Joyce – Independent Contractor: Venebio Group, LLC; Management Position: Venebio Group, LLC Hidekazu īsukamoto – Consulting: Shionogi & Co., S. P. Pharmaceutics; Grant/Research Support: The Toray Co. Arun J. Sanyal – Advisory Committees or Review Panels: Gore, Gilead, Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Bayer-Onyx, Genentech, Norgine, GalMed, Novartis, Echosens, Takeda; Grant/Research

Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, Gilead; Independent Contractor: UpToDate The following people have nothing to disclose: Jun Xu, Faridoddin Mirshahi, Hae K Min, Tommy Pacana, Vaishali Patel, Kalyani Daita, Kim Ekroos Background: Galectin-9 (Gal-9), predominantly expressed by activated Kupffer cells, has recently been demonstrated to be important for pro-inflammatory cytokine responses OSI-906 mouse as well as regulatory T cell (Treg) expansion within the liver. Recent data (Almeida J, 2013, PMID: 23550693) demonstrate that Tregs are significantly decreased in patients with alcoholic hepatitis. Moreover, as ample evidence indicates that inflammation is

Alisertib supplier central to the pathogenesis of ALD, we explored whether genetic polymorphisms of Gal-9 would associate with development of ALD. Methods: Genomic DNA samples from 375 patients with ALD were studied; 179 subjects with excessive alcohol intake who did not develop ALD served as controls (Acon). Based on Hapmap, we performed genotyping for 5 Gal-9 SNPs tagging the most common haplotypes. As shown in the Table below, Rs732222, Rs3751093, Rs4239242, Rs4239242 were all associated with protection against development of ALD. The H3 haplotype was less common in ALD (〇R 0.68, p = 0.016). Next, PBMCs from normal subjects with no significant medchemexpress history of alcohol consumption were stimulated with IFN-y 25 ng/ml and Et〇H 25 nM for 24 hrs and subject to RT-PCR. Compared to media, this stimulation yielded significant upregulation of Gal-9 (p = 0.0078). The SNPs

Rs4239242 and Rs4794976 correlated with higher transcription of Gal-9 and no difference between TNF- α(as a control). The H3 haplotype (GGGTT, ALD 133, Acon 86; p=0.016, 〇R 0.68) was also associated with higher Gal-9 transcription compared to H1(GAGTT)/H1 and H1/H3. Conclusions: In a targeted SNP approach, we found that genetic variation within the galectin-9 gene is associated with the risk of developing liver disease in patients with alcoholism as compared to alcoholics who do not develop liver disease. These data suggest functional correlates of Gal-9 SNPs, perhaps by expansion of Tregs as a protective mechanism. ALD Acon Odds ratio RS732222 GG 198 112 GA 159 57 1. 49 (1. 04-2. 15) P=0.035 AA 18 10 RS3751093 GG 217 123 GA 155 53 1. 52 (1. 06-2. 20) P=0.028 AA 12 9 RS4239242 TT 138 92 TC 194 74 1. 72 (1. 21-2. 46) P=0.0034 CC 46 19 RS4794976 TT 153 97 TG 196 67 1. 66 (1. 17-2. 34) P=0.0065 GG 29 19 Disclosures: Christopher P.