Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease
Open accessAbstract
BACKGROUND: Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. METHODS: In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. RESULTS: Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease. CONCLUSIONS: The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
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Written from the paper’s full text.
TL;DR
In healthy Asian Indian men, APOC3 promoter variants C-482T and T-455C were associated with higher plasma apolipoprotein C3, hypertriglyceridemia, reduced triglyceride clearance, nonalcoholic fatty liver disease, and insulin resistance. A validation cohort of non–Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease.
Key findings
- APOC3 variant-allele carriers had a 30% increase in fasting plasma apolipoprotein C3, a 60% increase in fasting plasma triglyceride, approximately doubled postprandial plasma triglyceride and retinyl fatty acid ester AUCs after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance.
- Nonalcoholic fatty liver disease prevalence was 38% among variant-allele carriers versus 0% among wild-type homozygotes (P<0.001); subjects with nonalcoholic fatty liver disease had marked insulin resistance (insulin-sensitivity index, 2.0±2.0 vs. 3.5±1.6; P<0.001).
- In 163 healthy non–Asian Indian men, nonalcoholic fatty liver disease prevalence was 9% among APOC3 variant-allele carriers versus 0% among wild-type homozygotes (P=0.02), and those with nonalcoholic fatty liver disease had lower insulin sensitivity (2.92±1.13 vs. 4.93±2.20; P<0.001).
- APOC3 variants alone, PNPLA3 rs738409 variants alone, and the two combined accounted for 11.0%, 6.5%, and 13.1% of the variance in nonalcoholic fatty liver disease risk, respectively.
Methods
- Prospective study of 95 healthy Asian Indian men genotyped for APOC3 SNPs rs2854116 (T-455C) and rs2854117 (C-482T); participants were classified as wild-type homozygotes at both SNPs or carriers of one or more variant alleles.
- Measured plasma apolipoprotein C3, fasting lipids, insulin sensitivity by 3-hour oral glucose-tolerance test, hepatic triglyceride content by proton magnetic resonance spectroscopy, and in subgroups, oral and intravenous fat-tolerance tests; a 7-subject subgroup underwent hypocaloric weight loss.
- Validation study in 163 healthy non–Asian Indian men (108 white, 26 Asian, 15 Hispanic, 14 black) assessed APOC3 genotypes and liver triglyceride content; analyses used log transformations, linear regression, ANOVA, t-tests, Mann–Whitney U tests, and Fisher’s exact test with alpha 0.05.
Limitations
- The paper does not state limitations explicitly.
- Evident from the text: all participants were men, limiting generalizability to women; the main cohort was small (95 Asian Indian men), and key subgroup analyses were smaller (oral fat-tolerance testing, 38 subjects; intravenous fat-tolerance testing, 19 subjects; weight-loss intervention, 7 subjects).
- Evident from the text: the design is observational and cannot establish causality, and the confirmation cohort had a low absolute prevalence of nonalcoholic fatty liver disease among variant-allele carriers (9%).
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
There were no significant differences between APOC3 variant-allele carriers and wild-type homozygotes in plasma concentrations of total cholesterol, HDL cholesterol, or LDL cholesterol.
“There were no significant differences between the two groups in plasma concentrations of total cholesterol, HDL cholesterol, or LDL cholesterol.”
Quote in the paperNot a substantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Findingown data
Non-Asian Indian men with nonalcoholic fatty liver disease had marked insulin resistance compared with those without nonalcoholic fatty liver disease (insulin-sensitivity index, 2.92±1.13 vs. 4.93±2.20; P<0.001).
“Similarly, the non–Asian Indian men with nonalcoholic fatty liver disease had marked insulin resistance, as reflected by their lower insulin-sensitivity index as compared with that in the non–Asian men without nonalcoholic fatty liver disease (2.92±1.13 vs. 4.93±2.20, P<0.001).”
Quote in the paperNot a substantial claim - Findingown data
Carriers of APOC3 variant alleles (C-482T, T-455C, or both) had approximately 30% higher fasting plasma apolipoprotein C3 concentrations than wild-type homozygotes.
“Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes.”
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
“Plasma apolipoprotein C3 concentrations were approximately 30% higher in the variant-allele carriers than in the wild-type homozygotes (Table 2).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
- Findingown data
In seven subjects with hepatic steatosis and insulin resistance, a hypocaloric dietary intervention over 3 to 6 months reduced average weight from 80.4±10.7 kg to 74.9±10.2 kg (P=0.003).
