Ann Dermatol.  2017 Oct;29(5):571-577. 10.5021/ad.2017.29.5.571.

Association of Single-Nucleotide Polymorphisms of the MBL2 with Atopic Dermatitis in Korean Patients

• Kim JS
• Lee SY
• Hahn HJ
• Lee YB
• Yu DS
• Kim JW

• KMID: 2388908
• DOI: http://doi.org/10.5021/ad.2017.29.5.571

Abstract

BACKGROUND
Human mannose-binding lectin (MBL) is a serum lectin taking part in the innate immunity by opsonizing various microorganisms for phagocytosis. The MBL serum concentration is affected by several single-nucleotide polymorphisms (SNPs) in the promoter region of the MBL2 gene.
OBJECTIVE
The purpose of this study was to examine the relationship between MBL2 polymorphisms and atopic dermatitis (AD) susceptibility.
METHODS
To examine whether the MBL2 SNPs are related to AD susceptibility, we examined 237 patients with AD and 94 controls by polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-sequence specific primer analyses of four polymorphic loci: two (H/L and X/Y) within the promoter region and the other two (P/Q and A/B) within exon 1. MBL concentrations in the blood were estimated by ELISA.
RESULTS
The prevalence of haplotype HYPB, leading to MBL deficiency, was significantly decreased in the AD patients compared to the controls (p=0.002), while the prevalence of haplotype HYPA was increased with a clear trend toward significance (p=0.056). The frequency of MBL2 LYPB/LXPA (odds ratio, 0.08; 95% confidence interval, 0.009~0.655; p=0.021) were significantly decreased in the AD patients. The blood log [total immunoglobulin E, IgE] levels of MBL2 HYPA/HYPA, HYPA/LYPA, HYPA/LYPB, HYPA/LYQA, and LYQA/LXPA haplotype pairs were significantly increased in the AD patients.
CONCLUSION
The frequency of MBL2 HYPB haplotype was significantly decreased in the AD patients compared to the controls. The frequency of LYPB/LXPA had a possibly protective effect on AD. Moreover, the MBL2 HYPA haplotype pairs, which were related to higher blood total IgE levels, were possibly associated with extrinsic AD.

Keyword

Atopic dermatitis; Innate immunity; Mannose-binding lectin

MeSH Terms

Dermatitis, Atopic*
Enzyme-Linked Immunosorbent Assay
Exons
Haplotypes
Humans
Immunity, Innate
Immunoglobulin E
Immunoglobulins
Mannose-Binding Lectin
Phagocytosis
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Prevalence
Promoter Regions, Genetic
Immunoglobulin E
Immunoglobulins
Mannose-Binding Lectin

Figure

• 

  Fig. 1 Gene map, haplotypes and linkage disequilibrium (LD) coefficients in MBL. (A) Gene map and single-nucleotide polymorphisms (SNPs) in MBL located on chromosome 10q11.2-q21. Polymorphic sites within the promoter region and exon-1 are marked by a gray block. Pairwise measures of linkage disequilibrium for the 4 polymorphisms are shown. (B) Haplotypes of MBL. Haplotypes with frequency >0.02 are presented. (C) LD coefficient (|D′|) among MBL SNP.

Reference

1. Akdis CA, Akdis M, Simon D, Dibbert B, Weber M, Gratzl S, et al. T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis. J Invest Dermatol. 1999; 113:628–634. PMID: 10504452.

2. Matsushita M, Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med. 1992; 176:1497–1502. PMID: 1460414.

3. Madsen HO, Satz ML, Hogh B, Svejgaard A, Garred P. Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America. J Immunol. 1998; 161:3169–3175. PMID: 9743385.

4. Garred P, Madsen HO, Hofmann B, Svejgaard A. Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency. Lancet. 1995; 346:941–943. PMID: 7564730.

5. Brandrup F, Homburg KM, Wang P, Garred P, Madsen HO. Mannan-binding lectin deficiency associated with recurrent cutaneous abscesses, prurigo and possibly atopic dermatitis. A family study. Br J Dermatol. 1999; 140:180–181. PMID: 10215800.

