ADAM33 Polymorphisms Are Associated with Susceptibility to Systemic Lupus Erythematosus in a Korean Population

Ji-Young Kim; Young Kim; Soo-Cheon Chae; Shin-Seok Lee; Mi-Kyoung Lim; Dong-Huyk Sheen; Hun-Taeg Chung; Seung-Cheol Shim

doi:10.4078/jrd.2016.23.2.88

Journal List > J Rheum Dis > v.23(2) > 1064308

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Kim, Kim, Chae, Lee, Lim, Sheen, Chung, and Shim: ADAM33 Polymorphisms Are Associated with Susceptibility to Systemic Lupus Erythematosus in a Korean Population

Original Article

J Rheum Dis 2016;23(2):88-95.

Published online: 31 October 2016

DOI: https://doi.org/10.4078/jrd.2016.23.2.88

ADAM33 Polymorphisms Are Associated with Susceptibility to Systemic Lupus Erythematosus in a Korean Population

Ji-Young Kim^1,^*, Young Kim^1,^*, Soo-Cheon Chae², Shin-Seok Lee³, Mi-Kyoung Lim⁴, Dong-Huyk Sheen⁴, Hun-Taeg Chung⁵, Seung-Cheol Shim¹

¹Division of Rheumatology, Department of Medicine, Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea

²Department of Pathology, Wonkwang University School of Medicine, Iksan, Korea

³Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea

⁴Department of Medicine, Eulji Medi-Bio Research Institute, Eulji University, Daejeon, Korea

⁵School of Biological Sciences, University of Ulsan, Ulsan, Korea

Corresponding to: Seung-Cheol Shim, Division of Rheumatology, Department of Medicine, Daejeon Rheumatoid and Degenerative Arthritis Center, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. E-mail: shimsc@cnuh.co.kr

^* The first two authors contributed equally to this work.

Received 18 May 2015 Revised 5 August 2015 Revised 23 October 2015 Accepted 23 October 2015

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

The objective of this study is to assess whether genetic functional variants of disintegrin and metalloprotease 33 (ADAM33) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population.

Methods

We previously identified 48 single nucleotide polymorphisms (SNPs) in ADAM33. Six SNPs were selected with regard to the linkage disequilibrium pattern. An association study of ADAM33 was conducted in 190 patients with SLE and 469 control subjects. SNPs were genotyped using the TaqMan Real-time polymerase chain reaction method, and haplotype analyses of related variants were performed.

Results

All SNPs were in Hardy-Weinberg equilibrium. Significant associations were found between the ADAM33 polymorphisms and SLE at rs2787094 (adjusted odds ratio [OR] 1.88, 95% confidence interval [CI] 1.00 to 3.54; p＜ 0.0001). The rs554743 polymorphism was associated with the presence of the immunoglobulin M anti-cardiolipin antibody (adjusted OR 0.29, 95% CI 0.10 to 0.83; p=0.021).

Conclusion

ADAM33 polymorphisms were associated with susceptibility to SLE and development of clinical disease manifestations in a Korean population. Further study is warranted to clarify the role of ADAM33 in SLE pathogenesis.

Keywords: Disintegrin and metalloproteinase domain 33 protein, Systemic lupus erythematosus, Single nucleotide polymorphism

REFERENCES

1. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989; 44:93–151.

2. Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004; 16:513–21.

3. Herrmann M, Voll RE, Kalden JR. Etiopathogenesis of systemic lupus erythematosus. Immunol Today. 2000; 21:424–6.

4. Gunn TM, Azarani A, Kim PH, Hyman RW, Davis RW, Barsh GS. Identification and preliminary characterization of mouse Adam33. BMC Genet. 2002; 3:2.

5. Yoshinaka T, Nishii K, Yamada K, Sawada H, Nishiwaki E, Smith K, et al. Identification and characterization of novel mouse and human ADAM33s with potential metalloprotease activity. Gene. 2002; 282:227–36.

6. Stone AL, Kroeger M, Sang QX. Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins (review). J Protein Chem. 1999; 18:447–65.