“Over a period of 3 to 6 months, their average weight decreased from 80.4±10.7 kg to 74.9±10.2 kg (P = 0.003).”
Quote in the paperSubstantial claim - Findingown data
Subjects with nonalcoholic fatty liver disease had marked insulin resistance compared with those without nonalcoholic fatty liver disease (insulin-sensitivity index, 2.0±2.0 vs. 3.5±1.6; P<0.001).
“The subjects with nonalcoholic fatty liver disease had marked insulin resistance.”
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
“Subjects with nonalcoholic fatty liver disease had marked insulin resistance as compared with those who did not have nonalcoholic fatty liver disease (insulin-sensitivity index, 2.0±2.0 [lower-third percentile for insulin sensitivity9], vs. 3.5±1.6; P<0.001).”
Quote in the paperNot a substantial claim - Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
- Findingown data
In an intravenous fat-tolerance test, APOC3 variant-allele carriers had a 46% reduction in plasma triglyceride clearance compared with wild-type homozygotes (171±21 vs. 249±71% per hour, P=0.046).
“a 46% reduction in plasma triglyceride clearance”
- Also stated in: § PLASMA TRIGLYCERIDE CLEARANCE · plain
“The variant-allele carriers had a 46% increase in the AUC for the relative plasma triglyceride concentration, reflecting decreased plasma triglyceride clearance, as compared with the wild-type homozygotes (171±21 vs. 249±71% per hour, P = 0.046) (Fig. 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § PLASMA TRIGLYCERIDE CLEARANCE · plain
- Findingown data
The prevalence of nonalcoholic fatty liver disease was 38% among APOC3 variant-allele carriers and 0% among wild-type homozygotes (P<0.001).
“The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001).”
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
“The prevalence of nonalcoholic fatty liver disease (hepatic lipid content >5.5%15) was 38% among the variant-allele carriers, whereas none of the wild-type homozygotes had nonalcoholic fatty liver disease (P<0.001) (Fig. 1A).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
- Findingown data
In an oral fat-tolerance test, the plasma triglyceride AUC was approximately doubled in APOC3 variant-allele carriers compared with wild-type homozygotes (746±102 vs. 383±41 mg per deciliter per hour, P=0.002).
“The average area under the curve (AUC) for the plasma triglyceride concentration was approximately doubled in the variant-allele carrier group as compared with the wild-type homozygote group (746±102 vs. 383±41 mg per deciliter per hour, P = 0.002) (Fig. 2A).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Findingown data
Carriers of APOC3 variant alleles had approximately 60% higher fasting plasma triglyceride concentrations than wild-type homozygotes.
“They also had a 60% increase in the fasting plasma triglyceride concentration”
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
“In addition, fasting plasma triglyceride concentrations were approximately 60% higher in the carriers of variant alleles.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § PLASMA LIPIDS, HEPATIC LIPID CONTENT, AND INSULIN RESISTANCE · plain
- Findingown data
In an oral fat-tolerance test, the retinyl fatty acid ester AUC was approximately twice as high in APOC3 variant-allele carriers as in wild-type homozygotes (60±36 vs. 36±19 μmol per liter per hour, P=0.01).
“Similarly, among the variant-allele carriers, the changes in the AUC for plasma concentrations of retinyl fatty acid ester (reflecting chylomicron remnants) was approximately twice those among the wild-type homozygotes (60±36 vs. 36±19 μmol per liter per hour, P = 0.01) (Fig. 2B).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Findingown data
In non-Asian Indian men, the prevalence of nonalcoholic fatty liver disease was higher among APOC3 variant-allele carriers than among wild-type homozygotes (9% vs. 0%, P=0.02).
“As was the case with the Asian Indian men, the prevalence of nonalcoholic fatty liver disease was higher among the APOC3 variant-allele carriers than among the wild-type homozygotes in this group (9% vs. 0%, P = 0.02) (Fig. 1B).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Findingown data
APOC3 variant-allele carriers had markedly higher average hepatic triglyceride content than wild-type homozygotes (mean, 7.5±10.3% vs. 1.5±1.3%; P<0.001).
“The average hepatic triglyceride content was markedly higher in the APOC3 variant-allele carriers than in the wild-type homozygotes (mean, 7.5±10.3% [median, 3.2%], vs. mean, 1.5±1.3% [median, 1.1%]; P<0.001) (Fig. 1A).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Findingown data
The CG and GG genotypes at rs738409 in PNPLA3 were associated with increased liver triglyceride content compared with the CC genotype (dominant model P=0.002; additive model P=0.008).
