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<p><strong>REVIEW&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp; nature medicine</strong></p> <p>&nbsp;</p> <p><strong>Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi</strong><br /> &nbsp;</p> <p><strong><a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-1">Yang Li</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-2">Marije Oosting</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-3">Patrick Deelen</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-4">Isis Rica&ntilde;o-Ponce</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-5">Sanne Smeekens</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-6">Martin Jaeger</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-7">Vasiliki Matzaraki</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-8">Morris A Swertz</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-9">Ramnik J Xavier</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-10">Lude Franke</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-11">Cisca Wijmenga</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-12">Leo A B Joosten</a>, <a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-13">Vinod Kumar</a> &amp;&nbsp;<a href="http://www.nature.com/nm/journal/v22/n8/full/nm.4139.html#auth-14">Mihai G Netea</a></strong></p> <p>&nbsp;</p> <p>Key Results<br /> &nbsp;</p> <p>#Stimulation increase inter individual variability in cytokine levels<br /> <br /> First, they measured seven cytokines that were induced by ten different stimuli<br /> After strickly quality control of cytokine distributions, they obtained a total of 62 (cytokine&ndash;stimulus pairs) different cytokine measurements.<br /> Cytokine production followed a nonGaussian or bimodal distribution, with a few exceptions<br /> In this figure, these graphs are cytokine-CA(Candida) pairs, Blue indicate normal(P is higher than 0.05), Yellow indicate non normal (P is lower than 0.05)and gray indicate distributions were not tested. there are normal distribution and non gaussian normal distribution. there are about 200 samples so I think there are nearly zero value ( not related) and others have peak at 200 because they have relation.</p> <p>In figure (e,f )RPMI is basal unstimulated state and comparing that ,Individuals exhibited significantly increased inter-individual variability (P &lt; 0.01) in cytokine secretion following stimulation,<br /> &nbsp;</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image002.png" style="height:307px; width:392px" /><br /> #Cytokine responses are organized in a pathogen- specific manner<br /> &nbsp;</p> <p>Correlations between the levels of various cytokines were found in response to stimulation with a certain pathogen, rather than in a cytokine pathway, and this conclusion was validated by additional analyses in the cohort bacterial-induced (lipopolysaccharide (LPS), Escherichia coli and Mycobacterium tuberculosis (MTB))</p> <p>cytokines (TNF-&alpha;, IL-6 and IL-10) were strongly clustered together(red color) and were clearly separated from the fungus-induced (Candida albicans) cytokine cluster.(blue color)<br /> Interferon (IFN)-&gamma; and IL-17 production were exceptions to this rule; however, the magnitude of IFN-&gamma; or IL-17 production by PBMCs from any individual correlated independently of the identity of the pathogen stimulus . This suggests an important evolutionary role for T helper 17 cell responses, which may be a general host defense pathway for both bacteria and fungi.<br /> &nbsp;In addition, the differentiation of naive T cells into TH1 or TH17 effector lymphocytes was under the control of monocyte-derived cytokines.</p> <p>Thus, a strong or weak monocyte-dependent cytokine production capacity may be associated with strong or weak helper T cell responses.<br /> <img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image004.jpg" style="height:284px; width:344px" /></p> <p>Following pair-wise correlation of cytokines, however, they observed two clusters, with cluster 1 consisting of cytokines mainly produced by monocytes, and cluster 2 consisting of cytokines known to be released mainly by T cells<br /> &nbsp;However, there was a poor correlation between monocyte-derived cytokine production and T cell cytokine production</p> <p>This indicates that one particular individual could be a high responder in terms of one set of cytokines, but a low responder for other cytokines associated with strong or weak helper T cell responses.