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Peer-reviewed

Research Article

Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis

• Satu Massinen,
• Tuula Siljander,
• Siru Mäkelä,
• Katja Kivinen,
• Rasko Leinonen,
• Hong Jiao,
• Päivi Aitos,
• Matti Karppelin,
• Jaana Vuopio,
• Jaana Syrjänen,
• Juha Kere

Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis

• Katariina Hannula-Jouppi,
• Satu Massinen,
• Tuula Siljander,
• Siru Mäkelä,
• Katja Kivinen,
• Rasko Leinonen,
• Hong Jiao,
• Päivi Aitos,
• Matti Karppelin,
• Jaana Vuopio

x

• Published: February xx, 2013
• https://doi.org/ten.1371/journal.pone.0056225

Figures

Abstract

Background

Bacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most usually by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of homo erysipelas exist.

Methods

Nosotros performed genome-broad linkage with the 10,000 variant Human Mapping Array (HMA10K) array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls.

Results

Significant linkage was institute at 9q34 (nonparametric multipoint linkage score (NPL_all) 3.84, p = 0.026), which is syntenic to a quantitative trait locus for susceptibility to grouping A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate whatever to erysipelas/cellulitis susceptibility. Suggestive linkage (NPL_all>3.0) was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin Ii receptor type I) suggestively associated with erysipelas/cellulitis susceptibility.

Conclusions

Specific host genetic factors may cause erysipelas/cellulitis susceptibility in humans.

Citation: Hannula-Jouppi One thousand, Massinen S, Siljander T, Mäkelä S, Kivinen K, Leinonen R, et al. (2013) Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis. PLoS One 8(2): e56225. https://doi.org/10.1371/journal.pone.0056225

Editor: Ramy M. Aziz, Cairo University, Egypt

Received: October 2, 2012; Accepted: January 7, 2013; Published: February xx, 2013

Copyright: © 2013 Hannula-Jouppi et al. This is an open-access commodity distributed nether the terms of the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Academy of Finland/Microbes and Human Inquiry Program, Helsinki Biomedical Graduate School, Sigrid Jusélius Foundation, and the Swedish Inquiry Quango. The funders had no part in study design, information collection and analysis, conclusion to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Bacterial non-necrotizing erysipelas and cellulitis are frequently recurring, diffuse, and spreading infections of the skin and subcutaneous tissues, which manifest with local erythema, pain, and warmth usually accompanied by fever, leukocytosis, lymphangitis, and lymphadenitis [1]. Both Group A (Streptococcus pyogenes) and G (typically Streptococcus dysgalactiae subsp. equisimilis) β-hemolytic streptococci are the predominant causative agents of cellulitis/erysipelas simply infections may likewise be caused by group B and C streptococci and Staphylococcus aureus [ane], [2]. Risk factors for erysipelas/cellulitis include impaired lymphatic drainage, venous insufficiency, skin eruptions and trauma, and obesity [3]–[5]. Erysipelas/cellulitis causes significant morbidity and recurrence is mutual especially with tibial involvement, history of malignancy, dermatitis or prior surgery of the affected limb [3]–[6]. The form of a clinical infection is the outcome of the host genome, the pathogens' virulence, and the environment. Interindividual variation between hosts can crusade infections to range from asymptomatic to fatal infection, e.chiliad. the aforementioned group A streptococcal (GAS) strain can be carried asymptomatically, crusade uncomplicated pharyngitis or potentially fatal bacteremia such as streptococcal toxic stupor syndrome or necrotizing fasciitis [7]. Twin, sibling, and adoption studies accept recognized genetic factors as important determinants of susceptibility to infectious diseases, but recurrent infections and clustering in families still involve unknown genetic and immunological factors [viii].