7. Wolfsberg TG, Primakoff P, Myles DG, White JM. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol. 1995; 131:275–8.

8. Black RA, White JM. ADAMs: focus on the protease domain. Curr Opin Cell Biol. 1998; 10:654–9.

9. Primakoff P, Myles DG. The ADAM gene family: surface proteins with adhesion and protease activity. Trends Genet. 2000; 16:83–7.

10. Howard L, Maciewicz RA, Blobel CP. Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28. Biochem J. 2000; 348:21–7.

11. Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem. 2000; 275:18574–80.

12. Wolfsberg TG, Straight PD, Gerena RL, Huovila AP, Primakoff P, Myles DG, et al. ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain. Dev Biol. 1995; 169:378–83.

13. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002; 418:426–30.

14. Sharma N, Tripathi P, Awasthi S. Role of ADAM33 gene and associated single nucleotide polymorphisms in asthma. Allergy Rhinol (Providence). 2011; 2:e63–70.

15. Xiao J, Han J, Wang X, Hua D, Su D, Bao Y, et al. Association of ADAM33 gene with susceptibility to COPD in Tibetan population of China. Mol Biol Rep. 2011; 38:4941–5.

16. Jie Z, Jin M, Cai Y, Bai C, Shen Y, Yuan Z, et al. The effects of Th2 cytokines on the expression of ADAM33 in aller-gen-induced chronic airway inflammation. Respir Physiol Neurobiol. 2009; 168:289–94.

17. Funauchi M, Ikoma S, Enomoto H, Horiuchi A. Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosus. Scand J Rheumatol. 1998; 27:219–24.

18. Llorente L, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Maillot MC, Durand-Gasselin I, et al. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine Netw. 1993; 4:421–7.

19. Rüger BM, Erb KJ, He Y, Lane JM, Davis PF, Hasan Q. Interleukin-4 transgenic mice develop glomerulosclerosis independent of immunoglobulin deposition. Eur J Immunol. 2000; 30:2698–703.

20. Zhao M, Tang J, Gao F, Wu X, Liang Y, Yin H, et al. Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J Biomed Biotechnol. 2010; 2010; 931018.

21. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40:1725.

22. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315–24.

23. Chae SC, Yoon KH, Chung HT. Identification of novel polymorphisms in the Adam33 gene. J Hum Genet. 2003; 48:278–81.

24. Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, et al. ADAM33 polymorphism: association with bronchial hyperresponsiveness in Korean asthmatics. Clin Exp Allergy. 2004; 34:860–5.

25. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982; 25:1271–7.

26. Priori R, Medda E, Conti F, Cassara EA, Danieli MG, Gerli R, et al. Familial autoimmunity as a risk factor for systemic lupus erythematosus and vice versa: a case-control study. Lupus. 2003; 12:735–40.

27. Schulze-Koops H, Kalden JR. The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2001; 15:677–91.

28. Mori M, Morris SC, Orekhova T, Marinaro M, Giannini E, Finkelman FD. IL-4 promotes the migration of circulating B cells to the spleen and increases splenic B cell survival. J Immunol. 2000; 164:5704–12.

29. Dörner T, Jacobi AM, Lee J, Lipsky PE. Abnormalities of B cell subsets in patients with systemic lupus erythematosus. J Immunol Methods. 2011; 363:187–97.

30. Cappione AJ, Pugh-Bernard AE, Anolik JH, Sanz I. Lupus IgG VH4.34 antibodies bind to a 220-kDa glycoform of CD45/B220 on the surface of human B lymphocytes. J Immunol. 2004; 172:4298–307.

31. Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005; 105:4390–8.

32. Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004; 113:161–71.

33. Beaman KD, Gilman-Sachs A, Cifuentes D, Miller ML, O'Gorman MR. Presence of multiple anti-phospholipid anti-body specificities in a pediatric population. Autoimmunity. 1995; 21:99–106.

Figure 1.

Linkage disequilibrium pattern in the ADAM33 gene.

Table 1.

