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February 10th 2017 NEWS FROM THE GRIFOLS CHAIR #2 Richard Moreau, Joan Clària, Vicente Arroyo

A lesson drawn from the CANONIC study was that among patients with acutely decompensated cirrhosis, systemic inflammation was much more marked in patients with acute-on-chronic liver failure (ACLF) than in those without. The mechanisms explaining exaggerated systemic inflammation in patients with ACLF are poorly understood.

There is more and more evidence in the general population that genetic heritability has a strong impact on cytokine production in response to a variety of stimuli. A study recently performed under the umbrella of the EF Clif (Grifols Chair) and the EASL-CLIF Consortium provides new results suggesting that genetic variations could influence the intensity of systemic inflammation in acutely decompensated patients with cirrhosis (Hepatology 2017;65:202-16). Because of their association with inflammation-related genes, six single-nucleotide polymorphism (SNPs) were considered. These included rs1143623 C/G (a SNP located at the -1473 position of the promoter region of the interleukin [IL] 1 beta gene [IL1B]); rs4251961 C/T (a promoter polymorphism of the interleukin 1 receptor antagonist gene [IL1RN]); rs1800871 (a promoter variant of the interleukin 10 gene [IL10]); rs4969170 A/G (an intron variant within LOC101928674, a gene close to suppressor of cytokine signaling 3 [SOCS3]); rs3135500 A/G (a microRNA (miRNA) binding site SNP in the 3' untranslated region of the nucleotide-binding oligomerization domain-containing protein 2 gene [NOD2]); and rs1878022 C/T (an intron variant within chemerin chemokine-like receptor 1 [CMKLR1]). The six SNPs of interest were genotyped in 279 patients with cirrhosis with (n=178) and without (n=101) ACLF from the CANONIC study. Among these SNPs, only rs1143623 and rs4251961 (i.e., in IL1B and IL1RN, respectively) were strongly associated with ACLF. The presence of the minor allele in homozygosity (CC) for the SNP rs1143623 under the recessive inheritance model was associated with a significantly lower prevalence of ACLF as compared to other genotypes (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05). In addition, the presence of the minor allele in heterozygosity (TC) for the SNP rs4251961 under the overdominant inheritance model was associated with a significantly lower prevalence of ACLF as compared to other genotypes (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05). The SNP genotypes associated with low ACLF prevalence were functional and associated with reduced circulating levels of: IL-1? (this cytokine being secreted after its precursor [encoded by IL1B] has been cleaved within the producing cells), IL-1 beta (an IL-1 family member, encoded by IL1A), IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. It is interesting to note that the two "protective" SNP genotypes are located on chromosome 2 in the region of the IL1 gene cluster. Together the present findings identify two SNPs in the IL1 gene cluster, which are associated with the inflammatory process related to development of ACLF. In other words, SNPs at the IL1 locus could represent quantitative trait loci (QTLs) that impact cytokine gene expression. Since the IL1 locus exhibits a large number of SNPs, future studies should address whether the two SNPs identified here are actually lead SNPs or are "overcome" by other SNP(s) at the same locus with respect to their association to the level of circulating cytokines in acutely decompensated patients. It is time now to launch a "Manhattan project" of the Grifols Chair, i.e., genome-wide association studies in acutely decompensated cirrhosis aimed to identify crucial QTLs that drive the intensity of cytokine production and the subsequent risk of organ failure. This would combine genotyping and transcriptome analysis or assessment of circulating levels of a large number of cytokines and chemokines. In addition, the "Manhattan project" should be inspired by the Human Functional Genomics Project and assess whether the impact of QTLs on inflammation is contextual (i.e., dependent on the nature of stimuli) or not. This kind of study should improve our understanding of mechanisms that drive the progression of cirrhosis toward very severe stages and perhaps those that govern the progression of chronic liver disease to cirrhosis.

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