Mendelian and polygenic host genetic factors are known to influence susceptibility to infection past bacteria, parasites, and viruses including Mycobacterium leprae, Mycobacterium tuberculosis, Streptococcus pneumoniae, Neisseria meningitidis, Schistosoma mansoni, Leishmania donovani, Epstein-Barr virus, and human being papilloma virus [9], [10]. Conversely, resistance is known for Plasmodium vivax, homo immunodeficiency virus-one, meningococcal disease, and norovirus [9], [10]. Genome-broad scans have identified susceptibility loci for leishmaniasis (22q12, 2q23-31), leprosy (10p13, 6q25), and tuberculosis (15q, Xq) [xi]–[xiv]. Host genetics is a pregnant factor in determining susceptibility to severe GAS sepsis in mouse and astringent invasive GAS infection in humans [7], [15]. Mouse susceptibility loci for GAS infection have been mapped to chromosome 17, including the mouse MHC region (syntenic to homo 6p21); chromosome 7, which is besides linked with susceptibility to Streptococcus pneumoniae infection in mice (syntenic to human 19q13.one-13.3); and chromosome 2, including genes of the interleukin ane blastoff, and prostaglandin East synthetase pathways (syntenic to human 2q14 and 9q33-34) [16]–[xviii]. Specific Human Leukocyte Antigen class Two (HLAII) haplotypes protect from severe systemic disease caused by GAS whereas other haplotypes increase the take a chance of severe affliction [19], [20]. HLAII molecules are receptors for microbial superantigens and their allelic variations can regulate cytokine responses. The intensity of an private'south inflammatory cytokine response correlates directly with the severity of infection: a higher cytokine response leads more often to astringent systemic affliction than lower cytokine levels [xix]. The HLA/MHC region in humans has also been associated with the susceptibility to many other infectious diseases, e.1000., HIV/AIDS, hepatitis, leprosy, tuberculosis, malaria, leishmaniasis, and schistosomiasis [21].

Nosotros have used erysipelas/cellulitis (hereafter referred to every bit erysipelas) equally a marker infection to identify families with 2 or more family members suffering from erysipelas and suggesting a possibly increased susceptibility to streptococcal infections. To identify putative susceptibility loci we performed a whole-genome genetic linkage browse and identified suggestive loci on chromosomes 9q34, 3q22-24, 21q22, and 22q13.

Materials and Methods

Ethics Statement

This study was approved by the Ethical Review Board of Pirkanmaa Hospital District, Tampere, Republic of finland. Written informed consent was obtained from all study participants. All clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki.

Patients and Families

Nosotros recruited individuals with recurrent erysipelas infections for which preventive monthly intramuscular benzathine penicillin injections are reimbursed in Finland. We contacted all 960 individuals reimbursed for benzathine penicillin through the National Wellness Insurance Institution in the twelvemonth 2000. Of these, 50% (483) gave consent to participate and 25% had a first-degree relative with a history of erysipelas. Nosotros then collected blood samples from 204 recurrent erysipelas patients and 124 relatives from 52 pedigrees with two or more than family members suffering from erysipelas. The diagnosis of erysipelas was verified from hospital records for all patients except for six who self-reported to have had erysipelas but no infirmary records were available for verification.

An acute erysipelas cohort of 90 patients with acute erysipelas and 90 population controls matched for age and sexual activity was too recruited. An infectious illness specialist recruited the patients from Tampere Academy Hospital and Hatanpää City Hospital, Tampere, Republic of finland when they were hospitalized for erysipelas. The cohort is described in item elsewhere [5].

Genomic Screen for Non-parametric Linkage

Samples from twenty afflicted individuals from six virtually representative families (Effigy 1) were genotyped using Affymetrix GeneChip Human being Mapping 10K Array v ane.0 (Affymetrix, Santa Clara, CA, USA). A total of 11,145 autosomal single nucleotide polymorphisms (SNPs) were used for analysis, with 82–962 SNPs per chromosome. The median concrete distance betwixt SNPs was 210 kb (genetic distance ranging from 0.24–i.12 cM), and the boilerplate heterozygosity was 0.37. Physical coordinates were mapped against the GRCh37.two man genome assembly and the deCODE genetic map was used for genetic locations [22].

