Insulin resistance (InsR) characterizes the metabolic syndrome (MetS) for which many genes were involved by GWAS. To further explore genetic susceptibility involving rare SNPs with major effect we genotyped patients from MEDIGENE collection using Affymetrix MEDISCOPE chip. Screening of French, Romanians and Albanians in Italy and Greece (n = 605) for metabolic pathways detected a new SNP associated with MetS in exon 3/4 of ATF5 (activating transcription factor 5) gene (Chr19q13.33). Genuine association was completed by imputation (BEAGLE4.1) at 1000 Genome Project adding new 6 SNPs and submitted to sliding window (SW) procedure for haplotypes detection. The strong association signal was found for rs61742136 with MetS (P < 1.8x10-7, Bonferroni 2.7x10-6, OR 9.37, 95% CI[3.3-26.8]), InsR (P < 0.00049, OR 3.4, 95% CI[1.7-8.4]) and with HOMA index (P < 0.023). Among MetS components, the strongest association concerned high blood pressure (HBP) (P < 2.1x 10-4, OR 4.8, 95% CI[1.8-12.4]) while HDL, TG and obesity were associated with OR < 3. In women, MetS association signal was much stronger with OR 10.9, 95% CI[3.2-36.6] (P < 8.5x10-7). SW detected associated haplotypes between 3 to 8 SNPs, the best value being that of ATGGGGTC haplotype with OR 12.2, 95% CI[3.2-46.65] (P < 1.98 x10-7, Bonferroni 1.13x10-5). Association of rs61742136 was replicated in MEDIGENE cohort (n = 948) with MetS, albeit with P < 2.0x10-3 (Bonferroni 0.026) and solely with low HDL (P < 0.05). Other SNPs were associated with HBP (rs75273180 and rs1152230 with P < 0.03 and 0.04, respectively) and with potential interactions in Haploreg V4 database. Overall fixation index (Fst = 0.001) indicates a minimal differentiation suggesting adaptive selection in Mediterranean populations. This is a first time report of implication of ATF5 in MetS and gives a new insight on its pathogenesis in view of this CREB valine/leucine zipper transcriptional factor in stress-induced anti-apoptosis or neuroprotective effects.


S. Haydar: None. F. Grigorescu: None. C. Lautier: None. C. Normand: None. J. Hadi: None. M. Vintila: None. M. Gheorghiu: None. A. Fountas: None. A. Tsatsoulis: None. A. Copola: None. D. Lauro: None. D. Ylli: None. A. Ylli: None. L. Brugnara: None. F. Hanzu: None. R. Gomis: None.

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