Genetic association between mannose-binding lectin polymorphisms

and viral hepatitis: a meta-analysis

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Running head: MBL polymorphisms and viral hepatitis

Chunhua Qie, M.D. 1*, Yamin Liu, M.D. 1, Ping Ma, M.D. 1, and Hongzhang Wu,
M.D. 1

* Corresponding author

Address:

1. Department of Laboratory Medicine, Tianjin Second People’s Hospital, Tianjin

300192, China

Correspondence to: Dr. Chunhua Qie, Department of Laboratory Medicine, Tianjin

Second People’s Hospital, No.7 South Sudi Road of Nankai district, Tianjin 300192,

China. E-mail: qiechunhua65@163.com

Abstract

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Background: Some previous genetic association studies tried to investigate potential

associations between mannose-binding lectin (MBL) polymorphisms and viral

hepatitis. However, the results of these studies were not consistent. Therefore, we

performed the present meta-analysis to explore associations between MBL

polymorphisms and viral hepatitis in a larger pooled population.

Methods: Systematic literature research of PubMed, Web of Science, Embase and

CNKI was performed to identify eligible studies for pooled analyses. We used

Review Manager Version 5.3.3 to conduct statistical analyses.

Results: Totally 27 studies were included for analyses (4,840 cases and 5,729

controls). The pooled analyses showed that MBL promoter (-211C/G, dominant

model: p=0.0002, I2=40%; over-dominant model: p=0.0001, I2=22%) and exon 1

(codon 52, 54 and 57, dominant model: p=0.04, I2=49%; allele model: p=0.01,

I2=48%) polymorphisms were both significantly associated with viral hepatitis in

overall population. Further subgroup analyses revealed similar significant findings for

MBL promoter polymorphism in HBV and HCV, but no any positive results were

detected in subgroup analyses for MBL exon 1 polymorphism.

Conclusions: These results suggested that MBL promoter and exon 1 polymorphisms

could be used to identify individuals at higher susceptibility to HBV and HCV.

Keywords: Mannose-binding lectin (MBL); Viral hepatitis; Hepatitis B virus

(HBV); Hepatitis C virus (HCV); Meta-analysis

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Introduction

Viral hepatitis is a common infectious disorder caused by various kinds of hepatitis

viruses (HAV, HBV, HCV, HDV and HEV), and it could lead to life-threatening liver

diseases such as cirrhosis and hepatocellular carcinoma (HCC) [1-2]. Despite rapid

advancements achieved in early diagnosis and anti-viral therapy over the past few

decades, viral hepatitis is still a major global health threat and it accounts for over 1.5

million deaths every year [3]. The course of viral hepatitis depends on a complex

interaction of pathogen, host and environmental factors, and the fact that only some of

infected individuals eventually develop active viral hepatitis and its associated liver

complications suggests that host genetic background is crucial for its development

[4-5].

Mannose-binding lectin (MBL) is a pattern recognition protein of the innate

immune system that is viral for the initiation of immune defenses against exogenous

pathogens [6]. The binding of MBLs with sugars on the surface of invading microbes

could lead to activation of the complement system, induction of phagocytosis and

elimination of pathogens [7-8]. Consequently, it is possible that MBL polymorphisms,

which may impact biological activities of MBLs, might also be involved in the

development of multiple infectious diseases including viral hepatitis.

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To date, numerous studies investigated potential associations between MBL

polymorphisms and viral hepatitis. However, the results of these studies were not

consistent. Previous studies failed to reach a consensus regarding associations

between MBL polymorphisms and viral hepatitis partially because of their relatively

small sample sizes. Thus, we performed the present meta-analysis to explore the

relationship between MBL polymorphisms and viral hepatitis in a larger pooled

population.

Materials and Methods

We reported this meta-analysis as suggested by the Reporting Items for Systematic

Reviews and Meta-analyses (PRISMA) guideline [9]. An Open Science Framework

(osf.io) account was created to make this meta-analysis more publicly available.