“The liver triglyceride content was also increased in subjects of the CG and GG genotypes at rs738409 in PNPLA3, as compared with subjects of the CC genotype, with the use of both a dominant model (P = 0.002 by Student’s t-test; P = 0.003 by linear regression) and an additive model (P = 0.008 by analysis of variance; P = 0.04 by linear regression).11”
Quote in the paperSubstantial claim - Findingown data
The weight loss was accompanied by a reduction in liver triglyceride content from 14.0% to 3.8% (P=0.05).
“This weight loss was accompanied by a significant reduction in the liver triglyceride content (from 14.0 to 3.8%, P = 0.05).”
Quote in the paperNot a substantial claim - Findingown data
The prevalence of variant APOC3 alleles was similar among Asian Indian men and non-Asian Indian men.
“We found that the prevalence of variant APOC3 alleles was similar among Asian Indian men and non–Asian Indian men”
Quote in the paperSubstantial claim - Interpretationown data
APOC3 variant alleles (C-482T and T-455C) are associated with insulin resistance.
“The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.”
- Also stated in: § DISCUSSION · plain
“In summary, we found that genetic variants in APOC3 were associated with nonalcoholic fatty liver disease and insulin resistance in a cohort of Asian Indian men.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § DISCUSSION · plain
- Study design and conductown data
The difference in hepatic triglyceride content between APOC3 variant-allele carriers and wild-type homozygotes remained significant after adjustment for age and body-mass index.
“These differences remained significant when the analysis was adjusted for age and body-mass index (P = 0.005 by Student’s t-test; P = 0.02 by the Mann–Whitney test).”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Interpretationown data
APOC3 variant alleles (C-482T and T-455C) are associated with nonalcoholic fatty liver disease.
“The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.”
- Also stated in: § DISCUSSION · plain
“In summary, we found that genetic variants in APOC3 were associated with nonalcoholic fatty liver disease and insulin resistance in a cohort of Asian Indian men.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- Also stated in: § DISCUSSION · plain
- Interpretationown data
Other factors are responsible for the increased prevalence of nonalcoholic fatty liver disease among Asian Indian men.
“suggesting that other factors are responsible for the increased prevalence of nonalcoholic fatty liver disease among the Asian Indian men.9”
Quote in the paperSubstantial claim - Premisecitation
Reversal of nonalcoholic fatty liver disease by modest weight reduction corrects hepatic insulin resistance and fasting hyperglycemia in patients with type 2 diabetes mellitus.
“Furthermore, the reversal of nonalcoholic fatty liver disease by modest weight reduction corrects hepatic insulin resistance and fasting hyperglycemia in patients with type 2 diabetes mellitus.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] source
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- Premisecitation
PNPLA3 variants have not been found to be associated with insulin resistance.
“However, in contrast to the APOC3 variants described here, the PNPLA3 variants have not been found to be associated with insulin resistance.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] source
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- Premisecitation
Nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.
“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
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- Premisecitation
Transgenic mice with overexpression of human apolipoprotein C3 had hypertriglyceridemia due to decreased lipoprotein lipase activity.
“These data are consistent with previous studies showing that transgenic mice with overexpression of human apolipoprotein C3 had hypertriglyceridemia due to decreased lipoprotein lipase activity,16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] source
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- Interpretationown data
APOC3 and PNPLA3 variants have an interactive effect on the risk of nonalcoholic fatty liver disease.
“suggesting that these gene variants have an interactive effect.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
- May combine two claims. 10
- Classified as probably not a substantial claim. 6
May combine two claims.
Findingown dataAPOC3 variants alone, PNPLA3 variants alone, and the two combined accounted for 11.0%, 6.5%, and 13.1% of the variance in the risk of nonalcoholic fatty liver disease, respectively.
“Variants in APOC3 alone, PNPLA3 alone, and the two types combined accounted, respectively, for 11.0, 6.5, and 13.1% of the variance in the risk of nonalcoholic fatty liver disease.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
May combine two claims.
Findingown dataAfter weight loss, insulin sensitivity improved, with an increase in the insulin-sensitivity index from 1.8±0.8 to 3.7±1.4 (P<0.01).
“After weight loss, there was a marked improvement in insulin sensitivity on oral glucose-tolerance testing, with reductions in plasma glucose and plasma insulin concentrations (Fig. 1 in the Supplementary Appendix) and an increase in the insulin-sensitivity index (from 1.8±0.8 to 3.7±1.4, P<0.01).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe SNP rs738409 in PNPLA3 is associated with increased hepatic triglyceride content.