Clinical characteristics of the study subjects

Clinical profile	SLE	RA	Control
No. of subject	190	490	469
Age (yr)	36.3±11.6	38.7±12.1	38.3±10.4
Sex (male/female)	1/20.1	1/3.2	1/1.1
Disease duration (yr)	6.7±4.04	7.1±4.21	-
ACR criteria
Malar rash	107 (56.4)
Discoid rash	6 (3.0)
Photosensitivity	75 (39.3)
Oral ulcers	62 (32.7)
Arthritis	93 (48.8)
Serositis	57 (30.3)
Renal involvement	76 (40.0)
CNS involvement	9 (5.0)
Hematologic abnormities	171 (90.0)
Immunologic abnormalities	114 (60.0)
Antinuclear antibodies	190 (100.0)

Values are presented as number only, mean±standard deviation, or number (%). ACR: American College of Rheumatology, CNS: central nervous system, RA: rheumatoid arthritis, SLE: systemic lupus erythematosus.

Table 2.

Basic information on the genotyped single nucleotide polymorphisms (SNPs) in the ADAM33 gene

SNP No.	NCBI rs No.	Chromosome position^*	e Location	Base change	Amino acid	MAF				HWE^‡	Success rate (%)
SNP No.	NCBI rs No.	Chromosome position^*	e Location	Base change	Amino acid	JPT^†	CHB^†	SLE	control	HWE^‡	Success rate (%)
1	rs554743	3662142	Intron1	A＞ G		0.43	0.39	0.403	0.382	0.602	92.39
2	rs3918395	3653149	Intron13	G＞ T		0.13	0.09	0.082	0.073	1	95.52
3	rs528557	3651742	Exon19	G＞ C	Gly717Gly	0.27	0.20	0.236	0.234	0.135	92.99
4	rs2280091	3650234	Exon20	T＞ C	Met764Thr	0.14	0.09	0.063	0.068	1	97.01
5	rs2280090	3650205	Exon20	C＞ T	Pro774Ser	0.16	0.11	0.060	0.077	0.670	95.37
6	rs2787094	3649161	3'UTR	C＞ G		0.28	0.40	0.367	0.337	0.591	93.88

CHB: Han Chinese in Bejing, China, JPT: Japanese in Tokyo, Japan; MAF: minor allele frequency, NCBI: National Center fo Biotechnology Information, SLE: systemic lupus erythematosus, UTR: untranslated region.

^* SNP position from the NCBI dbSNP (http://www.ncbi.nlm.nih.gov/snp).

^† MAF from http://browser.1000genomes.org/.

^‡ HWE indicates the p-value for the Hardy-Weinberg equilibrium in normal controls.

Table 3.

Genotypic and allelic analysis of the ADAM33 gene polymorphisms in the controls and patients with SLE or RA (disease control)