Literature search and inclusion criteria

Eligible studies were retrieved from PubMed, Web of Science, Embase and CNKI

using the following searching strategy: (Mannose-binding lectin OR Mannose binding

lectin OR Mannose-Binding Protein OR Mannose Binding Protein OR MBL OR

MBP) AND (polymorphism OR variant OR SNP OR mutation OR variation OR

genotype OR allele) AND (Viral hepatitis OR Hepatitis A OR HAV OR Hepatitis B

OR HBV OR Hepatitis C OR HCV OR Hepatitis D OR HDV OR Hepatitis E OR

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HEV). When searching CNKI, we translated the English keywords into Chinese. The

searching strategy of CKNI was identical to that for Pubmed, Web of Science and

Embase. The initial search was conducted in January 2019 and the latest update was

performed in May 2019. Moreover, we also screened the references of all retrieved

articles to identify other potential relevant studies.

Included studies must satisfy all the following criteria: 1. genetic association

studies about MBL polymorphisms and viral hepatitis in human beings; 2. provide

genotypic/allelic frequency of investigated polymorphisms in cases and controls; 3.

full text in English or Chinese available. Studies were excluded if one of the

following criteria was met: 1. not about MBL polymorphisms and viral hepatitis; 2.

studies that were not performed in human beings; 3. case reports or case series; 4.

reviews and comments.

Data extraction and quality assessment

We extracted following data from included studies: the last name of the first author,

publication year, country and ethnicity of study subjects, sample size and

genotypic/allelic distributions of MBL polymorphisms in cases and controls. The

probability value (p value) of Hardy-Weinberg equilibrium (HWE) was also

calculated. When necessary, we wrote to the corresponding authors for extra

information. We used the Newcastle-Ottawa scale (NOS) to assess the quality of

eligible studies [10]. This scale has a score range of zero to nine, and studies with a

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score of more than seven were thought to be of high quality. Data extraction and

quality assessment were performed by two independent reviewers. Any disagreement

between two reviewers was solved by discussion until a consensus was reached.

Statistical analyses

We used Review Manager Version 5.3.3 (The Cochrane Collaboration, Software

Update) to conduct statistical analyses. We calculated odds ratios (ORs) and 95%

confidence intervals (CIs) to estimate strength of associations in dominant, recessive,

over-dominant and allele genetic models, and statistical significances of pooled

analyses were determined by the Z test, with a p value of 0.05 or less was defined as

statistically significant. I2 statistics were employed to assess between-study

heterogeneities. If I2 was greater than 50%, random-effect models (REMs,

DerSimonian-Laird method) would be used to pool the data on account of significant

heterogeneities. Otherwise, fixed-effect models (FEMs, Mantel-Haenszel method)

would be used for synthetic analyses. Subgroup analyses by ethnicity of participants

and type of disease were performed. Stabilities of synthetic results were evaluated

with sensitivity analyses, and publication biases were evaluated with funnel plots.
Results

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Characteristics of included studies

The initial literature search found 164 potential relevant articles. Among these

articles, totally 27 studies met the inclusion criteria and thus were included for pooled

analyses (see Fig. 1). The NOS score of eligible articles ranged from 7 to 8, which

indicated that all included studies were of high quality. Baseline characteristics of

included studies were shown in Table 1.

Overall and subgroup analyses

The results of overall and subgroup analyses were summarized in Table 2. To be

brief, 4,840 cases and 5,729 controls were eligible for analyses, the pooled analyses

showed that MBL promoter (-211C/G, dominant model: p = 0.0002, OR = 0.75,

95%CI 0.64-0.87, I2 = 40%; over-dominant model: p = 0.0001, OR = 1.36, 95%CI

1.16-1.59, I2 = 22%) and exon 1 (codon 52, 54 and 57, dominant model: p = 0.04, OR

= 0.91, 95%CI 0.82-0.99, I2 = 49%; allele model: p = 0.01, OR = 0.91, 95%CI

0.84-0.98, I2 = 48%) polymorphisms were both significantly associated with viral

hepatitis in overall population. Further subgroup analyses revealed similar significant

findings for MBL promoter polymorphism in East Asians, HBV and HCV, whereas no
any positive results were detected in subgroup analyses for MBL exon 1

polymorphism (see Table 2).

