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CLINICAL RESEARCH: GENETIC POLYMORPHISMS AND ISCHEMIC HEART DISEASE

Hepatic lipase mutations,elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease

The Copenhagen City Heart Study

Rolf V. Andersen, MSc, PhD^*, Hans H. Wittrup, MD, PhD^*, Anne Tybjærg-Hansen, MD, DMSc, Rolf Steffensen, MD, Peter Schnohr, MD and B.ørge G. Nordestgaard, MD, DMSc^*,*

^* Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark
Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark
Department of Medicine B, Division of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, Copenhagen, Denmark

Manuscript received April 12, 2002; revised manuscript received September 19, 2002, accepted October 31, 2002.

^* Reprint requests and correspondence: Dr. Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
brno{at}herlevhosp.kbhamt.dk

	Abstract

Top Abstract Methods Results Discussion References

 
OBJECTIVES: We investigated associations between single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter, levels of high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). Our primary hypothesis was that these SNPs associate with IHD after adjustment for HDL levels.

BACKGROUND: Hepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD.

METHODS: We genotyped 9,121 white subjects aged 20 to 93 years from the Copenhagen City Heart Study, 456 of whom had incident IHD, as well as 921 Danish patients with IHD for the –216, –480, and –729 SNPs in the hepatic lipase promoter.

RESULTS: Frequencies of wild-type, triple heterozygotes, and triple mutation homozygotes in the general population were 61%, 33%, and 5%, respectively. Compared with wild-type, HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. In prospective and case-control studies, mutation homozygotes versus wild-type had relative risk (RR) and odds ratio (OR) for IHD of 1.5 (95% confidence interval [CI]: 1.0 to 2.2) and 1.4 (CI: 1.1 to 1.9) when adjusted for age, gender, and HDL cholesterol. In individuals with the 43 apolipoprotein E genotype, RR and OR for IHD in mutation homozygotes versus wild-type was 2.9 (CI: 1.5 to 5.6) and 2.0 (CI: 1.2 to 3.2).

CONCLUSIONS: Hepatic lipase promoter SNPs are associated with increased HDL cholesterol and, paradoxically, an increased risk of IHD after adjustment for HDL cholesterol, and particularly in individuals with apolipoprotein E 43 genotype. Implications are that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk.

Abbreviations and Acronyms   ANOVA   analysis of variance   HDL   high-density lipoprotein   IHD   ischemic heart disease   LDL   low-density lipoprotein   PCR   polymerase chain reaction   SNPs   single nucleotide polymorphisms

Hepatic lipase hydrolyzes phospholipids and triglycerides in HDL and may influence reverse cholesterol transport (4). Four linked single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter (5,6) (Table 1) associate with decreased hepatic lipase activity (7–12). These promoter SNPs may also influence levels of lipids and lipoproteins (5,7,9,10,13–15), and consequently affect risk of IHD. We hypothesized that dysfunctional hepatic lipase may associate with elevated HDL levels and paradoxical increased IHD risk, exactly as found for dysfunctional cholesteryl ester transfer protein (3,16).

	Methods

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For the cross-sectional study we included all genotyped individuals except 29 outliers with triglycerides >10 mmol/l. For the prospective and case-control studies, only those subjects with the three most common genotypes (Table 2) who did not receive lipid-lowering medication were included.

The Copenhagen City Heart Study was also studied prospectively from 1991 through 1994 until the end of 1998: 205 women and 251 men with incident IHD were diagnosed by experienced cardiologists based on myocardial infarction (MI) and/or angina pectoris (WHO International Classification of Diseases, 8th ed. pp. 410–14), by reviewing the Danish National Hospital Discharge Register, the Danish National Register of Causes of Deaths, and medical records from hospitals and general practitioners (16–18). Participants with prevalent IHD diagnosed before examination in 1991 through 1994 were excluded.

