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provided by Elsevier - Publisher Connector REPORT Identification of IL18RAP/IL18R1 and IL12B as Leprosy Risk Demonstrates Shared Pathogenesis between Inflammation and Infectious Diseases

Hong Liu,1,2,3,4,11 Astrid Irwanto,5,6,11 Hongqing Tian,1,4,11 Xi’an Fu,2,3 Yongxiang Yu,2,3 Gongqi Yu,2,3 Huiqi Low,5 Tongsheng Chu,2,3 Yi Li,5 Benqing Shi,1,4 Mingfei Chen,2,3 Yonghu Sun,2,3 Chunying Yuan,2,3 Nan Lu,2,3 Jiabao You,2,3 Fangfang Bao,2,3 Jinghui Li,2,3 Jian Liu,2,3 Huaxu Liu,2,3 Dianchang Liu,2,3 Xiulu Yu,2,3 Lin Zhang,2,3 Qing Yang,2,3 Na Wang,2,3 Guiye Niu,2,3 Shanshan Ma,2,3 Yan Zhou,2,3 Chuan Wang,2,3 Shumin Chen,2,3 Xuejun Zhang,7,8 Jianjun Liu,2,5,9,12 and Furen Zhang1,2,3,4,10,12,*

Of eight leprosy susceptibility loci identified by genome-wide association studies, five have been implicated in Crohn disease, suggesting a common genetic fingerprint between leprosy and inflammatory bowel disease (IBD). Here, we conducted a multiple-stage genetic asso- ciation study of 133 IBD susceptibility loci in multiple leprosy samples (totaling 4,971 leprosy cases and 5,503 controls) from a Chinese population and discovered two associations at rs2058660 on 2q12.1 (p ¼ 4.57 3 10 19; odds ratio [OR] ¼ 1.30) and rs6871626 on 5q33.3 (p ¼ 3.95 3 10 18;OR¼ 0.75), implicating IL18RAP/IL18R1 and IL12B as susceptibility genes for leprosy. Our study reveals the important role of IL12/IL18-mediated transcriptional regulation of IFN-g production in leprosy, and together with previous findings, it demon- strates the shared genetic susceptibility between infectious and inflammatory diseases.

Genome-wide association studies (GWASs) have offered tinal mucosa. Recent GWAS analyses of CD and UC have a powerful and unbiased approach for the identification corroborated that nearly one-third of their susceptibility of susceptibility genes for complex diseases. As of loci are shared.8 Leprosy is a chronic infectious disease September 2011, a total of 1,617 susceptibility loci have caused by Mycobacterium leprae and affects both the skin been identified in 249 complex traits (see Web Resources and the peripheral nerves. Although leprosy and CD are for the Catalog of Published GWASs). The enormous prog- distinct clinical entities, they both belong to chronic ress of GWASs has led to the revelation of biological inflammatory diseases, and there is some suggestive connections between some clinically unrelated diseases evidence that they share pathogenic mechanisms. For through the identification of shared risk variants; such example, the formation of granuloma is an important connections include associations between IL23R (MIM clinical hallmark of both leprosy and CD. In addition, it 607562) variants and leprosy (MIM 609888),1 Crohn has also been suggested that the development of CD, at disease (CD [MIM 266600]),2 ulcerative colitis (UC [MIM least in some individuals, might be triggered by myco- 266600]),3 psoriasis (MIM 177900),4 and ankylosing spon- bacterial infection.9,10 Mycobacterium avium subspecies dylitis (AS [MIM 106300]),5 as well as the association paratuberculosis has been cultured and identified from the between PTPN2 (MIM 176887) variants and CD2 and intestines and blood of CD-affected individuals.11 It has type 1 diabetes (IDDM [MIM 222100]).6 also been hypothesized that CD susceptibility genes, Of the eight leprosy susceptibility loci identified by such as NOD2, might interact with mycobacterium trig- GWASs,1,7 variants of NOD2 (16q12 [MIM 605956]), gers.12 Moreover, multibacillary infection of leprosy is TNFSF15 (9q32 [MIM 604052]), LRRK2 (12q12[MIM associated with a type 2 helper T (Th2) cell response, 609007]), IL23R (1p31.3), and LACC1/CCDC122 (13q14.11 whereas paucibacillary infection is associated with an [MIM 613409 and 613408]) have also been reported to be immune response mediated by type 1 helper T (Th1) associated with CD and UC, suggesting a strong biological cells.13 The development of IBD shows a similar pattern link among the genetic susceptibilities of these diseases. in which tissue injury was thought to be primarily medi- Both CD and UC belong to inflammatory bowel disease ated by Th1 cells in CD14 and by Th2 cells in UC.15 We (IBD [MIM 266600]), a chronic disorder affecting the intes- therefore hypothesized that there are additional shared

1Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250022, China; 2Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250022, China; 3Shandong Provincial Key Lab for Dermatovenereology, Jinan, Shandong 250022, China; 4Shandong Provincial Medical Center for Dermatovenereology, Jinan, Shandong 250022, China; 5Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore; 6Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; 7Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China; 8The Key Laboratory of Resource Utilization for Severe Diseases, Ministry of Education and Anhui Province, Hefei, Anhui 230032, China; 9School of Biological Sciences, Anhui Medical University, Hefei, Anhui 230032, China; 10Shandong Clinical College of Anhui Medical University, Jinan, Shandong 250022, China 11These authors contributed equally to this work 12These authors equally directed this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ajhg.2012.09.010. Ó2012 by The American Society of Human Genetics. All rights reserved.

The American Journal of Human Genetics 91, 935–941, November 2, 2012 935 Table 1. Summary of the Four Independent Leprosy Samples Used in the Current Study Cases Controls

Ethnicity Sample Size Mean Age Mean Age at Onset Male/Female Sample Size Mean Age Male/Female

Sample 1a Han 1,504 66.22 22.96 1,251/253 1,502 65.25 1,254/248

Sample 2b Han 1,154 66 23.57 934/220 2,605 57.01 1,313/1,292

Sample 3c Han 1,165 62.36 32.73 846/319 648 42.09 275/373

Sample 4d Chuang 334 54.76 24.68 224/110 310 45.6 195/115

Miao 277 53.03 27.88 193/84 190 41.48 152/38

Yizu 236 54.37 26.71 166/70 182 43.77 147/35

other 301 56.90 26.84 212/89 66 42.18 26/40

Total 4,971 62.63 26.19 3,826/1,145 5,503 55.71 3,362/2,141 aSamples collected in Shandong, Anhui, and Jiangsu provinces (eastern China). bSamples collected in Shandong, Anhui, and Jiangsu provinces (eastern China). cSamples collected in Yunnan, Guizhou, and Fujian provinces (southern China). dSamples collected in Yunnan, Guizhou, and Fujian provinces (southern China).

susceptibility loci between leprosy and IBD and searched Venereology, and informed consent was obtained from for more leprosy susceptibility genes by carrying out a all individuals. comprehensive association study of IBD susceptibility In each of the four independent leprosy cohorts, those loci in multiple independent leprosy samples from a SNPs with a call rate < 95%, a low minor allele frequency Chinese population. (<0.01), or a deviation from Hardy-Weinberg equilibrium We reviewed the findings from 12 CD GWASs and (p < 0.01) in the controls were excluded. We adopted seven UC GWASs through the Catalog of Published a Cochran-Armitage trend test to test the genotype- GWASs and identified within 118 genes a total of 155 phenotype association in each sample, and we performed SNPs that showed genome-wide significant associations the final analysis of the combined samples by using the (p values < 5.0 3 10 8) with CD, UC, or both. Of the Cochran-Mantel-Haenszel test. Q-tests were performed 155 SNPs, we excluded seven within the major-histocom- for evaluating the significance of heterogeneity among patibility-complex region and 15 SNPs within the five individual studies, and p values < 0.05 were considered known leprosy susceptibility genes (NOD2, TNFSF15, to be significant heterogeneity. IL23R, LACC1, and LRRK2). After exclusion, a total of Two associations were discovered: one at rs2058660 133 SNPs, including 75 CD-associated SNPs, 54 UC-associ- on 2q12.1 and one at rs6871626 on 5q33.3. Both of the ated SNPs, and four IBD (both CD and UC)-associated SNPs showed consistent association across the four SNPs, were selected for multistage association study in independent samples without any indication of genetic the four independent leprosy samples from the Chinese heterogeneity (p > 0.05). In the combined samples of a population. total of 4,971 cases and 5,503 controls, the associations We conducted genotyping analyses of the four leprosy at the two SNPs suppressed the genome-wide significance samples by using the Sequenom MassArray system (San (combined p ¼ 4.57 3 10 19 and odds ratio [OR] ¼ 1.30 Diego, USA). In stage 1, all 133 selected SNPs were geno- for rs2058660; combined p ¼ 3.95 3 10 18 and OR ¼ typed in 1,504 leprosy cases and 1,502 healthy controls 0.75 for rs6871626) (Table 2). from a northern Chinese Han population. Of the 119 We further investigated the association evidence SNPs that were successfully designed and genotyped, within the surrounding regions of the two loci by using 19 showed suggestive association (p < 0.05) in stage 1 our previously published GWAS data set.1 To maximize analysis and included nine CD-associated SNPs, eight the coverage of genetic variants, we imputed the UC-associated SNPs, and two IBD-associated SNPs (Table GWAS data set by using the genetic-variation data S1, available online). In stage 2, the 19 SNPs were further from the 1000 Genomes Project (version from February genotyped in an additional three independent leprosy 2012), which includes 1,092 individuals from Africa cohorts from the Chinese population: (1) 1,154 cases (246 samples), North America (181 samples), Asia (286 and 2,605 controls from a northern Chinese Han popu- samples), and Europe (379 samples). Imputed genotypes lation, (2) 1,165 cases and 648 controls from a southern with a probability < 90%, as well as SNPs with impu- Chinese Han population, and (3) 1,148 case and 748 tation certainty < 80%, a MAF < 5%, and a missing control minorities from southern China (Table 1). The rate > 1% were excluded from further analysis. In total, study was approved by the institutional review board there were 6,593 samples (706 individuals with leprosy at the Shandong Provincial Institute of Dermatology and and 5,587 controls subjects) and 1,987,713 SNPs that