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Sensitivity analyses

We performed sensitivity analyses by deleting one individual study each time to test

the effects of individual study on pooled results. No any altered results were observed

in overall and subgroup comparisons, which indicated that our findings were

statistically robust.

Publication biases

We used funnel plots to assess publication biases. We did not find obvious asymmetry

of funnel plots in any comparisons, which suggested that our findings were unlikely to

be impacted by severe publication biases (see Supplementary figure 1).

Discussion

To our knowledge, this is to date the first meta-analysis on associations between MBL

polymorphisms and viral hepatitis, and our pooled analyses suggested that MBL

promoter and exon 1 polymorphisms were both significantly associated with viral
hepatitis in overall population. Further subgroup analyses revealed similar significant

findings for MBL promoter polymorphism in HBV and HCV, but no any positive

results were detected for MBL exon 1 polymorphism in subgroup analyses. The

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stabilities of synthetic results were evaluated by sensitivity analyses, and no

alterations of results were observed in any comparisons, which suggested that our

findings were statistically robust.

There are several notable points about this meta-analysis. Firstly, although two

types of vital hepatitis were combined for analyses, between-study heterogeneities in

overall analyses were only mild to moderate, which suggested that pooled analyses of

these studies were feasible. Secondly, subgroup analyses by type of disease revealed

similar positive results for MBL promoter polymorphism in HBV and HCV, whereas

no any positive results were detected for MBL exon 1 polymorphism in subgroup

analyses. However, it is worth noting that the trends of associations for HBV and

HCV were identical to that of overall analyses for MBL exon 1 polymorphism.

Considering that the sample sizes of pooled analyses with regard to the HBV and

HCV were still relatively small. It is possible that our study was still not statistically

adequate to detect the actual associations between MBL exon 1 polymorphism and

HBV or HCV. Further studies with larger sample sizes are still needed to confirm our

speculations. Thirdly, the pathogenesis of viral hepatitis is extremely complex, and

therefore the probability that a specific genetic polymorphism could significantly

contribute to its development is low, and we strongly recommend further studies to

perform haplotype analyses and explore potential gene-gene interactions [11].

Fourthly, to more precisely measure the effects of certain genetic factors on disease

occurrence and development, gene-environmental interactions should also be

considered. However, since included studies only focused on the effects of MBL

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polymorphisms on individual susceptibility to viral hepatitis, such analyses were not

applicable in the current meta-analysis [12]. Fifthly, the present meta-analysis aimed

to explore associations between MBL polymorphisms and viral hepatitis. However,

only HBV and HCV could be analyzed in the current study because we did not find

any reports about other types of viral hepatitis. Sixthly, it is worth noting that a recent

meta-analysis conducted by Xu et al [13] also tried to explore potential associations

between MBL polymorphisms and HBV. However, the authors failed to analyze

associations between MBL polymorphisms and HCV in their meta-analysis.

Moreover, many related studies about HBV were published in the last five years.

Therefore, an update meta-analysis is warranted and the sample sizes of our analyses

were also significantly larger than that of the previous meta-analysis. So our work

should be considered as a valuable supplementary work to pre-existing literatures.

Like all meta-analysis, this study certainly has some limitations. First, due to

lack of raw data, adjusted analyses were inapplicable, and we have to admit that

failure to perform further adjusted analyses for potential confounding factors might

impact the reliability of our findings [14]. Second, associations between MBL

polymorphisms and viral hepatitis might also be modified by gene-environmental

interactions. However, we could not perform relevant analyses accordingly since most

of studies did not investigate these associations [15]. Third, grey literatures that were
not formally published in academic journals were not considered to be eligible for

analyses in this meta-analysis. However, since grey literatures were not analyzed,

although funnel plots suggested that severe publication biases were unlikely, it is still

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possible that our findings may be impacted by potential publication biases [16]. On

account of above mentioned limitations, our findings should be cautiously interpreted.

In conclusion, our meta-analysis suggested that MBL promoter and exon 1

polymorphisms were both significantly associated with HBV and HCV in overall

population. These results suggested that these two polymorphisms could be used to

identify individuals at higher susceptibility to HBV and HCV. However, it is worth

noting that some of genetic comparisons in the current study were only based on

limited number of studies, so further well-designed studies are still warranted to

confirm our findings.