For the case-control study to gain more statistical power, we pooled incident and prevalent IHD cases from the Copenhagen City Heart Study with other IHD cases referred for coronary angiography between 1991 and 1993, which added 383 women and 902 men with IHD to the incident cases. In cases referred for coronary angiography, IHD was diagnosed by experienced cardiologists based on stable angina pectoris plus at least one of the following: severe stenosis on coronary angiography (70% stenosis of at least one coronary artery or 50% stenosis of the left main coronary artery), previous MI, or a positive exercise electrocardiographic (ECG) test (16–18).

In all groups, more than 99% were white subjects of Danish descent. Danish ethical committees (No. 100.2039/91 and KA93125) approved the studies.

Both measurements and detection of conventional cardiovascular risk factors were as described previously (16–18). Colorimetric and turbidimetric assays were used to measure plasma levels of total cholesterol, HDL cholesterol, triglycerides, apolipoprotein AI, apolipoprotein B (all by Boehringer Mannheim, Mannheim, Germany), and lipoprotein(a) (DAKO A/S, Glostrup, Denmark). Non-HDL cholesterol was total cholesterol minus HDL cholesterol, whereas LDL cholesterol was total cholesterol minus both HDL cholesterol and very low density cholesterol (estimated as 0.45 x triglycerides).

DNA analyses.   The SNPs in the hepatic lipase promoter at positions –729, –480, and –216 (Table 1) were detected by polymerase chain reaction (PCR) followed by digestion with restriction enzymes. The PCR was performed using the sense primer 5'-TCCTGGCCAGAAATCTCTTCT-3' and the anti-sense primer 5'-GACTTGTGTCCATTTCTCCGT-3'. A PCR product aliquot was digested with DraI recognizing the –216A mutation and an internal control site (–216G: 756bp, 194bp; –216A: 640bp, 194bp, 116bp). A second aliquot was digested with NlaIII recognizing the –729G and –480T mutations and an internal control site (–729A/–480C: 822bp, 128bp; –729A/–480T: 440bp, 382bp, 128bp; –729G/–480C: 690bp, 132bp, 128bp; –729G/–480T: 440bp, 250bp, 132bp, 128bp). The DNA fragments were analyzed by electrophoresis in a 2% agarose gel. An assay developed for the –676 SNP necessitated polyacrylamide gel electrophoresis for sufficient resolution of DNA band sizes and was avoided due to time and toxicity considerations.

We sequenced parts of the hepatic lipase promoter in 157 subjects and confirmed the 11 different genotypes observed, as well as linkage disequilibrium between the three studied SNPs and the T(–676)C SNP (5). One subject apparently with a mutation at position –729 had instead a C(–764)T mutation. This generates another NlaIII site, explaining the initial result. We also discovered two other mutations not previously reported: G(–568)T (39 heterozygotes, 3 homozygotes) and G(–558)A (9 heterozygotes, 1 homozygote), which appeared primarily in individuals with genotypes found in 1% of the general population (Table 2). Because of the frequency and distribution of these SNPs, they do not invalidate the overall results in the present study and do not contradict previous results (5,7–15).

Apolipoprotein E genotyping was performed as previously described (16).

Statistical analyses.   Statistical analyses were performed using SPSS. A p value <0.05 on a two-sided test was significant. Except where explicitly stated, correction for multiple comparisons was not performed. A priori we stratified by gender; however, to increase the statistical power when analyzing risk of IHD, we also examined the two genders combined. We also a priori stratified for apolipoprotein E genotype, because this polymorphism has profound influence on lipids, lipoproteins, and IHD (18).

We used the Kruskal-Wallis analysis of variance (ANOVA) with Mann-Whitney U test for post hoc two-genotype comparisons. Analysis of covariance tested for multiplicative interaction among genotype and HDL cholesterol, apolipoprotein AI, triglycerides, non-HDL cholesterol, apolipoprotein B, lipoprotein(a), cholesteryl ester transfer genotype (16,17), apolipoprotein E genotype (18), body-mass index, waist/hip ratio, glucose, alcohol consumption, systolic blood pressure, diastolic blood pressure, age, hypertension, use of diuretics, diabetes mellitus, IHD, smoking, physical activity, menopause (women), and hormonal replacement therapy (women) in the prediction of HDL cholesterol, apolipoprotein AI, triglycerides, and non-HDL cholesterol. Triglycerides were log₁₀-transformed.

