Severe liver damage, low bone mineral content, and PDXDC1/TTC39B gene variations linked to NAFLD with metabolic syndrome

Background Fatty liver disease is a pathologic condition of liver due to excess deposition of fat in the liver and is considered as hepatic manifestation of metabolic syndrome (MetS). Metabolic syndrome is comorbid with multiorgan abnormalities and diseases. However, the phenotypic uniqueness and genetic background of fatty liver patients in the presence/absence of metabolic syndrome are unclear. Methods A cohort of 551 individuals with (FLD+) or without fatty liver (FLD-) was recruited.We subdivided the study cohort based on the presence or absence of metabolic syndrome (MetS) into four groups-Group4FLD+/MetS+; n=221, Group3FLD+/MetS-; n=39, Group2FLD-/MetS+; n=175 and Group1FLD-/MetS- n=116. Pathophysiology was compared between the study groups. Association of genomic variants with Group4FLD+/MetS+; n=167 was studied compared to Group1FLD-/MetS-; n=74. The effects of the associated variants on gene expression were studied using eQTL mapping. Results and conclusions Among 551 individuals, 47.2% had fatty liver (FLD+) and 71.87% had metabolic syndrome (MetS+). Compared to Group3FLD+/MetS-, Group4FLD+/MetS+ patients had significantly higher age, higher adiposity, severe diabetic and lipid profile, liver damage marker, CRP, low bone mineral content and higher liver damage, both among the obese and the non-obese. Non-obese Group2FLD-/MetS+ patients had significantly higher serum TG and lower HDL, while obese Group3FLD+/MetS-patients had higher liver damage markers. Additionally, we also showed that in our population, Group4FLD+/MetS+ patients carried higher risk allele frequency in rs3761472-G(SAMM50,OR=2.9(2.0-4.1); p=0.002), rs738409-G(PNPLA3,OR=2.8(1.9-4.07)p=0.003),rs58542926-A(TM6SF2,OR=2.7(1.9-3.9)p=0.021),rs35665085-A(CECR5,OR=2.7(1.9-3.9)p=0.038),rs471364-G(TTC39B,OR=3.1(2.1-4.5)p=0.001),rs2800-G(SLC9A9,OR=3.1(2-4.5)p=0.028),rs7200543-A(PDXDC1,OR=2.261(1.1-4.8)p=0.031). Group4 patients with rs7200543-AA showed poor skeletal health. Thus, fatty liver with metabolic syndrome showed the most severe disease phenotype. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Department of Biotechnology, Government of India. Intramural funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Institutional Ethical Boards of the National Institute of Biomedical Genomics, Kalyani, India and the SSKM Hospital, Kolkata (Ethical approval number:NIBMG/2012/1/6) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study (including the raw data, processed data and the metadata) are available upon reasonable request to the authors.