Ns and exon-intron boundaries were sequenced in six probands from the families showing strongest linkage to the 3q22 region. Twelve known SNPs were identified, including rs5186 (also known as 1166 A/C) in the 39UTR. The A allele ofChromosome 9q34 Microsatellite Fine Mapping by MicrosatellitesThe chromosome 9q34 region was further fine mapped with 22 microsatellite markers in the same 91 individuals (Table 2). Highest linkage (NPLall 2.9) was observed at D9S65 (132190620 bp) if allele 186 was called, otherwise it shifted to marker D9S64 (134380110 bp) (NPLall 2.7). NPL plots for the four configurations were essentially unchanged (Table 2, Figure S1).Genetic Susceptibility to ErysipelasFigure 2. The NPLall 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 six families and MERLIN was used for multipoint NPL analysis. doi:10.1371/journal.pone.0056225.grs5186 has been associated with increased serum levels of highsensitivity C-reactive protein and inflammation, and the CC genotype is putatively correlated with hypertension [36,37] (Table S2). Out of six probands, five were homozygous AA, LED-209 chemical information oneheterozygous AC, and none had the CC genotype, thus supporting a potential role in inflammation for the A allele. However, no statistically significant difference in allele frequencies was detected for rs5186 between cases and controls in the acute cohort. NoGenetic Susceptibility to ErysipelasTable 3. Non-parametric genome-wide linkage analysis results with MERLIN.Chromosomal locus 3q22 3p24 3p22 9q34 10q25 11q24 21q22 22qMax NPLall 3.25 2.53 2.64 3.84 2.40 2.27 3.24 2.Genome-wide p-value 0.64 0.97 0.94 0.24 0.98 1.00 0.64 0.Marker(s) rs361239-rs1429759 rs1994987 rs2167176 rs578802-rs708616 rs1337987-rs959127 rs1940007-rs1940006 rs743337-rs717205 rs719925-rsPhysical locus (bp) 136701295?37656598 30456489 35383108 135453277?35564946 113538188?13611569 22948146 126754451?Bexagliflozin site 26754515 35265524?5310905 45758758?Max NPLall = maximum non-parametric linkage score when testing for allele sharing among affected individuals. doi:10.1371/journal.pone.0056225.tother variants that might explain linkage to this region were found 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 material and in the acute erysipelas cohort by direct sequencing. The reference Gallele 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 Tallele of rs718424 showed suggestive association with a p-value of 0.017.DiscussionIndividual response to potentially fatal pathogens is modulated by both environmental and host genetic factors [8,9]. Streptococcal infections can vary from localized pharyngitis or erysipelas to potentially fatal necrotizing fasciitis and sepsis. We have used erysipelas/cellulitis, a localized infection of the skin and underlying subcutaneous tissues to identify 52 families with a possibly increased susceptibility to streptococcal infections. This is to our knowledge the largest systematically collected clinical material on familial segregation of recurrent erysipelas. We performed a linkage scan on the six most informative families segregating erysipelas and found evidence for suggestive linkag.Ns and exon-intron boundaries were sequenced in six probands from the families showing strongest linkage to the 3q22 region. Twelve known SNPs were identified, including rs5186 (also known as 1166 A/C) in the 39UTR. The A allele ofChromosome 9q34 Microsatellite Fine Mapping by MicrosatellitesThe chromosome 9q34 region was further fine mapped with 22 microsatellite markers in the same 91 individuals (Table 2). Highest linkage (NPLall 2.9) was observed at D9S65 (132190620 bp) if allele 186 was called, otherwise it shifted to marker D9S64 (134380110 bp) (NPLall 2.7). NPL plots for the four configurations were essentially unchanged (Table 2, Figure S1).Genetic Susceptibility to ErysipelasFigure 2. The NPLall 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 six families and MERLIN was used for multipoint NPL analysis. doi:10.1371/journal.pone.0056225.grs5186 has been associated with increased serum levels of highsensitivity C-reactive protein and inflammation, and the CC genotype is putatively correlated with hypertension [36,37] (Table S2). Out of six probands, five were homozygous AA, oneheterozygous AC, and none had the CC genotype, thus supporting a potential role in inflammation for the A allele. However, no statistically significant difference in allele frequencies was detected for rs5186 between cases and controls in the acute cohort. NoGenetic Susceptibility to ErysipelasTable 3. Non-parametric genome-wide linkage analysis results with MERLIN.Chromosomal locus 3q22 3p24 3p22 9q34 10q25 11q24 21q22 22qMax NPLall 3.25 2.53 2.64 3.84 2.40 2.27 3.24 2.Genome-wide p-value 0.64 0.97 0.94 0.24 0.98 1.00 0.64 0.Marker(s) rs361239-rs1429759 rs1994987 rs2167176 rs578802-rs708616 rs1337987-rs959127 rs1940007-rs1940006 rs743337-rs717205 rs719925-rsPhysical locus (bp) 136701295?37656598 30456489 35383108 135453277?35564946 113538188?13611569 22948146 126754451?26754515 35265524?5310905 45758758?Max NPLall = maximum non-parametric linkage score when testing for allele sharing among affected individuals. doi:10.1371/journal.pone.0056225.tother variants that might explain linkage to this region were found 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 material and in the acute erysipelas cohort by direct sequencing. The reference Gallele 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 Tallele of rs718424 showed suggestive association with a p-value of 0.017.DiscussionIndividual response to potentially fatal pathogens is modulated by both environmental and host genetic factors [8,9]. Streptococcal infections can vary from localized pharyngitis or erysipelas to potentially fatal necrotizing fasciitis and sepsis. We have used erysipelas/cellulitis, a localized infection of the skin and underlying subcutaneous tissues to identify 52 families with a possibly increased susceptibility to streptococcal infections. This is to our knowledge the largest systematically collected clinical material on familial segregation of recurrent erysipelas. We performed a linkage scan on the six most informative families segregating erysipelas and found evidence for suggestive linkag.