Cox and unconditional logistic regression examined associations between genotype and IHD. Regression analyses were made 1) adjusted for age and gender, and 2) adjusted for age, gender, and HDL cholesterol (in quintiles); when HDL is adjusted for, the strong inverse association between HDL and IHD risk cannot mask an association between these SNPs and IHD. Multiplicative interactions between genotype and gender and other cardiovascular risk factors on IHD risk were examined.

	Results

Top Abstract Methods Results Discussion References

 
Characteristics, levels of lipids and lipoproteins, and apolipoprotein E genotype frequencies have been presented previously (16–18).

Genotype frequencies.   Frequencies of hepatic lipase promoter genotypes in the general population are given in Table 2. It has previously been reported that the –729G, –480T, and –216A variants are in linkage disequilibrium (5), which was confirmed in our sample: noncarriers (wild-type), heterozygotes, and mutation homozygotes for this haplotype constituted 61%, 33%, and 5%, respectively, of all genotype combinations. The remaining 1% was distributed between eight other genotype combinations, all hitherto undescribed. Allele frequencies of –729G, –480T, and –216A were 0.218, 0.212, and 0.218, respectively. Genotype distributions did not differ significantly from Hardy-Weinberg equilibrium (chi-square, p > 0.5 for each SNP).

Lipids and lipoproteins.   Relative to wild-type, levels of HDL cholesterol were 4% (0.07 mmol/l) and 3% (0.04 mmol/l) higher in triple heterozygous women and men and 10% (0.17 mmol/l) and 9% (0.12 mmol/l) higher in triple mutation homozygous women and men, respectively (Fig. 1, Table 2); the equivalent values for apolipoprotein AI (the main protein constituent of HDL) were 3% and 2% for heterozygous and 7% and 6% for mutation homozygous women and men, respectively (all ANOVAs: p < 0.001). No significant differences existed in levels of triglycerides, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) among the three major genotypes (Fig. 1, latter two not shown). Additionally, no difference was seen in LDL cholesterol levels among the three genotypes, in the general population, or among IHD patients (data not shown).

View larger version (45K): [in this window] [in a new window]   Figure 1 Levels of lipids and lipoproteins in individuals from the general population who are wild-type (Wild), triple heterozygotes (Hetero), or triple mutation homozygotes (Homo) for hepatic lipase promoter single nucleotide polymorphisms. A, C = women; B, D = men. ANOVA = analysis of variance; post-hoc Mann-Whitney U test: *p < 0.05; **p < 0.01; ***p < 0.001. HDL = high-density lipoprotein. E, G = women; F, H = men.

Lipoproteins across apolipoprotein E genotypes.   Levels of HDL cholesterol and apolipoprotein AI increased from wild-type to triple heterozygotes to triple mutation homozygotes among subjects with 33 and 43 genotypes of both genders and in women with the 32 genotype (Fig. 2). Levels of HDL cholesterol and apolipoprotein AI in 32/homozygous women were 19% (0.32 mmol/l) and 15% (22 mg/dl) above levels in 43/wild-type women. Equivalent values for men were 11% (0.14 mmol/l) and 13% (16 mg/dl), respectively.

View larger version (37K): [in this window] [in a new window]   Figure 2 Levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein AI in individuals from the general population who are wild-type (Wild), triple heterozygotes (Hetero), or triple mutation homozygotes (Homo) for hepatic lipase promoter single nucleotide polymorphisms, stratified for apolipoprotein E genotype. The p values are by analysis of variance within each apolipoprotein E genotype stratum; post-hoc Mann-Whitney U test. *p < 0.05; **p < 0.01; ***p < 0.001. A, B = women. C, D = men.

