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Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy.
Sci Rep 2018; 8(1):3702SR

Abstract

NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001). A 4-SNPs weighted genetic risk score value >0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity.

Authors+Show Affiliations

Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy. alessia.dicostanzo@uniroma1.it.Molecular Medicine, "Sapienza" University, Rome, Italy.Experimental Medicine, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy. Anatomical, Histological, Forensic Medicine and Ortopedics Sciences, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy. Anatomical, Histological, Forensic Medicine and Ortopedics Sciences, "Sapienza" University, Rome, Italy.Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.Immunohematology and Transfusion Medicine Unit, "Sapienza" University, Rome, Italy.Immunohematology and Transfusion Medicine Unit, "Sapienza" University, Rome, Italy.Molecular Medicine, "Sapienza" University, Rome, Italy.Molecular Medicine, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.Public Health and Infectious Diseases, "Sapienza" University, Rome, Italy.Departments of Internal Medicine and Medical Specialties, "Sapienza" University, Rome, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29487372

Citation

Di Costanzo, Alessia, et al. "Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy." Scientific Reports, vol. 8, no. 1, 2018, p. 3702.
Di Costanzo A, Belardinilli F, Bailetti D, et al. Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy. Sci Rep. 2018;8(1):3702.
Di Costanzo, A., Belardinilli, F., Bailetti, D., Sponziello, M., D'Erasmo, L., Polimeni, L., ... Arca, M. (2018). Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy. Scientific Reports, 8(1), p. 3702. doi:10.1038/s41598-018-21939-0.
Di Costanzo A, et al. Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy. Sci Rep. 2018 02 27;8(1):3702. PubMed PMID: 29487372.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy. AU - Di Costanzo,Alessia, AU - Belardinilli,Francesca, AU - Bailetti,Diego, AU - Sponziello,Marialuisa, AU - D'Erasmo,Laura, AU - Polimeni,Licia, AU - Baratta,Francesco, AU - Pastori,Daniele, AU - Ceci,Fabrizio, AU - Montali,Anna, AU - Girelli,Gabriella, AU - De Masi,Bruna, AU - Angeloni,Antonio, AU - Giannini,Giuseppe, AU - Del Ben,Maria, AU - Angelico,Francesco, AU - Arca,Marcello, Y1 - 2018/02/27/ PY - 2017/10/03/received PY - 2018/02/13/accepted PY - 2018/3/1/entrez PY - 2018/3/1/pubmed PY - 2019/9/24/medline SP - 3702 EP - 3702 JF - Scientific reports JO - Sci Rep VL - 8 IS - 1 N2 - NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001). A 4-SNPs weighted genetic risk score value >0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/29487372/Evaluation_of_Polygenic_Determinants_of_Non_Alcoholic_Fatty_Liver_Disease__NAFLD__By_a_Candidate_Genes_Resequencing_Strategy_ L2 - http://dx.doi.org/10.1038/s41598-018-21939-0 DB - PRIME DP - Unbound Medicine ER -