<br /> &nbsp;</p> <p>&nbsp;</p> <table cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>Monocyte<br /> &nbsp;</p> <p><br /> &nbsp;</p> <p><br /> <br /> T-cell</p> </div> </td> </tr> </tbody> </table> </td> </tr> </tbody> </table> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image006.png" style="height:295px; width:401px" /><br /> Others show strong correlation, whereas IL17 show poor correlation with others<br /> This indicates that one particular individual could be a high responder in terms</p> <p>of one set of cytokines, but a low responder for other cytokines</p> <p>&nbsp;</p> <table cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>Supplementary Figure 5.<br /> The cytokine responses are organized around a physiological response towards specific pathogens.<br /> (a,b)An example of strong correlation between Candida induced IL6 and IL8 between IL10 and TNF-&alpha;</p> </div> </td> </tr> </tbody> </table> </td> </tr> </tbody> </table> <p><br /> &nbsp;</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image008.jpg" style="height:215px; width:634px" /></p> <p>&nbsp;</p> <p># Genome wide cQTL mapping identifies cell-count independednt cQTLs<br /> &nbsp;</p> <p>The cytokine and genotype data available enabled us to study cQTLs for three stimuli: a Gram-negative stimulus (LPS), a mycobacterium (MTB) and a fungus (C. albicans), which provided 18 measurements (three stimulations &times; six cytokines; IL-6, IL-8, IL-10, IL1-RA, IL-1&beta; and TNF-&alpha;).<br /> Raw cytokine levels were first log-transformed and then mapped to genotype data using a linear regression model with age and gender as covariates.<br /> This analysis revealed six significant cQTLs that have Pvlaue lower than 5 &times; 10&minus;8)<br /> They identified two independent cQTLs for C. albicans&ndash;induced IL-6 levels (Fig. 3a&ndash;c), two independent cQTLs for MTB-induced IL-8 levels (Fig. 3d&ndash;f), one for C. albicans&ndash;induced TNF-&alpha; and one for LPS-induced IL-10 levels,</p> <p>(a,d) Manhattan plots showing the genome-wide QTL mapping results for C. albicans&ndash;induced IL-6 levels (a) and MTB-induced IL-8 levels (d). Horizontal dashed line corresponds to P &lt; 5 &times; 10&minus;8.<br /> <br /> <br /> (b,c,e,f) Box plots showing the association of genotypes at chromosome 9 SNP rs11141235 (b), chromosome 15 SNP rs77181278 with C. albicans&ndash;induced IL-6 levels (c), chromosome 1 SNP rs75839717 (e), and chromosome 7 SNP rs74513903 with MTB-induced IL-8 levels</p> <p>&nbsp;</p> <p>They identified two independent cQTLs for C. albicans&ndash;induced IL-6 levels (Fig. a&ndash;c),<br /> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;two independent cQTLs for MTB-induced IL-8 levels (Fig. d&ndash;f),<br /> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; one for C. albicans&ndash;induced TNF-&alpha; &nbsp;<br /> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; one for LPS-induced IL-10 levels</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image010.jpg" style="height:210px; width:585px" /></p> <p>First, they analyzed the correlation structure between cell counts and cytokine measurements and observed weak correlations,<br /> &nbsp;For example, candida induced IL6 levels in PBMC showed a weak correlation with monocyte counts, but not with other cell type.</p> <p>they tested the association of Candida-induced cQTLs with cytokine levels in the cohort after correcting for age, gender and cell counts.<br /> Of those three cQTLs tested, SNP rs11141235, which associated with Candida-induced IL-6 levels, showed a clear replication of association (P = 0.017; Supplementary Table 4) even after correction for monocyte cell counts (P = 0.030).<br /> In contrast, none of the six cQTLs were directly associated with cell counts , suggesting an independent role for genetic variation in regulating cytokine production</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image012.jpg" style="height:254px; width:384px" /></p> <p>To assess whether this observation may denote a genetic component, they tested whether strong cQTLs of one pathogen-induced cytokine could also be associated with cytokine levels induced by other pathogen,<br /> Figure A, QTLs of IL-10 were more likely to be pathogen specific ,<br /> &nbsp;whereas In B, QTLs of other cytokines (IL-6, IL-8 and TNF-&alpha;) were more likely to be shared genetic loci that respond to all pathogens</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image014.jpg" style="height:339px; width:382px" /></p> <p># Correlations between cytokine responses are partially genetically determined<br /> &nbsp;</p> <p>Figure A, SNPs affecting fungus-induced IL-6 and IL-8 were also strongly