MERLIN (Multipoint Engine for Rapid Likelihood Inference) software [23] was used for multipoint nonparametric linkage (NPL) analysis. Allele frequencies were estimated from data on 20 affected individuals, and SNPs with unlikely genotypes were removed prior to analysis. The genome-wide significance of NPL_all scores was estimated past simulating data 100 times with MERLIN and extracting the highest NPL_all score from each simulation. The minimum NPL_all score for suggestive linkage was 2.one (occurring once at random in a genome browse) and the threshold for pregnant linkage four.77 (occurring with a 5% probability in a genome scan). Non-parametric linkage analysis was repeated using Caucasian allele frequency estimates obtained from Affymetrix.

Verification of Linkage Peaks

The NPL results were verified with 31 microsatellites surrounding the suggested linkage peaks at 3q22-24, 9q34, 21q22, and 22q13 at approximately 2 cM (0.85–ii.2 Mb) intervals (Table 1). We genotyped 91 individuals (54 afflicted, 31 non-affected, and six who were defined unconfirmed as their erysipelas diagnosis could not be verified) from 19 families using PCR followed by capillary electrophoresis. Further fine mapping of the 9q34 linkage peak (131527468 - 135831155 bp) was performed with 22 microsatellites from 130457260 to 136035489 bp (Table 2). PCR assays were performed in 5 µl volumes containing 20 ng of Dna with standard reagent concentrations and temperature profiles. Fluorescently labeled PCR products were run on an ABI 377 sequencer. Allele calling was performed using Genotyper 2.0 (Applied Biosystems).

MERLIN was used for multipoint NPL analysis as described above. Allele frequencies were estimated from all individuals, non-affected individuals were assigned affection status unknown, and Mendelian inconsistent genotypes were removed prior to analysis. Linkage analysis was washed using 2 configurations: 0; the unconfirmed afflicted individuals were analyzed as unknown, and ii; they were analyzed as affected. The genome-wide significance of NPL_all scores for configuration 0 was estimated by simulating information g times with MERLIN and extracting the highest NPL_all score from each simulation. Minimum NPL_all score for meaning linkage was 2.49, p = 0.05. For fine mapping of 9q34, linkage analysis was washed using four configurations: 0; unconfirmed affected individuals were analyzed as unknown, and 2; they were analyzed every bit afflicted. In configurations 0_186 and 2_186, assay was identical except that allele 186 was chosen for marker D9S65.

Follow-upwards Genomic Screening with College-density Array

We selected xv affected patients and 15 unaffected controls for additional genomic screening with the Affymetrix GeneChip Man Mapping 250KSty Assortment to search for possible allele or haplotype associations assuming a stiff genetic effect. Twelve patients were from the families 1, 2, 4, 5, viii, 9, 12, fourteen, 22, 32, 37, and 38, and their genetically independent family unit members served as controls. Three patients and three controls were from the astute cohort. Genotypes were chosen with BRLMM using Affymetrix default parameters. Analysis focused on the defined linkage peaks: 3q22-24 (D3S1306-D3S1299), 9q34 (D9S290-D9S1863), 21q22 (D21S1898-D21S1920), and 22q31 (D22S1159-D22S1141) (Table 1). To evaluate potential differences of haplotype frequencies between cases and controls, shared heterozygosity among cases was checked, allelic association was analyzed by using Haploview, and haplotype association was analyzed by both Haploview and Haplotype Pattern Mining [24], [25].

Candidate Gene Analyses

Altogether 5 candidate genes in the 9q34 linkage meridian were called based on their biological relevance in immunity or infections (Table 2). After PCR with flanking intronic primers, all exons were sequenced in index individuals from the six families (xi, 12, 13, 28, 40, and 46) showing most significant linkage (Tabular array S1). Similarly, exons and exon-intron boundaries of AGTR1 (Angiotensin II receptor, type ane) were sequenced in six probands from the families (seven, 13, 37, 40, 43, and 46) showing linkage to the 3q22 area. All PCR reactions were performed in five µl volumes containing 20 ng of DNA, with standard reagent concentrations and temperature profiles. Sequencing was performed using dye-terminator chemistry and automated sequencers (ABI, Columbia, Maryland, United States). Primer sequences are bachelor on request.