936 The American Journal of Human Genetics 91, 935–941, November 2, 2012 genome-wide significant associations were also reported Table 2. Summary of the Association Results for the Two 16 Confirmed Loci in Four Independent Samples and the Combined within the regions for (at rs3771166) and celiac Samples disease (MIM 212750) (at rs917997 and rs13015714).17,18 SNP Although asthma-associated rs3771166 (p ¼ 9.91 3 10 1; rs2058660 rs6871626 OR ¼ 1.00) did not show any evidence of association in our previous GWAS data set, the two celiac-disease-related 2 5 SNPs (p ¼ 1.64 3 10 3 and p ¼ 1.92 3 10 3) did show asso- Position 103,054,449 158,826,792 ciation. However, these two SNPs were in strong LD with Minor/major allele T/C A/C rs2058660 (r2 > 0.8), and their associations were therefore

Test allelea TAnot independent from the one at rs2058660. Intriguingly, we found the associations between rs2058660 and leprosy Gene IL18RAP/IL18R1 IL12B and CD to be in the direction opposite of that of the b AF 0.49 0.35 T allele, suggesting that this SNP is a risk variant for Sample 1 leprosy but a protective variant for CD. Our study has indi-

cated that the susceptibility locus for leprosy on 2q12.1 p 5.67 3 10 10 2.75 3 10 5 is also associated with CD and celiac disease but has the OR 1.41 0.77 opposite genetic effect (Table S2). 95% CI 1.26–1.56 0.69–0.87 We found rs6871626 to be located within a small LD