associated with bacteria-induced IL-6 and IL-8 levels, but not with IL-10 and TNF-&alpha;</p> <p>This indicates that the SNPs associated with IL-6 and IL-8 levels are pathogen independent, and are therefore shared between pathogens<br /> they maybe because these SNPs act on genes or proteins that are downstream of pathogen recognition receptors</p> <p>The top association for Candida induced IL-6 at the chr9q21 locus provides an illustrative example for a strong shared cQTL (Fig. 4b,c), where the minor allele C at SNP rs11141235 was not only associated with lower C. albicans&ndash;induced IL-6 production that show before, but also with LPS-induced (Fig. 4b) and MTB-induced IL-6 production (Fig. 4c).</p> <p>&nbsp;</p> <table cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>SNP rs11141235 associated</p> <p>(before example figure.b)</p> </div> </td> </tr> </tbody> </table> </td> </tr> </tbody> </table> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image016.jpg" style="height:281px; width:409px" /><br /> # A cQTL gene GOLM1 on chr9q21 modulates cytokine production</p> <p style="margin-left:6.0pt">(P values for differential expression of genes (&plusmn;250 kb around the SNP) selected from genome-wide significant</p> <p style="margin-left:5.5pt">cQTL loci following different stimulations in human PBMCs (n = 8). P values were from differential expression</p> <p>analysis using threshold of false discovery rate (FDR) = 0.05 and fold change &gt; 2. Genes were selected on the</p> <p>basis of their physical positions, which were in a &plusmn;250-kb window around the SNP. PBMC stimulations were</p> <p style="margin-left:5.5pt">carried out for either 4 h or 24 h. Results are shown for both 4-h and 24-h stimulations. Red indicates upregulation,</p> <p style="margin-left:5.5pt">and blue indicates downregulation; Asterisks indicate genes with suggestive cQTLs in RNA-seq data to identify</p> <p style="margin-left:5.5pt">the putative causal genes at six significant cQTLs, they tested the expression levels of all genes located within a</p> <p style="margin-left:5.5pt">500-kb cis-window of the six cQTLs in PBMCs stimulated with different microbial antigens (Fig. 4d). Genes</p> <p style="margin-left:5.5pt">identified by this differential expression analysis were not cytokine genes, suggesting that the cQTLs that they</p> <p style="margin-left:5.5pt">identified are mainly trans-QTLs of regulatory genes modulating cytokine production.))</p> <p style="margin-left:5.5pt">The top associated cQTL, rs11141235, which is on the chromosome 9q21 region, was associated with Candida</p> <p style="margin-left:5.5pt">induced IL-6 levels (Fig. 3a).<br /> &nbsp;</p> <p style="margin-left:6.0pt">To identify the causal mechanism at this locus, they generated gene expression data by RNA sequencing in</p> <p style="margin-left:5.5pt">PBMCs from 70 individuals with and without Candida stimulation.<br /> &nbsp;</p> <p style="margin-left:6.0pt">they reconfirmed the significant differential expression of GOLM1 in response to Candida stimulation</p> <p>&nbsp;</p> <table cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>Rs11141235 at chromosome 9q21</p> </div> </td> </tr> </tbody> </table> </td> </tr> </tbody> </table> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image018.jpg" style="height:293px; width:296px" /><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image020.jpg" style="height:231px; width:268px" /></p> <p>Next mapped Candida-response cQTL at rs11141235 and at another SNP, rs11141242, in the locus (D&prime; = 0.95), which is a more frequent polymorphism. The cQTL results revealed that rs11141242 was significantly associated with the expression levels of Golgi membrane protein 1 (GOLM1), and the minor allele was associated with lower levels of GOLM1 (Fig. 5a), with rs11141235 showing a similar trend (Fig. 5b), suggesting the regulatory role of haplotypes in regulating GOLM1 expression.</p> <p><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image022.jpg" style="height:256px; width:568px" />&nbsp;<br /> <br /> # GOLM1 cQTL is associated with susceptibility to candidemia<br /> <br /> &nbsp;Pathway enrichment analysis on strongly co-expressed genes with GOLM1 during Candida stimulation revealed with cytokine signaling in figure D. The enrichment of genes for cytokine signaling after stimulation could also be a consequence of the stimulation and not necessarily specific to GOLM1 co-expression.