Longitudinal Changes in Triglycerides According to ANGPTL4[E40K] Genotype and Longitudinal Body Weight Change in the Atherosclerosis Risk in Communities Study

doi:10.1016/j.annepidem.2008.07.004

Annals of Epidemiology

Volume 18, Issue 11, November 2008, Pages 842-846

https://doi.org/10.1016/j.annepidem.2008.07.004 Get rights and content

Purpose

Allelic variation in the adipokine angiopoietin-like 4 gene (ANGPTL4[E40 K]) has been cross-sectionally associated with triglycerides, but the effects of genotype, or the interaction between genotype and body weight, on longitudinal triglyceride change have not been studied.

Methods

Body weight, triglycerides, and ANGPTL4[E40 K] genotype were determined at baseline (1987–1989) and at 3 follow-up exams (1990–1992, 1993–1995, 1996–1998) in 7,939 white ANGPTL4[E40 K] G allele homozygotes and 344 A allele carriers. Changes in body weight and triglycerides were characterized as the difference between exam 4 and baseline measurements.

Results

ANGPTL4[E40 K] A allele carriers had triglyceride concentrations that were 15 to 18 mg/dL lower than G allele homozygotes at all exams (P < 0.0001). Triglycerides increased in both genotype groups over the 9-year period (+19.1 ± 0.9 and +16.2 ± 4.1 mg/dL in GG and GA/AA, respectively; P difference, 0.48). Weight gain was associated with increased triglycerides to a comparable degree in both genotype groups (+5.5 ± 0.3 and +4.3 ± 0.9 mg/dL per 2-kg increase in body weight in GG and GA/AA, respectively, p interaction = 0.30).

Conclusions

Differences in triglyceride concentrations between ANGPTL4[E40 K] A allele carriers and G allele homozygotes are maintained over time, but the degree of increase in triglycerides was similar between groups and was not modified by body weight changes.

Introduction

The adipokine angiopoietin-like 4 (ANGPTL4) is thought to regulate fatty acid transport among tissues by inhibiting lipoprotein lipase, a key enzyme in triglyceride (TG) metabolism 1, 2, 3. Consistent with its suspected role, a recent cross-sectional analysis in white participants from three different cohorts showed a strong association between baseline TG levels and the non-synonymous sequence variant [E40 K] in the ANGPTL4 gene (4). Homozygous (AA) and heterozygous A allele carriers (GA) had significantly lower TG concentrations compared with their homozygous wild-type counterparts (GG). The influence of this polymorphism on longitudinal changes in TG has not yet been investigated. Given the relation between TG concentrations and the risk of cardiovascular disease (CVD), the effect of ANGPTL4[E40 K] polymorphisms may have important implications for risk of incident disease, especially if one considers the potential for lifetime low TG concentrations to have a greater impact than might be expected from a single measure of TG (analogous to that reported for low-density lipoprotein cholesterol and PCSK9 polymorphisms) (5).

Changes in body weight predict changes in TGs 6, 7, 8, 9, but it is possible that the influence of body weight change on changes in TG concentration may be dampened in individuals with a genetic predisposition to lower TG concentrations (i.e., ANGPTL4[E40 K] A allele carriers). Therefore we characterized the 9-year longitudinal changes in TG in ANGPTL4[E40 K] GG and A allele carriers. We also examined the potential interaction between longitudinal body weight change and ANGPTL4[E40 K] genotype with respect to longitudinal TG changes. These analyses were conducted with data from white men and women who participated in the Atherosclerosis Risk in Communities (ARIC) study, one of the three cohorts involved in the original cross-sectional study demonstrating the strong effect of ANGPTL4[E40 K] variation and TG concentration (4).

Section snippets

Subjects

The ARIC study was initiated in 1987 to investigate the etiology and occurrence of atherosclerosis and atherosclerotic diseases (10). Men and women, 45 to 64 years of age, were recruited from four U.S. communities: Forsyth County, North Carolina; Jackson, Mississippi (African Americans only); northwest Minneapolis suburbs, Minnesota; Washington County, Maryland. After providing informed consent, 15,792 participants were enrolled in the study (8,710 women and 7,082 men). Study protocols were

Results

Participant demographic and lifestyle characteristics, as well as baseline body weight, BMI, and waist circumference, did not differ between ANGPTL4[E40 K] G allele homozygotes and A allele carriers with the exception of greater alcohol intake in carriers (P = 0.02) (Table 1). Plasma concentrations of TGs were 14 to 23 mg/dL lower in A allele carriers than in G allele homozygotes at each exam, but the degree of change (increase) between the baseline exam and exam 4 was similar: +17 to 19 mg/dL.