Results

Initial Non-parametric Genome-wide Linkage Results

We found seven suggestive linkage peaks on chromosomes 9q34, 3q22-24, 21q22, 22q13, 3p24, 10q25, and 11q24, in descending order of genomic significance, on the Affymetrix HMA10K Array (Table 3, Figure two). The strongest linkage was on chromosome 9q34 (rs578802- rs708616), with an NPL_all score of 3.84 and a suggestive genome-broad p-value of 0.24. Results were identical when the assay was repeated with Caucasian allele frequency estimates from Affymetrix, except that the chromosome 3 peak marking moved from 3p24 (rs1994987) to 3p22 (rs2167176) with an NPL_all score of ii.64 and a genome-wide P-value 0.94. Generally, different families contributed strongest to the most significant peaks: 9q34 (Families 12 NPL_all 3.ii and thirteen NPL_all 4.8); 3q22-q24 (Families thirteen NPL_all>v and 37 NPL_all 2.0); 21q22 (Families 12 NPL_all 3.7 and 21 NPL_all 2.five); and 22q13 (Families 12 NPL_all ii.0 and 31 NPL_all ane.7).

Figure 2. The NPL_all scores from initial non-parametric linkage analysis for the chromosomes showing suggestive linkage.

Allele frequencies for the Affymetrix HMA10K Array were estimated using 20 affected individuals from half dozen families and MERLIN was used for multipoint NPL assay.

https://doi.org/10.1371/journal.pone.0056225.g002

Verification of Linkage Peaks

Genotyping 91 affected and non-affected individuals from 19 families with 31 microsatellite markers surrounding the four most suggestive linkage peaks on 3q22-24, 9q34, 21q22, and 22q13 revealed one meaning linkage acme for 9q34 with the highest NPL_all of two.77 and p = 0.026 for D9S159 (minimum NPL_all score for meaning linkage was 2.49) (Table i). Only suggestive linkage was seen for 3q22-24, 21q22, and 22q13 (Table ane). The highest NPL_all score was at 9q34 in both configurations. Families 12 and 13 contributed again strongest to the linkage peak on chromosome 9q34, with the highest NPL_all scores of iii.64 at D9S179 and 5.02 at D9S313, respectively, and four other families showed suggestive linkage (NPL_all scores of 1.34–1.41) (Table S1).

Chromosome 9q34 Microsatellite Fine Mapping by Microsatellites

The chromosome 9q34 region was further fine mapped with 22 microsatellite markers in the same 91 individuals (Table 2). Highest linkage (NPL_all two.9) was observed at D9S65 (132190620 bp) if allele 186 was called, otherwise it shifted to mark D9S64 (134380110 bp) (NPL_all ii.seven). NPL plots for the four configurations were substantially unchanged (Table 2, Figure S1).