“In addition, we genotyped all study participants for the SNP rs738409 in the gene encoding patatin-like phospholipase domain–containing 3 (PNPLA3), which has also been shown to be associated with increased hepatic triglyceride content.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] source
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PremisecitationSeveral studies have shown a strong relationship among nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes mellitus.
“Several studies have shown a strong relationship among nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes mellitus.1–3”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAsian Indian men have a high prevalence of nonalcoholic fatty liver disease and insulin resistance.
“We began by studying a cohort of healthy Asian Indian men, a group that has been shown to have a high prevalence of nonalcoholic fatty liver disease and insulin resistance.9”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] source
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May combine two claims.
Interpretationown dataThe APOC3 variants promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance.
“These findings support the hypothesis that the APOC3 variants we studied promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
May combine two claims.
InterpretationcitationIncreased circulating chylomicron-remnant particles are preferentially taken up by the liver by a receptor-mediated process, resulting in nonalcoholic fatty liver disease and hepatic insulin resistance.
“Increased concentrations of circulating chylomicron-remnant particles are then preferentially taken up by the liver by means of a receptor-mediated process,18–22 resulting in non-alcoholic fatty liver disease and hepatic insulin resistance.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [18] Cooper AD, 1985, Gastroenterology source
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- cites [19] Windler EE, 1988, Biochem J source
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- cites [20] Sherrill BC, 1978, J Biol Chem source
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- cites [21] Nagata Y, 1988, J Biol Chem source
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- cites [22] source
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- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
Classified as probably not a substantial claim.
PremisecitationPrevious studies have suggested that two single-nucleotide polymorphisms in the gene encoding apolipoprotein C3 (APOC3) may be associated with hypertriglyceridemia.
“Previous studies have suggested that two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) may be associated with hypertriglyceridemia.4–8”
Quote in the paperSubstantial claim0 of 5 sources checkedMay combine two claims.
PremisecitationThe variant alleles at rs2854116 (T-455C) and rs2854117 (C-482T) are each associated with higher apolipoprotein C3 expression in vitro than the respective wild-type alleles.
“The variant alleles at rs2854116 (T-455C) and at rs2854117 (C-482T) are each associated with higher apolipoprotein C3 expression in vitro than are the respective wild-type alleles.12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] source
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May combine two claims.
PremisecitationThe associations of the variant alleles with higher apolipoprotein C3 expression are independent and not additive.
“Because these associations are independent and not additive, we divided the study participants into two genetically defined groups for the purposes of analysis: those who were homozygous for the low-expression (wild-type) allele at both SNPs and those who were carriers of one or more high-expression (variant) alleles at either SNP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] source
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May combine two claims.
Interpretationown dataThe APOC3 variants lead to increased plasma apolipoprotein C3 concentrations, which inhibit lipoprotein lipase and triglyceride clearance, conferring a predisposition to fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.
“Taken together, these results suggest that the APOC3 variants C-482T and T-455C lead to increased plasma concentrations of apolipoprotein C3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.”
Quote in the paperSubstantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
May combine two claims.
Study design and conductown dataThe APOC3 variant-allele carriers and wild-type homozygotes were similar with respect to age, body weight, body-mass index, physical activity level, and percentages of total daily caloric intake from fat, carbohydrate, and protein.
“The 76 carriers of either high-expression variant allele were similar to the 19 wild-type homozygotes with respect to age, body weight, body-mass index, and physical activity level (see Table 2 in the Supplementary Appendix). The percentages of total daily caloric intake represented by fat, carbohydrate, and protein were also similar in the two groups.”
Quote in the paperNot a substantial claim- Rests on an assumption: The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of protein kinase C epsilon, resulting in reduced insulin signaling and hepatic insulin resistance.
“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
Quote in the paperNot a substantial claim0 of 5 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA null mutation in human APOC3 results in lower plasma triglyceride levels and apparent cardioprotection in Amish subjects.
“as well as a recent study by Pollin et al. showing that a different mutation in the apolipoprotein C3 gene resulted in lower plasma triglyceride levels and had cardioprotective effects in Amish subjects.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] source
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The paper relies on this without support.
The genetic basis of the association between nonalcoholic fatty liver disease and insulin resistance is unknown.
“Whether this association has a genetic basis is unknown.”