Sample 2 block of 40 kb on 5q33 (Figure 1B). Besides rs6871626, six surrounding SNPs showed stronger association with 3 7 3 7 p 7.29 10 7.01 10 the most significant SNP at rs1422877 (p ¼ 2.93 3 10 4; OR 1.29 0.75 OR ¼ 0.78). These six SNPs were in high LD (r2 > 0.8) 95% CI 1.17–1.42 0.67–0.84 and were not independent from each other. Conditioning on the top SNP, rs1422877, eliminated the association Sample 3 ¼ at rs6871626 (pconditional 0.49). SNP rs6871626 was p 8.34 3 10 3 1.59 3 10 3 reported to be associated with UC.3 The associations OR 1.20 0.78 between rs6871626 and leprosy and UC were in the direc- tion opposite of that of the C allele, suggesting that 95% CI 1.05–1.38 0.67–0.91 this SNP is a risk variant for leprosy but a protective allele Sample 4 for UC. In addition to the reported UC association at p 4.52 3 10 4 6.29 3 10 7 rs6871626, genome-wide significant association was 2,19 OR 1.28 0.69 also reported for CD (rs10045431 and rs6887695), multiple sclerosis (MS [MIM 126200]) (rs10866713 and 95% CI 1.12–1.47 0.60–0.80 rs2546890),20 psoriasis (rs2546890, rs3213094, and All Samples Combined rs2082412),4,21,22 psoriatic arthritis (PSA [MIM 607507]) 23 5 p 4.57 3 10 19 3.95 3 10 18 (rs12188300), and AS (rs6556416). However, none of these previously reported SNPs showed association with OR 1.30 0.75 leprosy (p > 0.10) in our previously published GWAS 95% CI 1.23–1.38 0.71–0.81 data set, although our power calculation indicated that Q-test 0.35 0.58 our GWAS data set should provide sufficient power (>80%) to detect these associations at p ¼ 0.05. Further- The following abbreviations are used: AF, average allele frequency; OR, odds ratio; and CI, confidence interval. more, none of these previously reported SNPs were in LD aTest allele: the allele that was used for estimating the OR. with rs6871626 (r2 < 0.01), and they (except for bAF of the test allele in the controls of the four independent samples. rs12188300) were separated from rs6871626 by a strong recombination hot spot. All together, our analyses have passed quality control and remained in the association indicated that the leprosy susceptibility locus at 5q33.3 is analysis. also involved in the development of UC but is indepen- We found rs2058660 to be located within a linkage- dent from the previously published associations with disequilibrium (LD) block of about 480 kb on 2q12.1 (Fig- CD, MS, psoriasis, PSA, and AS within the region (Table S2). ure 1A). Besides rs2058660 (p ¼ 1.49 3 10 3;OR¼ 1.22), The LD region of the leprosy susceptibility locus on additional associations (p < 5.00 3 10 3) were also ob- 2q12.1 contained five genes: IL1RL1 (MIM 601203), served at a large number of surrounding SNPs; the most IL18RAP (MIM 604509), IL18R1 (MIM 604494), SLC9A4 significant association was at rs1916307 (p ¼ 7.11 3 10 4; (MIM 600531), and SLC9A2 (MIM 600530) (Figure 1A). OR ¼ 1.24). Conditioning on the top SNP, rs1916307, IL1RL1, IL18RAP, and IL18R1 are part of the cytokine abolished the association at rs2058660, as well as asso- receptor cluster on 2q12. Whereas IL1RL1 encodes the > IL18RAP IL18R1 ciations at the surrounding SNPs (pconditional 0.1). In receptor of IL33, and encode the receptors addition to the reported CD association at rs2058660, of IL18. IL33 is a ligand that is selectively expressed on

The American Journal of Human Genetics 91, 935–941, November 2, 2012 937 Figure 1. Regional Association Plots of rs2058660 and rs6871626 y x 2 The p values of SNPs (shown as log10p) ( axis) are plotted against their map positions ( axis). The color of each SNP spot reflects its r with the confirmed SNP within each locus. The confirmed SNP, the top SNP, and previously reported SNPs of each locus are all in pink and are labeled with arrows. Estimated recombination rates (based on the combined CHB [Han Chinese in Beijing, China] and JPT [Japanese in Tokyo, Japan] samples from the 1000 Genomes Project) are plotted in blue. Gene annotations were adapted from the UCSC Genome Browser (see Web Resources). (A) rs2058660 on 2q12.1. (B) rs6871626 on 5q33.3.

Th2 cells and mast cells and potently drives production quent inflammatory response.24,25 Binding of IL18 to its of Th2-associatied cytokines. The signaling of different receptors stimulates both Th1 and Th2 cytokine release isoforms of IL1RL1 binding to IL33 plays diverse roles in and ultimately leads to the activation of NF-kB, which is the activation of nuclear factor kB (NFkB) and the subse- a central element in the pathogenesis of leprosy.7 It has

