Mannose-binding lectin and its genetic variants

Garred, Peter; Larsen, Frank Wugt; Seyfarth, Jeanette; Fujita, Ricardo; Madsen, Hans O.

doi:10.1038/sj.gene.6364283

Cited by 366 publications

(359 citation statements)

References 62 publications

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“…Haplotypes based on some specific SNPs in MBL2 are known to be associated with MBL serum concentration variability (29). MBL serum concentration influences susceptibility to and clinical course of many infectious and chronic diseases (30).…”

Section: Resultsmentioning

confidence: 99%

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Mukherjee

Sarkar-Roy

Wagener

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We tested the opposing views concerning evolution of genes of the innate immune system that (i) being evolutionary ancient, the system may have been highly optimized by natural selection and therefore should be under purifying selection, and (ii) the system may be plastic and continuing to evolve under balancing selection. We have resequenced 12 important innate-immunity genes (CAMP, DEFA4, DEFA5, DEFA6, DEFB1, MBL2, and TLRs 1, 2, 4, 5, 6, and 9) in healthy volunteers (n ‫؍‬ 171) recruited from a region of India with high microbial load. We have compared these data with those of European-Americans (EUR) and African-Americans (AFR). We have found that most of the human haplotypes are many mutational steps away from the ancestral (chimpanzee) haplotypes, indicating that humans may have had to adapt to new pathogens. The haplotype structures in India are significantly different from those of EUR and AFR populations, indicating local adaptation to pathogens. In these genes, there is (i) generally an excess of rare variants, (ii) high, but variable, degrees of extended haplotype homozygosity, (iii) low tolerance to nonsynonymous changes, (iv) essentially one or a few high-frequency haplotypes, with star-like phylogenies of other infrequent haplotypes radiating from the modal haplotypes. Purifying selection is the most parsimonious explanation operating on these innate immunity genes. This genetic surveillance system recognizes motifs in pathogens that are perhaps conserved across a broad range of pathogens. Hence, functional constraints are imposed on mutations that diminish the ablility of these proteins to detect pathogens. extended haplotype homozygosity ͉ haplotype networks ͉ neutrality tests ͉ resequencing

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Section: Resultsmentioning

confidence: 99%

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Mukherjee

Sarkar-Roy

Wagener

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Haplotypes based on some specific loci in MBL2 are known to be associated with MBL serum concentration variability (Garred et al, 2006). MBL serum concentration influences susceptibility to and clinical course of many infectious and chronic diseases (Nuytinck and Shapiro, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…While α-defensins are produced primarily by intestinal Paneth cells and neutrophils, the β-defensins are primarily produced by epithelial cells. MBL is a calcium-dependent serum protein that plays a role in the innate immune response by binding to carbohydrates on the surface of a wide range of pathogens (Garred et al, 2006). It is also an important component of the complement-activation pathway for activation of macrophages by forming membrane-attack complexes (MACs).…”

Section: Genes Studied and Resequencingmentioning

confidence: 99%

Genetic variation and haplotype structures of innate immunity genes in eastern India

Bairagya

Bhattacharya

et al. 2008

Infection, Genetics and Evolution

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This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing ~75 kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19 kb (chromosome 22) to one SNP per 2.18 kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3 SNPs kb −1 ) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection.

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“…MBL pathway-mediated protection efficacy depends on the serum and tissue concentration of biologically active MBL (4,9). Low MBL levels are primarily due to single-nucleotide polymorphisms residing in the mbl2 gene on chromosome 10.…”

Section: Yme Borreliosis (Lb) Is the Most Common Pathogenic Tick-mentioning

confidence: 99%

Lyme Borreliosis and Deficient Mannose-Binding Lectin Pathway of Complement

Sajanti

Gröndahl-Yli-Hannuksela

Kauko

et al. 2015

The Journal of Immunology

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Risk factors for the widely endemic and much-debated tick-borne infection, Lyme borreliosis (LB), are unknown. The mannose-binding lectin (MBL) pathway of the complement cascade has an essential role in the eradication of Borrelia burgdorferi. A sufficient concentration of biologically active MBL in body fluids is an indicator of proper function of the MBL pathway. In this study, we investigated whether impaired MBL pathway function, represented by reduced serum MBL concentration, predisposes individuals to LB. First, we determined a serum MBL concentration cut-off level associated with diminished MBL pathway function in a group of 201 individuals. Then, we identified 350 borrelia Ab+ LB patient serum samples and 350 Ab− control samples from the archives of our laboratory and measured serum MBL concentrations in both sample groups. The concentration data were analyzed statistically using logistic regression, controlling for MBL cut-off, age, gender, and age and gender interaction. Serum MBL concentrations < 787 and < 445 ng/ml were associated with diminished and deficient MBL pathway function, respectively. Using these cut-offs, diminished (41.4 versus 27.4%, p = 0.0027) and deficient (26.3 versus 17.1%, p = 0.0361) MBL pathway functions were observed statistically more frequently in the LB patient samples than in the control samples. Also, the age-adjusted median serum MBL concentrations were significantly lower in the LB patient samples than in the non-LB controls. Our findings indicate that a deficiency in the MBL pathway of the complement cascade is a risk factor for developing disseminated Ab+ LB.

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Mannose-binding lectin and its genetic variants

Cited by 366 publications

References 62 publications

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Genetic variation and haplotype structures of innate immunity genes in eastern India

Lyme Borreliosis and Deficient Mannose-Binding Lectin Pathway of Complement

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