SNP No.	NCBI rs No.	Genotype	Control	SLE	Adjusted OR (95% CI)	p-value^* (control vs. SLE)	p-value^* (control vs. RA)
1	rs554743	Total (AA, AG, GG)	429 (100.0)	190 (100.0)			487
		AA	165 (38.5)	62 (32.6)	1.00 (reference)	0.796	0.616
		AG	200 (46.6)	97 (51.1)	1.13 (0.69∼1.87)
		GG	64 (14.9)	31 (16.3)	0.93 (0.48∼1.80)
		AG/GG vs. AA	264 (61.5)	128 (67.4)	1.07 (0.67∼1.72)	0.768	0.650
		AA/AG vs. GG	365 (85.1)	159 (83.7)	0.87 (0.48∼1.57)	0.637	0.502
		G allele freq.	0.382	0.403	1.09 (0.12∼0.87)	0.459	0.271
2	rs3918395	Total (GG, GT, TT)	462 (100.0)	178 (100.0)			485
		GG	389 (84.2)	156 (87.6)	1.00 (reference)	0.801	1.000
		GT	71 (15.4)	19 (10.7)	0.83 (0.43∼1.59)
		TT	2 (0.4)	3 (1.7)	1.41 (0.16∼12.20)
		GT/TT vs. GG GG/GT vs. TT	73 (15.8) 460 (99.6)	22 (12.4) 175 (98.3)	0.86 (0.46∼1.61) 1.44 (0.17∼12.46)	0.641 0.740	0.990 0.997
		T allele freq.	0.074	0.082	1.12 (0.74∼1.69)	0.588	0.482
3	rs528557	Total (GG, GC, CC)	463 (100.0)	160 (100.0)			477
		GG	274 (59.2)	98 (61.3)	1.00 (reference)	0.864	0.281
		GC	156 (33.7)	52 (32.5)	0.87 (0.53∼1.43)
		CC	33 (7.1)	10 (6.3)	0.97 (0.38∼2.45)
		GC/CC vs. GG	189 (40.8)	62 (38.8)	0.89 (0.56∼1.42)	0.618	0.914
		GG/GC vs. CC	430 (92.9)	150 (93.8)	1.02 (0.41∼2.54)	0.969	0.122
		C allele freq.	0.234	0.237	1.02 (0.78∼1.32)	0.913	0.810
4	rs2280091	Total (AA, AG, GG)	457 (100.0)	192 (100.0)			487
		TT	389 (85.1)	178 (92.7)	1.00 (reference)	0.172	0.864
		TC	66 (14.4)	13 (6.8)	0.50 (0.24∼1.05)
		CC	2 (0.4)	1 (0.5)	0.52 (0.04∼7.72)
		TC/CC vs. TT	68 (14.9)	14 (7.3)	0.50 (0.25∼1.03)	0.061	0.603
		TT/TC vs. CC	389 (85.1)	191 (99.5)	2.04 (0.14∼30.29)	0.604	0.985
		C allele freq.	0.069	0.063	0.92 (0.59∼1.43)	0.702	0.282
5	rs2280090	Total (AA, AG, GG)	449 (100.0)	190 (100.0)			489
		CC	379 (84.4)	177 (93.2)	1.00 (reference)	0.141	0.245
		CT	68 (15.1)	12 (6.3)	0.47 (0.22∼1.01)
		TT	2 (0.4)	1 (0.5)	1.89 (0.06∼56.43)
		CT/TT vs. CC	70 (15.6)	13 (6.8)	0.50 (0.24∼1.05)	0.066	0.147
		CC/CT vs. TT	447 (99.6)	189 (99.5)	2.02 (0.07∼60.49)	0.684	0.250
		T allele freq.	0.077	0.060	0.77 (0.50∼1.19)	0.235	0.348
6	rs2787094	Total (CC, CG, GG)	445 (100.0)	184 (100.0)			489
		CC	186 (41.8)	91 (49.5)	1.00 (reference)	0.000	0.913
		CG	211 (47.4)	48 (26.1)	0.36 (0.21∼0.61)
		GG	48 (10.8)	45 (24.5)	1.88 (1.00∼3.54)
		CG/GG vs. CC	259 (58.2)	93 (50.5)	0.63 (0.40∼1.00)	0.048	0.970
		CC/CG vs. GG	397 (89.2)	139 (75.5)	2.09 (1.60∼5.26)	0.000	0.970
		G allele freq.	0.338	0.368	1.14 (0.90∼1.44)	0.266	0.768

Values are presented as number only or number (%). CI: confidence interval, freq.: frequency, NCBI: National Center for Biotechnology Information, OR: odds ratio, RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, SNP: single nucleotide polymorphism.

^* Sex and age adjusted.

Table 4.

Genotype frequencies of the ADAM33 polymorphisms in dominant phenotypic model for patients with SLE

