) rs2305479 A 2,765 IKZF3 0.14 NA 2.20E-07 ILMN_1669692 Blood (6) rs2305479 A 2,765 PGAP3 −0.29 NA 7.90E-26 ILMN_1805636 Blood (6) rs2305479 A 2,765 GSDMB −0.35 NA 1.10E-36 ILMN_2260756 Blood (6) rs2305479 A 2,765 IKZF3 0.49 NA 8.30E-70 ILMN_2300695 Blood (6) rs2305479 A 2,765 GSDMB −0.71 NA 7.70E-145 ILMN_2347193 Blood (6) rs2305480 T 2,765 ORMDL3 −0.74 NA 2.60E-156 ILMN_1662174 Blood (6) rs2305480 T 2,765 GSDMB −0.86 NA 6.10E-218 ILMN_1666206 Blood (6) rs2305480 T 2,765 PGAP3 −0.26 NA 2.30E-20 ILMN_1805636 Blood (6) rs2305480 T 2,765 GSDMB −0.33 NA 1.70E-32 ILMN_2260756 Blood (6) rs2305480 T 2,765 IKZF3 0.38 NA 1.40E-41 ILMN_2300695 Blood (6) rs2305480 T 2,765 GSDMB −0.65 NA 5.40E-120 ILMN_2347193 Blood (10) rs2305479 A 313 GSDMB NA −9.18 4.14E-20 6270615 CD4+ (10) rs2305479 A 313 ORMDL3 NA −8.72 2.72E-18 1500112 CD4+ (10) rs2305479 A 313 GSDMB NA −8.27 1.34E-16 5390608 CD4+ (10) rs2305480 T 313 ORMDL3 NA −11.1 1.23E-28 1500112 CD4+ (10) rs2305480 T 313 GSDMB NA −9.99 1.76E-23 6270615 CD4+ (10) rs2305480 T 313 GSDMB NA −7.91 2.65E-15 5390608 CD4+ (10) rs2305479 A 313 GSDMB NA −14.7 6.11E-49 6270615 CD8+ (10) rs2305479 A 313 ORMDL3 NA −13.3 2.22E-40 1500112 CD8+ (10) rs2305479 A 313 GSDMB NA −11.4 4.09E-30 5390608 CD8+ (10) rs2305480 T 313 GSDMB NA −12.85 8.62E-38 6270615 CD8+ (10) rs2305480 T 313 ORMDL3 NA −12.59 2.40E-36 1500112 CD8+ (10) rs2305480 T 313 GSDMB NA −10.63 2.07E-26 5390608 CD8+ (9) rs2305479 A 377 PGAP3 −0.43 NA 9.91E-09 55616_at RA blood (9) rs2305479 A 377 ORMDL3 −0.44 NA 5.20E-09 235136_at RA blood (9) rs2305479 A 377 GSDMB −0.92 NA 3.23E-43 219233_s_at RA blood (9) rs2305479 A 377 GSDMB −0.96 NA 3.99E-48 240701_at RA blood (9) rs2305479 A 377 GSDMB −0.46 NA 4.49E-10 215659_at RA blood (9) rs2305479 A 377 ORMDL3 −0.80 NA 4.95E-30 223259_at RA blood (9) rs2305480 T 377 ORMDL3 −0.78 NA 9.20E-28 223259_at RA blood (9) rs2305480 T 377 GSDMB −0.88 NA 8.86E-38 240701_at RA blood (9) rs2305480 T 377 GSDMB −0.46 NA 9.20E-10 215659_at RA blood (9) rs2305480 T 377 GSDMB −0.88 NA 7.59E-37 219233_s_at RA blood (9) rs2305480 T 377 ORMDL3 −0.50 NA 2.25E-11 235136_at RA blood (9) rs2305480 T 377 PGAP3 −0.41 NA 5.90E-08 55616_at RA blood (7) rs2305479 A 2,116 ORMDL3 NA −47.51 3.27E-310 ENSG00000172057 Blood (7) rs2305479 A 2,116 GSDMB NA −44.89 3.27E-310 ENSG00000073605 Blood (7) rs2305479 A 2,116 RP11-94L15.2 NA 16.45 8.55E-61 ENSG00000264198 Blood (7) rs2305479 A 2,116 PGAP3 NA −11.66 2.13E-31 ENSG00000161395 Blood (7) rs2305479 A 2,116 IKZF3 NA 9.40 5.64E-21 ENSG00000161405 Blood (7) rs2305479 A 2,116 GSDMA NA −6.01 1.81E-09 ENSG00000167914 Blood (7) rs2305479 A 2,116 ZPBP2 NA 5.61 2.02E-08 ENSG00000186075 Blood (7) rs2305479 A 2,116 PNMT NA −4.26 2.04E-05 ENSG00000141744 Blood (7) rs2305479 A 2,116 MSL1 NA 4.23 2.31E-05 ENSG00000188895 Blood (7) rs2305480 T 2,116 ORMDL3 NA −45.13 3.27E-310 ENSG00000172057 Blood (7) rs2305480 T 2,116 GSDMB NA −41.61 3.27E-310 ENSG00000073605 Blood (7) rs2305480 T 2,116 RP11-94L15.2 NA 14.60 2.87E-48 ENSG00000264198 Blood (7) rs2305480 T 2,116 GSDMA NA −12.77 2.28E-37 ENSG00000167914 Blood (7) rs2305480 T 2,116 PGAP3 NA −9.04 1.53E-19 ENSG00000161395 Blood (7) rs2305480 T 2,116 IKZF3 NA 7.35 2.03E-13 ENSG00000161405 Blood (7) rs2305480 T 2,116 ZPBP2 NA 5.78 7.40E-09 ENSG00000186075 Blood (7) rs2305480 T 2,116 MSL1 NA 4.21 2.57E-05 ENSG00000188895 Blood (8) rs2305479 A 5,257 GSDMB −0.16 −57.65 8.90E-570 3755903 Blood (8) rs2305479 A 5,257 ORMDL3 −0.07 −24.83 9.00E-129 3755934 Blood (8) rs2305479 A 5,257 IKZF3 0.03 13.22 2.79E-39 3755862 Blood

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1712127114 Hu et al. Downloaded by guest on September 29, 2021 Table 1. Cont. Dataset (ref.) SNP Effect allele Samples Gene Beta Z-score P value ID Cell

(8) rs2305480 T 5,257 GSDMB −0.16 −54.76 2.2E-520 3755903 Blood (8) rs2305480 T 5,257 ORMDL3 −0.07 −24.07 1.81E-121 3755934 Blood (8) rs2305480 T 5,257 IKZF3 0.03 11.71 2.74E-31 3755862 Blood (8) rs2305480 T 5,257 KRT14jKRT16 0.02 3.92 9.06E-05 3757154 Blood

Z-score = effect (Beta)/SE; Beta is the regression coefficient based on the effect allele. Beta > 0 and Beta < 0 mean that this effect allele regulates increased and reduced gene expression, respectively. rs2305479 position (hg19), chr17:38062217; rs2305480 position (hg19), chr17:38062196; (rs2305479 G > A and rs2305480 C > T). NA, not available; RA, rheumatoid arthritis.

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