6. Brandão LA, Guimarães RL, Carrera M, Milanese M, Segat L, Luiz de Lima-Filho J, et al. MBL2 functional allelic variants and increased risk for the development of atopic dermatitis in Brazilian children. Arch Dermatol. 2008; 144:412–413. PMID: 18347304.

7. Carréra MC, Moura P, Crovella S, de Souza PR, de Souza LC, Sarinho E. High polymorphism of the MBL2 gene in patients with atopic dermatitis. Ann Allergy Asthma Immunol. 2010; 105:39–42. PMID: 20642202.

8. Hashimoto S, Nakamura K, Oyama N, Kaneko F, Fujita T, Tsunemi Y, et al. Mannose-binding lectin (MBL) single nucleotide polymorphism is not associated with atopic dermatitis in Japanese patients. J Dermatol. 2005; 32:1038–1040. PMID: 16471473.

9. Hanifin JM. Atopic dermatitis. J Am Acad Dermatol. 1982; 6:1–13. PMID: 7045169.

10. Tsutsumi A, Sasaki K, Wakamiya N, Ichikawa K, Atsumi T, Ohtani K, et al. Mannose-binding lectin gene: polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. Genes Immun. 2001; 2:99–104. PMID: 11393663.

11. Matsushita M, Hijikata M, Ohta Y, Iwata K, Matsumoto M, Nakao K, et al. Hepatitis C virus infection and mutations of mannose-binding lectin gene MBL. Arch Virol. 1998; 143:645–651. PMID: 9638138.

12. Steffensen R, Thiel S, Varming K, Jersild C, Jensenius JC. Detection of structural gene mutations and promoter polymorphisms in the mannan-binding lectin (MBL) gene by polymerase chain reaction with sequence-specific primers. J Immunol Methods. 2000; 241:33–42. PMID: 10915847.

13. Madsen HO, Garred P, Thiel S, Kurtzhals JA, Lamm LU, Ryder LP, et al. Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol. 1995; 155:3013–3020. PMID: 7673719.

14. Garred P, Madsen HO, Kurtzhals JA, Lamm LU, Thiel S, Hey AS, et al. Diallelic polymorphism may explain variations of the blood concentration of mannan-binding protein in Eskimos, but not in black Africans. Eur J Immunogenet. 1992; 19:403–412. PMID: 1477092.

15. Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics. 1987; 117:331–341. PMID: 3666445.

16. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003; 73:1162–1169. PMID: 14574645.

17. Bundy KW, McGirt LY, Bankova LG, Wollenberg A, Beck LA, De Benedetto A. Mannan-binding lectin levels and activity are not altered in atopic dermatitis patients with a history of eczema herpeticum. Dermatol Res Pract. 2011; 2011:769890. PMID: 22110485.

18. Werth VP, Berlin JA, Callen JP, Mick R, Sullivan KE. Mannose binding lectin (MBL) polymorphisms associated with low MBL production in patients with dermatomyositis. J Invest Dermatol. 2002; 119:1394–1399. PMID: 12485445.

19. Park KS, Min K, Nam JH, Bang D, Lee ES, Lee S. Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behçet's disease. Tissue Antigens. 2005; 65:260–265. PMID: 15730518.

20. Kim J, Im CH, Kang EH, Lee EY, Lee YJ, Park KS, et al. Mannose-binding lectin gene-2 polymorphisms and serum mannose-binding lectin levels in Behçet's disease. Clin Exp Rheumatol. 2009; 27:S13–S17. PMID: 19796526.

21. Takahashi R, Tsutsumi A, Ohtani K, Muraki Y, Goto D, Matsumoto I, et al. Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus. Ann Rheum Dis. 2005; 64:311–314. PMID: 15647440.

22. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci. 2010; 58:1–7. PMID: 20207111.

23. Kim JS, Choi J, Hahn HJ, Lee YB, Yu DS, Kim JW. Association of macrophage migration inhibitory factor polymorphisms with total plasma IgE Levels in patients with atopic dermatitis in Korea. PLoS One. 2016; 11:e0162477. PMID: 27598332.