Phenotype	NCBI rs No.
	rs554743		rs3918395		rs528557		rs2280091		rs2280090		rs2787094
	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Sm	0.90(0.10∼1.79)	0.790	0.83(0.20∼3.38)	0.791	1.60(0.65∼3.91)	0.302	0.59(0.06∼5.55)	0.646	-	0.999	0.83(0.39∼1.77)	0.638
RNP	2.10(0.97∼4.59)	0.061	0.56(0.17∼1.84)	0.343	0.98(0.42∼2.26)	0.973	1.05(0.21∼5.23)	0.952	0.88(0.15∼4.93)	0.890	1.18(0.56∼2.48)	0.651
Ro	1.58(0.75∼3.35)	0.232	0.89(0.26∼3.00)	0.859	1.24(0.54∼2.83)	0.601	1.28(0.22∼7.18)	0.777	0.95(0.15∼5.72)	0.955	1.37(0.67∼2.18)	0.382
La	1.29(0.54∼3.09)	0.562	0.19(0.02∼1.65)	0.135	0.44(0.16∼1.18)	0.104	-	0.999	-	0.999	1.49(0.66∼3.37)	0.336
Anticoagulant	1.21(0.39∼3.71)	0.728	1.98(0.46∼8.49)	0.353	0.60(0.19∼1.91)	0.394	3.10(0.48∼9.95)	0.233	2.66(0.41∼6.95)	0.299	1.45(0.52∼4.03)	0.475
IgG aCL	0.70(0.26∼1.93)	0.501	2.31(0.62∼8.58)	0.211	0.96(0.35∼2.65)	0.947	0.87(0.09∼8.01)	0.903	1.00(0.10∼9.63)	0.995	1.47(0.57∼3.81)	0.424
IgM aCL	0.29(0.10∼0.83)	0.021	0.92(0.18∼4.67)	0.927	0.26(0.19∼1.98)	0.425	1.17(0.12∼0.96)	0.887	1.39(0.14∼3.54)	0.777	1.07(0.39∼2.88)	0.892
Malar rash	1.11(0.54∼2.24)	0.771	1.45(0.49∼4.21)	0.494	1.07(0.51∼2.23)	0.857	0.61(0.13∼2.77)	0.526	0.44(0.08∼2.47)	0.354	0.892(0.46∼1.73)	0.738
Serositis	1.56(0.71∼3.41)	0.265	0.68(0.20∼2.30)	0.539	0.58(0.25∼1.34)	0.206	0.29(0.03∼2.51)	0.263	0.33(0.03∼2.98)	0.329	0.85(0.42∼1.72)	0.653
Nephritis	0.36(0.31∼1.30)	0.215	0.51(0.15∼1.72)	0.284	0.91(0.43∼1.94)	0.823	0.23(0.02∼1.96)	0.179	-	0.999	1.10(0.57∼2.12)	0.776
Hemolyticanemia	1.43(0.55∼3.70)	0.465	0.73(0.15∼3.54)	0.699	1.11(0.43∼2.84)	0.827	-	0.999	-	0.999	1.09(0.46∼2.57)	0.840
Leukopenia	0.96(0.48∼1.97)	0.945	0.90(0.31∼2.61)	0.854	1.09(0.52∼2.25)	0.817	0.41(0.09∼1.83)	0.244	0.27(0.05∼1.52)	0.140	1.18(0.61∼2.28)	0.614
Lymphopenia	0.36(1.10∼1.48)	0.165	3.8(0.41∼34.63)	0.236	1.31(0.39∼4.32)	0.656	1.47(0.14∼5.06)	0.744	1.37(0.13∼4.57)	0.790	0.79(0.26∼2.42)	0.685
Thrombocytopenia	1.19(0.58∼2.41)	0.630	1.59(0.56∼4.53)	0.380	1.71(0.81∼3.58)	0.153	1.74(0.40∼7.44)	0.455	0.24(0.26∼5.97)	0.783	0.72(0.37∼1.40)	0.337

aCL: anti-cardiolipin antibodies, CI: confidence interval, Ig: immunoglobulin, NCBI: National Center for Biotechnology Information, OR: odds ratio, RNP: ribonucleoprotein, SLE: systemic lupus erythematosus.

Table 5.

The distribution of rs554743 genotype in SLE patient with IgM aCL feature

Genotype	IgM aCL		p-value	OR (95% CI)
Genotype	Negative	Positive	p-value	OR (95% CI)
AA	30 (27.5)	10 (52.6)	0.021	0.293 (0.103∼0.831)
AG/GG	79 (72.5)	9 (47.4)

Values are presented as number (%). aCL: anti-cardiolipin antibodies, CI: confidence interval, IgM: immunoglobulin M, OR: odds ratio, SLE: systemic lupus erythematosus.

TOOLS

Similar articles