Birthday, 59 annotated poly peptide-coding genes are located within the chromosome 9q34 linkage acme (D9S290 to D9S1199) (Tabular array two). The five functionally nearly interesting genes were sequenced in the index individuals from the six families showing most significant linkage to 9q34 (Table S1, Table 2). PRRX2 (Paired related homeobox 2) is expressed in proliferating fetal fibroblasts and the developing dermal layer, with lower expression in developed skin. An increase in expression of this gene during fetal but not developed wound healing suggests a role in decision-making mammalian dermal regeneration and prevention of scar formation [26]. The LAMC3 (Laminin, gamma-3) gene belongs to the family of laminins, which are extracellular matrix glycoproteins and the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including intracellular invasion past several bacterial pathogens such as GAS strains [27]. FIBCD1 (Fibrinogen C domain-containing 1) is a transmembrane endocytic receptor that binds acetylated structures via a highly conserved fibrinogen-related domain (FReD). Ficolins likewise have FReDs and they play an of import office in innate immunity [28]. FIBCD1 binds chitin and has been suggested to control the exposure of intestine to chitin and its fragments, which is important in the allowed defence against parasites and fungi and the modulation of immune response [29]. In improver, fibrinogen is a plasma poly peptide that streptococci adhere to in order to avoid host defense. ABL1 (c-abl oncogene ane, non-receptor tyrosine kinase) is a proto-oncogene which encodes a cytoplasmic and nuclear poly peptide tyrosine kinase implicated in the processes of jail cell differentiation, cell division, cell adhesion, and stress response. ABL tyrosine kinases are related to the cell penetration of Shigellae and their signaling is required T-cell development and mature T-cell function [30], [31]. Sequencing revealed no specific genetic variations that would implicate any of these genes in erysipelas susceptibility.

PTGES (prostaglandin Due east synthase) is induced past proinflammatory cytokine interleukin 1 beta (IL1B) and synthesizes prostaglandin E2 (PGE2), a fundamental regulator of inflammation by modulating the regulation and activity of T cells and the development and activity of B cells, and past enhancing the production of cytokines and antibodies [32]. PGE2 also modulates the severity of infection acquired past GAS [33]. Upon contact with GAS, pare keratinocytes exert a stiff proinflammatory response, resulting in the increased expression of several cytokines and the rapid release of PGE2 [34]. PTGES is associated with inflammatory diseases, fever, and hurting associated with inflammation, and the deletion of Ptges leads to an impaired delirious response in mice [35]. We sequenced the introns and 10kb upstream of the transcription start site of PTGES equally well equally the coding region, just found no specific variants, mutations or indels implicating it directly in erysipelas susceptibility.

Follow-upwards Genotyping with Higher-density Array

We screened xv affected patients and xv unaffected control individuals with the Affymetrix GeneChip Human Mapping 250KSty Array and focused analysis on the previously identified regions on chromosomes 3q22 (D3S1306 to D3S1299), 9q34 (D9S290 to D9S1863), 21q22 (D21S1898 to D21S1920), and 22q23 (D22S1159 to D22S1141). The 3q22 locus was the nigh significant with several SNPs in the promoter region of the Angiotensin Two type receptor one (AGTR1) betwixt SNPs rs9862062 (148359724 bp) and rs4681157 (148412408 bp) showing nominal clan (Table iv).

AGTR1 exons and exon-intron boundaries were sequenced in 6 probands from the families showing strongest linkage to the 3q22 region. Twelve known SNPs were identified, including rs5186 (besides known every bit 1166 A/C) in the iii′UTR. The A allele of rs5186 has been associated with increased serum levels of high-sensitivity C-reactive protein and inflammation, and the CC genotype is putatively correlated with hypertension [36], [37] (Tabular array S2). Out of six probands, v were homozygous AA, one heterozygous Air conditioning, and none had the CC genotype, thus supporting a potential role in inflammation for the A allele. Nevertheless, no statistically pregnant departure in allele frequencies was detected for rs5186 between cases and controls in the acute accomplice. No other variants that might explicate linkage to this region were plant in AGTR1.

We chose two AGTR1 promoter area SNPs (rs9862062 and rs718424) that showed association to erysipelas in Haploview analysis, and genotyped them in the family fabric and in the acute erysipelas cohort by straight sequencing. The reference Yard-allele of rs9862062 was suggestively associated in the combined family (probands and marry-ins) and acute erysipelas cohort (Fisher's exact test, two-tailed p-value 0.006) and the reference T-allele of rs718424 showed suggestive association with a p-value of 0.017.

