UNASSIGNED: The @entity14895 @entity14894 polymorphism ( @entity14896 ) is a major determinant of hepatic fat and predisposes to the full spectrum of @entity409 in @entity1561 ( @entity1561 ). Aim of this study was to evaluate whether additional @entity14895 coding variants contribute to @entity1561 susceptibility, first in individuals with contrasting phenotypes (with early onset @entity1561 vs. very low aminotransferases), and then in a large validation cohort. Rare @entity14895 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 @entity1 with early-onset @entity1561 , nor in 100 healthy individuals with ALT <22/20 IU/ml. Besides @entity14894 @entity14896 , the @entity69162 @entity13284 polymorphism ( @entity69163 sequence variant) was over-represented in @entity1561 (adjusted p=0.01). In 1447 subjects with and without @entity1561 , the 148M-434E (p<0.0001), but not the 148M-434K haplotype (p>0.9), was associated with histological @entity1561 and @entity1560 . Both the @entity14896 (p=0.0002) and @entity69163 variants (p=0.044) were associated with serum ALT levels, by interacting each other, in that the 434K hampered the association with @entity409 of the 148M allele (p=0.006). The @entity69163 variant did not affect @entity14895 enzymatic activity, but carriers of the @entity69162 A allele (434K) displayed lower hepatic @entity14895 mRNA and protein levels (p<0.05). CONCLUSIONS: rare loss-of-function @entity14895 variants were not detected in early-onset @entity1561 . However, @entity14895 @entity69162 @entity69163 decreased @entity14895 expression, lessening the effect of the @entity14896 variant on the predisposition to @entity1560 and @entity409 . This suggests that @entity14895 @entity14896 variant has a co-dominant negative effect on @entity1674 mobilization from lipid droplets, mediated by the inhibition of other lipases. This article is protected by copyright. All rights reserved.

The @entity69162 @entity69163 variant modulates @entity14895 expression and XXXX .

@entity1 :: ('9606', 'Species') :: ['patients'] @entity14896 :: ('p|SUB|I|148|M', 'ProteinMutation') :: ['I148M'] @entity1560 :: ('MESH:D005234', 'Disease') :: ['steatohepatitis', 'steatosis'] @entity1674 :: ('MESH:D014280', 'Chemical') :: ['triglycerides'] @entity409 :: ('MESH:D008107', 'Disease') :: ['liver damage'] @entity14894 :: ('rs738409', 'SNP') :: ['rs738409'] @entity69162 :: ('rs2294918', 'SNP') :: ['rs2294918'] @entity1561 :: ('MESH:D065626', 'Disease') :: ['NAFLD', 'nonalcoholic fatty liver disease'] @entity13284 :: ('c|SUB|G||A', 'DNAMutation') :: ['G>A'] @entity69163 :: ('p|SUB|E|434|K', 'DNAMutation') :: ['E434K'] @entity14895 :: ('80339', 'Gene') :: ['PNPLA3']
@entity409 :: (MESH:D008107,Disease) :: ['liver damage']