Discussion

The current longitudinal investigation, including 8,283 white men and women from the ARIC study, showed that both body weight and ANGPTL4[E40 K] genotype independently influence plasma TG concentrations, but together genotype and body weight do not interactively determine TG concentration. Persons carrying the ANGPTL4[E40 K] A allele had lower concentrations of TGs than non-carriers at all exams, but TG concentrations increased as body weight increased uniformly in both genotype groups. These

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Cited by (10)

Regulation of triglyceride metabolism by Angiopoietin-like proteins
2012, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Citation Excerpt :
One particular variant, which is carried by approximately 2% of Caucasians and causes a substitution of glutamine by lysine at position 40 (E40K), was associated with decreased plasma TG and increased plasma HDL-C concentrations [34,35]. The lower TG levels in E40K carriers compared to non-carriers persisted over a nine-year period during which TG concentrations went up in both groups [36]. Another ANGPTL4 gene variant, T266M, was also found to be associated with lower plasma TG.
Plasma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has emerged as important regulators of circulating triglyceride (TG) levels. Specifically, ANGPTL3 and ANGPTL4 impair TG clearance by inhibiting lipoprotein lipase (LPL). Whereas ANGPTL4 irreversibly inactivates LPL by promoting conversion of active LPL dimers into inactive monomers, ANGPTL3 reversibly inhibits LPL activity. Studies using transgenic or knockout mice have clearly demonstrated the stimulatory effect of Angptl3 and Angptl4 on plasma TG, which is further supported by human genetic data including genome wide association studies. Whereas ANGPTL3 is mainly active in the fed state, ANGPTL4 is elevated by fasting and mediates fasting-induced changes in plasma TG and free fatty acid metabolism. Both proteins undergo oligomerization and are subject to proteolytic cleavage to generate N- and C-terminal fragments with highly divergent biological activities. Expression of ANGPTL3 is exclusive to liver and governed by the liver X receptor (LXR). In contrast, ANGPTL4 is expressed ubiquitously and under sensitive control of the Peroxisome proliferator-activated receptor (PPAR) family and fatty acids. Induction of ANGPTL4 gene expression by fatty acids and via PPARs is part of a feedback mechanism aimed at protecting cells against lipotoxicity. So far there is very little evidence that other ANGPTLs directly impact plasma lipoprotein metabolism. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
Angiopoietin-like protein 4: A therapeutic target for triglycerides and coronary disease?
2018, Journal of Clinical Lipidology
Citation Excerpt :
Higher HDL-C levels in E40K carriers were also observed. Similarly, the decreased TG levels were observed in ANGPTL4 E40K carriers throughout a longitudinal observation and during a period of weight gain.29 A major question had been whether genetically reduced function of ANGPTL4 was associated with protection from CAD.
The angiopoietin-like proteins are a family of proteins that share structural similarities to the angiopoietins. These proteins have been described to play a key role in the regulation of a myriad of physiologic processes, including serving as essential modulators of lipid and glucose metabolism. Angiopoietin-like protein 4 (ANGPTL4) is a key regulator of lipoprotein lipase, and its modulation has been shown to significantly impact the body's processing and distribution of triglycerides and cholesterol. Although more research remains to elucidate the full range of mechanisms through which ANGPTL4 affects triglyceride and cholesterol homeostasis, current research has associated decreased ANGPTL4 function with a beneficial effect on lipid parameters and overall cardiovascular disease risk, opening the possibility of ANGPTL4 as a new therapeutic target for the treatment of cardiovascular disease.
Ancestry specific associations of a genetic risk score, dietary patterns and metabolic syndrome: a longitudinal ARIC study
2021, BMC Medical Genomics
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2016, Current Opinion in Lipidology
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Longitudinal Changes in Triglycerides According to ANGPTL4[E40K] Genotype and Longitudinal Body Weight Change in the Atherosclerosis Risk in Communities Study

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

J Lipid Res

J Lipid Res

Am J Clin Nutr

Am J Clin Nutr

Mol Genet Metab

J Nutr

J Lipid Res

Genetics and regulation of angiopoietin-like proteins 3 and 4

Curr Opin Lipidol

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

Nat Genet

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease

N Engl J Med