View larger version (18K): [in this window] [in a new window]   Figure 3 Risk of ischemic heart disease in prospective study analyzed by Cox regression. Results are relative risks (95% confidence interval [CI]): CI is not corrected for multiple comparisons. Individuals on cholesterol-lowering treatment (53 subjects, 8 events) and with unknown treatment status (87 subjects, 8 events) were excluded. *No homozygotes among cases in the 32 strata. HDL = high-density lipoprotein; IHD = ischemic heart disease.

View larger version (17K): [in this window] [in a new window]   Figure 4 Risk of ischemic heart disease in case-control study analyzed by unconditional logistic regression. Results are odds ratios (95% confidence interval [CI]): CI is not corrected for multiple comparisons. Individuals on cholesterol-lowering treatment (122 cases, 45 controls) and with unknown treatment status (15 cases, 79 controls) were excluded. HDL = high-density lipoprotein.

	Discussion

Top Abstract Methods Results Discussion References

 
We hypothesized that dysfunctional hepatic lipase may associate with elevated HDL levels and paradoxical increased IHD risk, exactly like dysfunctional cholesteryl ester transfer protein (3,16,19). Both enzymes are important in reverse cholesterol transport, and elevated HDL levels may in these situations therefore mark reduced flux of cholesterol from the arterial intima back to the liver for excretion.

Our primary hypothesis was that hepatic lipase SNPs were associated with risk of IHD, particularly after adjustment for HDL cholesterol levels, as in our two previous studies on cholesteryl ester transfer protein SNPs (16,17). Generally, reduced HDL levels (also associated with triglyceride-rich lipoproteins and small dense LDL [1,2]) is a strong predictor of IHD (1). We wanted to examine the effect of mutation homozygosity without interference from this association between HDL and IHD: when HDL is adjusted for, the inverse association between HDL and IHD risk can no longer mask a direct association between these SNPs and increased IHD risk.

We found that hepatic lipase promoter genotype was associated with a stepwise increase in HDL cholesterol and apolipoprotein AI, from wild-type to heterozygotes to mutation homozygotes. Despite this, mutation homozygosity was associated with increased risk of IHD after adjustment for HDL cholesterol, and particularly in apolipoprotein 43 individuals.

Other researchers have previously asked questions similar to ours in much smaller studies; however, associations among hepatic lipase promoter mutations, HDL, and IHD have never been examined in such large studies as ours, and particularly not by using a prospective design of the general population. In addition, our findings, namely that these mutations are associated with both elevated HDL and paradoxically with increased risk of ischemic heart disease, are novel.

HDL cholesterol and apolipoprotein AI.   The results presented in this study demonstrate an incremental increase in levels of both HDL cholesterol and apolipoprotein AI from wild-type to triple heterozygotes to triple mutation homozygotes among both women and men, not demonstrated previously (5,7,9,10,13–15). Reduced hepatic lipase activity associated with these mutations in the hepatic lipase promoter (7–12) could lead to an increase in atherogenic remnant particles; however, we did not observe differences in levels of triglycerides and non-HDL cholesterol. Nevertheless, reduced hepatic lipase activity may very well explain reduced HDL metabolism with consequently higher HDL levels (1). The HDL cholesterol received from nonliver cells may be transferred to the liver in at least two ways as part of the reverse cholesterol transport pathway. Cholesteryl esters may be transferred to triglyceride-rich lipoproteins by cholesteryl ester transfer protein followed by liver uptake of these lipoproteins via LDL receptors. Alternatively, HDL particles may be processed by hepatic lipase followed by selective uptake of HDL cholesteryl esters by liver and steroidogenic tissues: the class B scavenger receptor SR-BI expressed primarily in these tissues has been shown to bind HDL with high affinity and to mediate selective uptake of cholesteryl esters (20).