Discussion

Individual response to potentially fatal pathogens is modulated by both ecology and host genetic factors [8], [9]. Streptococcal infections can vary from localized pharyngitis or erysipelas to potentially fatal necrotizing fasciitis and sepsis. We accept used erysipelas/cellulitis, a localized infection of the skin and underlying subcutaneous tissues to identify 52 families with a perchance increased susceptibility to streptococcal infections. This is to our cognition the largest systematically nerveless clinical material on familial segregation of recurrent erysipelas. Nosotros performed a linkage scan on the six most informative families segregating erysipelas and found bear witness for suggestive linkage in seven chromosomal regions, with a maximum NPL score of iii.84 at 9q34. Further fine mapping of the 4 most significant regions in all of the collected families revealed significant linkage to the chromosome 9q34 region which is syntenic to mouse chromosome two (22 to 34 Mb), where a quantitative trait locus (QTL) for GAS susceptibility in mice has been identified [xviii]. In mouse, 37 candidate genes involved in immune response, cell signalling, cellular associates and system, and lipid metabolism were studied for quantitative expression levels pre- and postinfection in strains resistant and susceptible to astringent GAS infection. Genes associated with early allowed response and upregulated in susceptible strains and downregulated in resistant strains included Il1a, Il1rn (both located on 2q14 in humans), Ptges (located on 9q34 the linkage height identified here), and Ptges2 (located proximal to the 9q34 linkage elevation) (Tabular array 2). Increased production of prostaglandins has likewise been associated with Gram positive infections including Streptococcus suis, group B streptococcal, and GAS skin infections [34], [38]–[40]. All the same, sequencing of PTGES and four other chosen candidate genes in the 9q34 linkage region did not reveal significant genetic variations implicating any of these genes in erysipelas susceptibility. All the same, it is possible that quantitative expression level assay of candidate genes could have revealed variation associated with erysipelas [18]. Expression analysis for the candidate genes was non performed in this study. The genes for sequencing were chosen based on their known function and thus, we could accept missed genes with yet unknown roles in immunity and infection. The inherent property of genetic linkage is the relatively broad genomic area that is implicated. In this case, the 9q34 region contained 59 genes that in this written report were impractical to sequence. Our rationale for choosing target genes was so necessarily based on known functional information and biological plausibility, and we admit this approach has its limitations. More candidate genes will need to be considered as data accumulate. Susceptibility to infection is a complex trait where multiple genes in an immunological pathway or multiple intertwining pathways play a office in disease event [18].

Higher density analysis with the Affymetrix HMA250K Array revealed the nominal clan to erysipelas of several SNPs in the promoter region of AGTR1 on 3q22. AGTR1 is a G-protein-coupled receptor that mediates the major cardiovascular effects of angiotensin Ii, a strong vasopressor hormone involved in the evolution of hypertension, atherosclerosis, and insulin resistance. Angiotensin Ii is the cease production of the renin-angiotensin system (RAS), where renin stimulates the production of angiotensin I from angiotensinogen, which is then converted to angiotensin 2 by angiotensin converting enzyme (ACE). The activation of the RAS correlates with organ injury and mortality in clinical sepsis, possibly past contributing to the enhanced microvascular tone [41]. Angiotensin II also exerts proinflammatory effects on leukocytes, endothelial cells, and vascular shine musculus cells and by acting through AGTR1, it increases the expression of cytokines, chemokines, growth factors, and adhesion molecules [42].

Polymorphisms in both ACE and other angiotensinogen genes have been associated with susceptibility to inflammatory diseases such every bit SLE and psoriasis with frequent tonsillitis [43], [44]. The Angiotensin 2 pathway besides plays a potential role in septic shock [45]. Selected SNPs in ACE, AGTR1, and Angiotensin receptor associated protein (AGTRAP) showed meaning association with increased 28-day mortality to septic stupor for the GG genotype of AGTRAP rs11121816. AGTRAP interacts specifically with the C-terminal tail of AGTR1, and negatively regulates the receptor leading to a functional desensitization to angiotensin II. Pharmacological blockage of the RAS is used to treat hypertension, diabetic nephropathy, and congestive centre failure, simply antigen II receptor blockers (ARBs) and ACE inhibitors also suppress proinflammatory cytokines and reduce oxidative stress. Prior usage of ARBs has been shown to reduce mortality in patients hospitalized for sepsis [46].

