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

BackgroundFatty 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. MethodsA 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 conclusionsAmong 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.