“Whether there is a genetic basis for this association remains unknown.”
The paper relies on this without support.
The two APOC3 SNPs rs2854116 and rs2854117 are in strong linkage disequilibrium.
“The two SNPs in APOC3 (rs2854116 and rs2854117) are located in the promoter region (upstream of the transcription start site) and are in strong linkage disequilibrium.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Two polymorphisms (rs2854116 and rs2854117) in the ApoC3 gene seem to predispose individuals to the development of non-alcoholic fatty liver disease and insulin resistance.
“Two polymorphisms (rs2854116 and rs2854117) in the apolipoprotein C3 (ApoC3) gene that seem to predispose individuals to the development of non-alcoholic fatty liver disease and insulin resistance have been identified.93”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [93]
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Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men
Petersen, K. F., Dufour, S., Feng, J., Befroy, D., Dziura, J., Man, C. D., Cobelli, C., & Shulman, G. I. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608537103 · Cited by 403 · see citing works
Self-citationChoi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704213200 · Cited by 383 · see citing works
Self-citationZhang, D., Liu, Z.-X., Choi, C. S., Tian, L., Kibbey, R., Dong, J., Cline, G. W., Wood, P. A., & Shulman, G. I. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707060104 · Cited by 291 · see citing works
Self-citationLi, W. W., Dammerman, M. M., Smith, J. D., Metzger, S., Breslow, J. L., & Leff, T. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118324 · Cited by 278 · see citing works
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Willems van Dijk, K., Rensen, P. C., Voshol, P. J., & Havekes, L. M. (2004) · Current Opinion in Lipidology · doi:10.1097/00041433-200406000-00002 · Cited by 154 · see citing works
Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease
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APOC3 Promoter Polymorphisms C-482T and T-455C Are Associated with the Metabolic Syndrome
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ApoC-III gene polymorphisms and risk of coronary artery disease
Olivieri, O., Stranieri, C., Bassi, A., Zaia, B., Girelli, D., Pizzolo, F., Trabetti, E., Cheng, S., Grow, M. A., Pignatti, P. F., et al. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200145-jlr200 · Cited by 70 · see citing works
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Role of the Liver in the Degradation of Lipoproteins
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Mechanisms of Insulin Action and Insulin Resistance
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Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., Gudnason, V., Eiriksdottir, G., Garcia, M. E., Launer, L. J., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001324 · Cited by 984 · see citing works
Loss-of-Function Mutations in <i>APOC3</i> and Risk of Ischemic Vascular Disease
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Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
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“Multiple polymorphisms in ApoC3 (Peter et al., 2012; Petersen et al., 2010; Zhang et al., 2016) associated with NAFLD may increase plasma ApoC3 concentrations, which in turn inhibits lipoprotein lipase activity, leading to fasting and postprandial hypertriglyceridemia and prediposing lean individuals to NAFLD and insu…”
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Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects
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Genetic-related and carbohydrate-related factors affecting liver fat accumulation
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- Authors
- Petersen, K. F., Dufour, S., Hariri, A., Nelson-Williams, C., Foo, J. N., Zhang, X.-M., Dziura, J., Lifton, R. P., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-03-25
- Volume
- 362
- Issue
- 12
- Pages
- 1082-1089
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2976042
- OpenAlex
- W2025242285
- Semantic Scholar
- abb7b9f1cbdf68847d39d1efe6711ea3847cefd7
- Cited by
- 428
- References
- 27
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 12 · 2023: 7 · 2022: 28 · 2021: 17 · 2020: 28 · 2019: 15 · 2018: 12 · 2017: 23 · 2016: 29 · 2015: 34 · 2014: 36 · 2013: 43 · 2012: 38
- FWCI
- 39.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R01-AG-23686, R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01DK049230, R01DK040936, R01 DK-49230, R24DK085638, P30DK045735, P01DK068229)
- National Center for Research Resources (UL1RR024139)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- non-alcoholic fatty liver disease, apolipoprotein C-III, single nucleotide polymorphisms, insulin resistance, plasma triglycerides, hepatic triglyceride content, triglyceride clearance, hypertriglyceridemia, type 2 diabetes, genetic susceptibility
- MeSH terms
- Adult, Connecticut, Fatty Liver, Heterozygote, Homozygote, Humans, India, Insulin Resistance, Liver, Male, Triglycerides, Weight Loss, Prevalence, Linear Models, Statistics, Nonparametric, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Apolipoprotein C-III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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