938 The American Journal of Human Genetics 91, 935–941, November 2, 2012 also been reported that IL18 can promote Th1 responses previous studies (Table S3). According to the published specific to M. leprae and can enhance IFN-g production association results, the SNP showed consistent association from natural-killer cells and Ag-stimulated T cells in between leprosy and IBD. Although consistent association response to M. Leprae.26 In vitro, monocytes produce between the two diseases supports the hypothesis that IL18 in response to M. leprae.27 Mycobacteria infection might trigger or enhance the devel- The association at 5q33.3 was located within a small opment of IBD, the opposite associations at rs2058660 LD region in which only one unannotated transcript and rs6871626 might suggest that historical selection (LOC285627) could be found. However, IL12B (MIM against infectious diseases (such as leprosy) might prompt 161561) is located next to the LD region and is a strong strong immunity whose overreaction might increase the biological candidate (Figure 1B). IL12B encodes the p40 risk of developing inflammatory diseases (such as IBD). subunit of both heterodimeric IL12 and Further studies are warranted for identifying the causal IL23, which play an important role in Th17-cell-mediated variants of these susceptibility loci through fine mapp- chronic inflammation by promoting Th17 cell mainte- ing and functional investigation and for further under- nances and the production of proinflammatory cyto- standing the complex genetic basis of shared susceptibility kines.28 In addition, IL12B has also been reported to play between infectious and inflammatory diseases. a role in increased susceptibility to tuberculosis (MIM We also investigated the population-frequency differ- 607948), although the reported association results were ences of the reported IBD SNPs between Chinese and not conclusive and were inconsistent across different European populations and evaluated the power of our studies.29–31 Furthermore, in vitro studies have shown study to detect these previously reported IBD SNPs in our that the expression of IL12B could be triggered by DNA leprosy samples. We used CaTs software to calculate power of M. tuberculosis in dendritic cells through TLR9 signaling, by using a nominal significance of 0.05, the reported ORs which in turn regulates the level of IFN-g production in the IBD GWAS catalogue, and allele frequencies from during infection and that IL12B is required for the gene- the Chinese population. Regarding the 114 SNPs for ration of activated CD4 T cells and dendritic cell migration which power analysis was performed, our study had suffi- after M. tuberculosis infection.32,33 cient (>80%) power to detect 35 SNPs, good (50%–80%) In particular, it has been demonstrated that the syner- power to detect 20 SNPs, and insufficient (<50%) power gistic action of IL18 and IL12 plays an important role in to detect 59 SNPs (Table S4). Of these 59 SNPs, about half IFN-g production.34 The synergistic action can be reflected had a substantially lower population frequency (by at least by the induction of the IL18 receptors by IL12; this in turn 30%) in the Chinese population than in the European leads to the induction of IL12 receptors in Th1 cells. The population. A much bigger study will be needed for inves- synergistic action can also be seen in their cooperated tigating the role of these IBD SNPs in leprosy development. transcriptional regulation of IFN-g production—different In conclusion, we have discovered two susceptibility loci transcription factors activated by IL12 and IL18 can syner- for leprosy by carrying out a comprehensive association gistically activate the IFN-g promoter. Although further study of IBD susceptibility loci in leprosy samples from fine mapping and functional investigations are needed a Chinese population. The discovery of the two suscepti- for confirming true susceptibility genes within these two bility loci has implicated IL18RAP/IL18R1 and IL12B loci, our findings have strongly suggested that the IL12/ as susceptibility genes for leprosy and highlighted the IL18-mediated transcriptional regulation of IFN-g pro- important role of IL12/IL18-mediated transcriptional duction plays an important role in the development of regulation of IFN-g production in the development of leprosy. leprosy. Together with previous findings, our study has Both IL12 and IL18 pathways have been shown to be further demonstrated the shared genetic susceptibility involved in the development of IBD. The IL12/IL23- basis between inflammation and infectious diseases. mediated Th17 pathway has been shown to play an important role in the development of IBD, as well as Supplemental Data autoimmune diseases, such as psoriasis.28,35 In addition, previous studies have shown that the balance between Supplemental Data include four tables and can be found with this IL18 and IL18-binding might contribute to the article online at http://www.cell.com/AJHG. pathogenesis of IBD.36 IL18 expression is higher in the mucosa of CD-affected individuals than in uninvolved Acknowledgments areas and normal controls.37 Mouse models for CD show We thank the individuals who participated in this project. This that blocking IL18 with an IL18-binding attenu- work was funded by grants from the National Natural Science ates the intestinal inflammation.38 Foundation of China (81071288, 81072391, and 81101187), the It is intriguing to see that the two susceptibility loci National 973 program (2011CB512105), the Project of Taishan showed opposite associations between leprosy and IBD. scholar (2008–present), the Project of Medical leading scholar of In addition, of the five known shared susceptibility loci Shandong Province (2010–present), the Natural Science Founda- that were excluded from the current study, one SNP, tion of Shandong Province (ZR2011HQ003), the Innovative rs3764147, was also analyzed in both leprosy and IBD by Research Team of the Ministry of Education of China (IRT-1046),

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