Authors' contributions

Chunhua Qie and Yamin Liu conceived of the study, participated in its design.

Chunhua Qie, Yamin Liu and Ping Ma conducted the systematic literature review.

Hongzhang Wu performed data analyses. Chunhua Qie and Yamin Liu drafted the

manuscript. All gave final approval and agree to be accountable for all aspects of

work ensuring integrity and accuracy.

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The authors declare that they have no conflict of interest.
Conflict of interest
Acknowledgments

Funding
None.

None.
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16. Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene

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Fig. 1. Flowchart of study selection for the present study.
Figure legends
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Table 1. The characteristics of included studies.

Genotype distribution
First author, year Country Ethnicity Type of disease Sample size P-value for HWE NOS score
Cases Controls

Promoter (-211C/G)

Chatzidaki 2012 Greece Caucasian HBV 33/68 20/11/2 42/19/7 0.048 8

Chen 2010 China East Asian HBV 304/361 200/95/9 251/100/10 0.992 8

Filho 2010 Brazil Mixed HBV 102/232 64/35/3 165/58/9 0.183 7

Fletcher 2010 India South Asian HBV 133/137 76/51/6 68/57/12 0.991 8

Gu 2016 China East Asian HBV 564/171 392/161/11 131/33/7 0.015 8

Halla 2010 Brazil Mixed HCV 186/232 105/74/7 165/58/9 0.183 7

Lin 2016 China East Asian HBV 315/315 207/91/17 239/72/4 0.583 7

Zupin 2016 Italy Caucasian HCV 203/61 110/82/11 34/24/3 0.634 8

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Exon 1 (Codon 52, 54 and 57)

Bellamy 1998 UK African HBV 180/810 80/86/16 383/366/61 0.037 7

Chatzidaki 2012 Greece Caucasian HBV 33/68 26/6/1 54/12/2 0.216 8

Chen 2010 China East Asian HBV 304/361 222/75/7 270/79/12 0.045 8

Cheong 2005 Korea East Asian HBV 372/126 241/119/12 70/52/4 0.123 8

Chong 2005 China East Asian HBV 407/485 274/102/31 362/92/30 <0.001 7

Erdemir 2015 Turkey Caucasian HBV 67/99 53/8/6 71/27/1 0.366 8

Filho 2010 Brazil Mixed HBV 102/232 57/40/5 147/78/7 0.381 7

Fletcher 2010 India South Asian HBV 133/147 NA NA NA 8

Gu 2016 China East Asian HBV 564/171 399/149/16 104/59/8 0.920 8

Halla 2010 Brazil Mixed HCV 186/232 98/76/12 147/78/7 0.381 7

Hakozaki 2002 Japan East Asian HBV 43/260 32/7/4 194/50/16 <0.001 8

He 2013 China East Asian HCV 150/75 106/36/8 54/18/3 0.353 7

Höhler 1998 Germany Caucasian HBV 61/92 31/29/1 51/39/2 0.078 7

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Lin 2016 China East Asian HBV 315/315 207/88/20 239/69/7 0.450 7

Ma 2008 China East Asian HBV 82/111 59/21/2 78/32/1 0.241 8

Matsushita 1998 Japan East Asian HCV 93/218 61/24/8 130/65/23 0.002 7

Moura 2017 Brazil Mixed HBV 65/300 37/25/3 167/123/10 0.025 7

Moura 2017 Brazil Mixed HCV 92/300 52/36/4 167/123/10 0.025 7

Sasaki 2000 Japan East Asian HCV 52/50 34/17/1 29/21/0 0.060 8

Segat 2008 Italy Caucasian HBV 79/164 47/30/2 102/49/13 0.050 8

Segat 2008 Italy Caucasian HCV 99/164 57/36/6 102/49/13 0.050 8

Shi 2001 China East Asian HBV 285/150 199/73/13 96/47/7 0.687 7

Song 2003 Vietnam East Asian HBV 92/143 81/11/0 126/17/0 0.450 7

Thomas 1996 UK East Asian HBV 20/117 11/9/0 88/29/0 0.126 8

Thomas 1996 UK Caucasian HBV 33/117 19/12/2 74/41/2 0.166 8

Tong 2008 China East Asian HBV 114/64 NA NA NA 8

Vallinoto 2009 Brazil Mixed HCV 73/92 35/31/7 42/38/12 0.468 7

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Yuen 1999 China East Asian HBV 146/117 NA NA NA 7