<br /> &nbsp;Thus, they tested whether the extent of gene enrichment for IL-6 signaling was specifically linked to GOLM1</p> <table cellpadding="0" cellspacing="0"> <tbody> <tr> <td> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>A cQTL gene GOLM1 on chr9q21 modulates cytokine production</p> </div> </td> </tr> </tbody> </table> </td> </tr> </tbody> </table> <p>with Candida stimulation when compared with randomly chosen differentially expressed genes in response to Candida stimulation.<br /> They found a much stronger enrichment of genes co-expressed with GOLM1 for IL-6 signaling than randomly chosen genes</p> <p><br /> # Correlation between secreted IL-6 levels and genotypes at rs7036187 of 117 candidemia patients</p> <p>&nbsp;</p> <p>In addition, in patients with candidemia, they also assessed the effects of the rs7036187 polymorphism, a SNP that is associated with susceptibility to disease, on serum IL-6 concentrations.<br /> This SNP was associated with circulating IL-6 concentration, and heterozygous AG genotypes were associated with lower levels of IL-6 (P = 0.015), suggesting that the polymorphisms in the GOLM1 locus may influence Candida-induced cytokines and susceptibility to candidemia.</p> <table cellpadding="0" cellspacing="0" style="width:100%"> <tbody> <tr> <td> <div> <p>rs7036187</p> </div> </td> </tr> </tbody> </table> <p><!--[endif]----><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image025.png" style="height:224px; width:500px" /><!--![endif]----><!--[endif]----><br /> # Cytokine QTLs overlap with human-disease-associated SNPs</p> <p>&nbsp;</p> <p>they tested whether SNPs that were previously associated with human diseases, particularly with infectious diseases, are enriched with cQTLs. they extracted GWAS SNPs from the National Human Genome Research Institute GWAS catalog and binned them into eight categories on the basis of their association with different human phenotypes (Online Methods).<br /> &nbsp;Next they identified all cQTLs that were associated with cytokine levels with P &lt; 0.05 (Supplementary Table 6) and tested whether these cQTLs are linked to GWAS SNPs or their proxies.<br /> In figure A, they found that 61% of infectious-disease-associated SNPs were also cQTLs, and 43% of immune-mediated disease&ndash; associated SNPs were also cQTLs.<br /> &nbsp;They used height-associated SNPs as null set of SNPs to determine whether cQTLs are more often associated with a particular human disease. (the reason why height is standard)</p> <p>&nbsp;</p> <p>Given that a large number of genetic loci were associated with height (for example, 19,798 SNPs from 955 loci), they expected to find a considerable proportion of these SNPs to be co-localized with cytokine QTLs just by chance. Indeed, they found that 38.5% of height-associated SNPs were also cQTLs.<br /> &nbsp;Thus, they used these height-associated SNPs as a background set to test whether other disease-associated SNPs are overrepresented in cQTLs than in height-associated SNPs.</p> <p style="margin-left:12.0pt">&nbsp;</p> <p style="margin-left:5.5pt">They observed a significant enrichment (P &lt; 9.99 &times; 10&minus;8) of cQTLs among infectious-disease-associated SNPs. Nearly 60% of heart disease-associated SNPs were also cQTLs, suggesting a role for cytokine pathways in the pathogenesis of cardiovascular diseases.</p> <p style="margin-left:5.5pt"><img src="file:///C:\Users\문지훈\AppData\Local\Temp\msohtmlclip1\01\clip_image027.jpg" style="height:363px; width:496px" /></p> <p>&nbsp;</p> <p>Conclusions</p> <p>&nbsp;</p> <p>First, They not only confirmed the non-normal nature of cytokine production distribution of monocyte-derived pro-inflammatory cytokines, but our findings also extend this to T lymphocyte&ndash; derived cytokines.</p> <p>Second, the production capacity of various cytokines strongly correlated with cells being stimulated with a specific pathogen, whereas the correlation was poor when comparing bacterial versus fungal stimulation.</p> <p>Third, they identified six genome-wide significant cQTLs that influence cytokine responses</p> <p>&nbsp;</p> <p>Notably, regulation of the pathogen-specific cytokine responses is most likely only partially genetic, as some genetic polymorphisms regulate multiple cytokine responses to a certain pathogen (especially for monocyte-derived production), whereas others regulate the monocyte-derived production of cytokine responses resulting from multiple pathogens (see below). It is therefore likely that nongenetic external factors encountered during one&rsquo;s lifetime also are important for long-term modulation of cytokine responses, and epigenetic regulation may represent one of the molecular substrates for this process32,33. 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