E in seven chromosomal regions, with a maximum NPL score of 3.84 at 9q34. Further fine mapping of the four most significant regions in all of the collected families Dimethylenastron revealed significant linkage to the chromosome 9q34 region which is syntenic to mouse chromosome 2 (22 to 34 Mb), where a quantitative trait locus (QTL) for GAS susceptibility in mice has been identified [18]. In mouse, 37 candidate genes involved in immune response, cell signalling, cellular assembly and organization, and lipid metabolism were studied for quantitative expression levels pre- and postEledoisin site infection in strains resistant and susceptible to severe GAS infection. Genes associated with early immune 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 peak identified here), and Ptges2 (located proximal to the 9q34 linkage peak) (Table 2). Increased production of prostaglandins has also been associated with Gram positive infections including Streptococcus suis, group B streptococcal, and GAS skin infections [34,38?0]. However, 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. However, it is possible that quantitative expression level analysis of candidate genes couldhave revealed variation associated with erysipelas [18]. Expression analysis for the candidate genes was not performed in this study. The genes for sequencing were chosen based on their known function and thus, we could have 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 study were impractical to sequence. Our rationale for choosing target genes was then 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 role in disease outcome [18]. Higher density analysis with the Affymetrix HMA250K Array revealed the nominal association to erysipelas of several SNPs in the promoter region of AGTR1 on 3q22. AGTR1 is a G-proteincoupled receptor that mediates the major cardiovascular effects of angiotensin II, a potent vasopressor hormone involved in the development of hypertension, atherosclerosis, and insulin resistance. Angiotensin II is the end product of the renin-angiotensin system (RAS), where renin stimulates the production of angiotensin I from angiotensinogen, which is then converted to angiotensin II by angiotensin converting enzyme (ACE). The activation of the RAS correlates with organ injury and mortality in clinical sepsis, possibly by contributing to the enhanced microvascular tone [41]. Angiotensin II also exerts proinflammatory effects on leukocytes, endothelial cells, and vascular smooth muscle 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 as SLE and psoriasis with frequent tonsillitis.E in seven chromosomal regions, with a maximum NPL score of 3.84 at 9q34. Further fine mapping of the four most significant regions in all of the collected families revealed significant linkage to the chromosome 9q34 region which is syntenic to mouse chromosome 2 (22 to 34 Mb), where a quantitative trait locus (QTL) for GAS susceptibility in mice has been identified [18]. In mouse, 37 candidate genes involved in immune response, cell signalling, cellular assembly and organization, and lipid metabolism were studied for quantitative expression levels pre- and postinfection in strains resistant and susceptible to severe GAS infection. Genes associated with early immune 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 peak identified here), and Ptges2 (located proximal to the 9q34 linkage peak) (Table 2). Increased production of prostaglandins has also been associated with Gram positive infections including Streptococcus suis, group B streptococcal, and GAS skin infections [34,38?0]. However, 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. However, it is possible that quantitative expression level analysis of candidate genes couldhave revealed variation associated with erysipelas [18]. Expression analysis for the candidate genes was not performed in this study. The genes for sequencing were chosen based on their known function and thus, we could have 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 study were impractical to sequence. Our rationale for choosing target genes was then 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 role in disease outcome [18]. Higher density analysis with the Affymetrix HMA250K Array revealed the nominal association to erysipelas of several SNPs in the promoter region of AGTR1 on 3q22. AGTR1 is a G-proteincoupled receptor that mediates the major cardiovascular effects of angiotensin II, a potent vasopressor hormone involved in the development of hypertension, atherosclerosis, and insulin resistance. Angiotensin II is the end product of the renin-angiotensin system (RAS), where renin stimulates the production of angiotensin I from angiotensinogen, which is then converted to angiotensin II by angiotensin converting enzyme (ACE). The activation of the RAS correlates with organ injury and mortality in clinical sepsis, possibly by contributing to the enhanced microvascular tone [41]. Angiotensin II also exerts proinflammatory effects on leukocytes, endothelial cells, and vascular smooth muscle 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 as SLE and psoriasis with frequent tonsillitis.