Polymorphisms in AGTR1 and specially the C allele of rs5186 (+1166A>C) take been associated with hypertension and the A allele of rs5186 has been associated with higher serum levels of high-sensitivity C-reactive poly peptide (CRP) and inflammation [36], [37]. Out of our six probands five were homozygous AA, i heterozygous AC, and none had the CC genotype. In the presence of AA or AC genotypes microRNA-155 (miR-155) represses expression of the AGTR1 protein [47]. MiR-155 mediated translational repression can exist regulated by, e.chiliad., TGFB1, and MiR-155 expression is significantly increased with the AA or Air-conditioning genotypes as compared to the CC genotype. MiR-155 is critically involved in the command of specific differentiation processes in the allowed response. It functions specifically in regulating T helper cell differentiation and the germinal eye reaction to produce an optimal T cell–dependent antibody response, mediated at least partly by regulating cytokine production [48]. Furthermore, the loss of MiR-155 leads to an overall attenuation of immune responses in mouse [49]. High CRP levels and leukocyte counts (i.e., a more than severe inflammatory response) in erysipelas are associated with recurrence of erysipelas [5]. Our finding of predominance of the A-allele in our six probands is consistent with these earlier observations. Interestingly, AGTR1 and PTGES are involved in the same pathway, as AGTR1 induces the production of COX, which coverts arachidonic acid into Prostaglandin H2 that in plow is converted past PTGES into Prostaglandin E2.

We institute evidence for host genetic factors influencing susceptibility to bacterial non-necrotizing erysipelas/cellulitis, but did not find a common susceptibility gene in all families. Nosotros did non find linkage or clan with the HLA region previously linked with GAS infection severity in humans [19], [20]. Information technology is probable that as the inflammatory pathways are very complex and the defence against infections is nether stiff selection, different families are likely to accept private genetic susceptibilities. Genetic heterogeneity makes it hard to find significant correlations, which is a common pitfall of studies on host genetic factors predisposing to infections. Much larger patient and command groups will be needed to verify these preliminary results. Yet, our linkage height and the region of strongest association coincide with genes and pathways suggested to play important roles in susceptibility to streptococcal infections. The identification of the susceptibility genes would aid to understand better the course of infections and ultimately reduce morbidity.

Supporting Information

Figure S1.

NPL plots for the fine mapping of the chromosome 9q34 linkage height with 22 microsatellite markers. The NPL plots for the four configurations were essentially identical. MERLIN was used for multipoint NPL analyses using four configurations. (A) In configuration 0, unconfirmed afflicted individuals were analyzed as unknown, and (B) in configuration 2, they were analyzed as afflicted. In configurations (C) 0_186 and (D) 2_186, analysis was identical to configurations 0 and ii, respectively, except that allele 186 was called for marker D9S65.

https://doi.org/x.1371/journal.pone.0056225.s001

(TIF)

Acknowledgments

The authors thank all patients and families who participated in this study. Riitta Lehtinen is acknowledged for laboratory help, Hannu Turunen for computational assistance, Henna Degerlund, Susanna Vähäkuopus, Maija Toropainen, Eira Leinonen, and Kirsi Kuismin for assistance in sample collection.

Author Contributions

Managed all patient consents and samples: PA. Conceived and designed the experiments: KHJ S. Massinen S. Mäkelä JK JS JV TS MK. Performed the experiments: KHJ S. Massinen S. Mäkelä RL KK HJ. Analyzed the data: KHJ S. Massinen Southward. Mäkelä RL KK HJ TS MK JS JV JK. Contributed reagents/materials/analysis tools: JK JS JV MK PA HJ. Wrote the newspaper: KHJ S. Massinen TS JK.

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