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Objective: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids., Design and Methods: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800)., Results: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed., Conclusion: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

Background: Fatty liver disease (FLD) is characterized by increased intrahepatic triglyceride content with or without inflammation and is associated with obesity, and features of the metabolic syndrome. Several recent genome-wide association studies have reported an association between single-nucleotide polymorphism rs738409 in the (patatin-like phospholipase domain-containing protein 3) PNPLA3 gene and FLD. Liver attenuation (LA; hounsfield units, HU) by computed tomography is a non-invasive measure of liver fat, with lower values of HU indicating higher liver fat content. Clinically, a LA value of 40 HU indicates moderate-to-severe hepatic steatosis., Objective: We investigated whether missense rs738409 PNPLA3 interacted with abdominal visceral adipose tissue (VAT) volume (cm) to reduce LA (that is, increased liver fat) in 1019 European American men and 1238 European American women from the Family Heart Study., Methods: We used linear regression to test the additive effect of genotype, abdominal VAT, and their multiplicative interaction on LA adjusted for age, body mass index, high-density lipoprotein-cholesterol, insulin resistance, serum triglycerides, abdominal subcutaneous adipose tissue and alcohol intake., Results: In men and women combined, the interaction between each copy of the rs738409 variant allele (minor allele frequency 0.23) and 100 cm/150 mm slice VAT decreased LA by 2.68±0.35 HU (P<0.01). The interaction of 100 cm VAT and the variant allele was associated with a greater decrease in LA in women than men (-4.8±0.6 and -2.2±0.5 HU, respectively)., Conclusions: The interaction between genotype and VAT volume suggest key differences in the role of PNPLA3 genotype in conjunction with abdominal VAT in liver fat accrual. The stronger association of the PNPLA3 genotype and liver fat in women suggests that women may be more sensitive to liver fat accumulation in the setting of increased visceral fat, compared with men. The presence of the PNPLA3 variant genotype, particularly in the context of high VAT content may have an important role in FLD.