Zheng 2012 China East Asian HBV 395/88 187/206/2 62/26/0 0.104 8

Zupin 2016 Italy Caucasian HCV 203/61 128/64/11 39/17/5 0.135 8

Abbreviations: HBV, Hepatitis B virus infection; HCV, Hepatitis C virus infection; HWE, Hardy-Weinberg equilibrium; NOS, Newcastle-Ottawa scale; NA, Not available.

HWE assumes that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary
influences. Consider a population of monoecious diploids, where each organism produces male and female gametes at equal frequency, and has two alleles at each
gene locus. The allele frequencies at each generation are obtained by pooling together the alleles from each genotype of the same generation according to the
expected contribution from the homozygote and heterozygote genotypes.
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Table 2. Results of pooled analyses for MBL gene polymorphisms and viral hepatitis.

Population Sample size Dominant comparison Recessive comparison Over-dominant comparison Allele comparison

P value OR (95%CI) I2 statistic P value OR (95%CI) I2 statistic P value OR (95%CI) I2 statistic P value OR (95%CI) I2 statistic

-211C/G

Overall 1840/1577 0.0002 0.75 (0.64-0.87) 40% 0.95 0.99 (0.68-1.43) 42% 0.0001 1.36 (1.16-1.59) 22% 0.06 0.83 (0.68-1.01) 52%

East Asian 1183/847 0.001 0.72 (0.58-0.88) 0% 0.71 1.27 (0.37-4.39) 79% 0.004 1.37 (1.11-1.69) 0% 0.002 0.75 (0.63-0.90) 48%

Caucasian 236/129 0.81 0.94 (0.59-1.52) 0% 0.72 0.84 (0.31-2.23) 0% 0.67 1.11 (0.68-1.82) 0% 0.96 0.99 (0.67-1.46) 0%

HBV 1451/1284 0.005 0.78 (0.66-0.93) 38% 0.75 0.89 (0.44-1.81) 58% 0.003 1.31 (1.09-1.56) 0% 0.21 0.86 (0.68-1.09) 58%

HCV 389/293 0.008 0.64 (0.46-0.89) 61% 0.96 1.02 (0.46-2.26) 0% 0.21 1.49 (0.80-2.78) 67% 0.03 0.73 (0.55-0.96) 46%

Codon 52, 54 and 57

Overall 4840/5729 0.04 0.91 (0.82-0.99) 49% 0.17 1.15 (0.94-1.42) 0% 0.09 1.09 (0.99-1.19) 45% 0.01 0.91 (0.84-0.98) 48%

East Asian 3434/2851 0.59 0.94 (0.74-1.19) 70% 0.30 1.16 (0.88-1.53) 0% 0.72 1.04 (0.83-1.31) 64% 0.47 0.93 (0.76-1.13) 67%

Caucasian 575/765 0.53 0.93 (0.73-1.18) 0% 0.75 0.92 (0.54-1.55) 35% 0.42 1.11 (0.86-1.43) 25% 0.44 0.92 (0.75-1.13) 0%
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HBV 3892/4537 0.27 0.90 (0.75-1.08) 59% 0.11 1.22 (0.96-1.56) 9% 0.44 1.07 (0.89-1.29) 58% 0.13 0.89 (0.76-1.03) 58%

HCV 948/1192 0.47 0.93 (0.77-1.12) 0% 0.96 1.01 (0.69-1.48) 0% 0.47 1.07 (0.89-1.30) 0% 0.38 0.93 (0.80-1.09) 0%

Abbreviations: HBV, Hepatitis B virus infection; HCV, Hepatitis C virus infection; OR, Odds ratio; CI, Confidence interval; NA, Not available.

The values in bold represent there is statistically significant differences between cases and controls.