Risk of IHD.   A new and important finding in the present study is the 40% to 50% increased risk of IHD among individuals homozygous for hepatic lipase promoter mutations relative to wild-type after adjustment for HDL cholesterol. Previous studies were smaller than the present and were not able to document this association in mutation homozygous individuals (7,8,14,15). Results compatible with the present study were, however, observed in two of the studies, in heterozygous (7) and mutation homozygous (14) individuals, respectively. In another study (8), only patients with HDL cholesterol 1.1 mmol/l were included, essentially preselecting against these SNPs. If we apply this preselection criterion to male IHD patients in our study, we find an OR for IHD of 0.8 for mutation homozygotes versus wild-type. In other words, if only individuals with low HDL levels are studied, many of those with the mutations associated with high HDL levels (and high risk of IHD) simply are excluded from the study.

There are data, however, that at first hand would seem to contradict our results: in a prospective angiographic lipid-lowering study, Zambon et al. (21) demonstrated that a decrease in hepatic lipase activity is associated with regression of coronary artery disease. The researchers noted, however, that response to lipid-lowering therapy was defective in those with the rarer allele (22). Other "paradoxical" evidence suggests that a) low hepatic lipase activity (observed in premenopausal women and lean individuals) is associated with a less atherogenic lipoprotein profile and thus possibly with lower risk of IHD, and b) high hepatic lipase activity (in obese individuals, those with type II diabetes, and postmenopausal women) is associated with a more atherogenic lipoprotein profile and thus possibly with increased risk of IHD (23–25).

We believe that the association of hepatic lipase promoter mutations with increased risk of IHD despite higher levels of HDL can be explained in a straightforward manner. The hepatic lipase promoter mutations are associated with reduced activity of the enzyme (7–12) and owing to this, catabolism of HDL-2 particles decreases. The higher levels of HDL-2 cholesterol due to reduced flux through the reverse cholesterol transport system suggest an insufficient removal of cholesterol from the arterial intima, ultimately leading to increased risk of atherosclerosis and IHD (1); HDL-2 was unfortunately not measured in the Copenhagen City Heart Study. In essence, higher levels of HDL cholesterol and apolipoprotein AI may—in this particular context—be regarded as a secondary result of reduced flux through the reverse cholesterol transport system, whereas in most other contexts high levels of HDL cholesterol and apolipoprotein AI may reflect a high capacity of this system.

Findings analogous to the present results show that mutations in the cholesteryl ester transfer protein associated with elevated HDL levels and reduced enzyme activity also associate with increased risk of IHD (3,16,19), whereas mutations in this protein associated with reduced HDL levels and increased enzyme activity (which could mark increased reverse cholesterol transport) associate with reduced risk of IHD (17).

The significant findings after adjustment for HDL cholesterol that suggest an inverse relationship between hepatic lipase levels—strongly associated with the promoter genotypes—and risk of IHD, could also be completely indepen-dent of reverse cholesterol transport and atheroprotective effects of HDL. An alternative plausible explanation could be the role of hepatic lipase in the clearance of remnant particles and possibly the effect of increase in hepatic lipase activity on faster clearance of these atherogenic particles, hence association of triple mutation homozygosity with lower hepatic lipase activity and increased levels of IHD. Potential interaction of apolipoprotein E genotypes and hepatic lipase variants may suggest a coordinated function in remnant clearance and risk of IHD.

Apolipoprotein E genotype stratification.   Because the apolipoprotein E polymorphism has profound influence on lipids, lipoproteins, and IHD risk (18), analyses in this study were stratified for the three common apolipoprotein E genotypes 32, 33, and 43. Our data support a model where apolipoprotein E genotypes and hepatic lipase promoter genotypes contribute independently (that is, demonstrate additive rather than multiplicative interaction) to plasma levels of HDL cholesterol and apolipoprotein AI, and together they may explain 19% and 15% differences in levels of HDL cholesterol and apolipoprotein AI, respectively.

The finding that, among individuals with the 43 genotype, the risk of IHD in hepatic lipase SNP homozygotes versus wild-type was larger than in all individuals combined suggests that apolipoprotein E variability may mask association between hepatic lipase SNPs and risk of IHD. In support of this concept, apolipoprotein E variants associated with higher HDL levels associate with reduced IHD risk (18), in contrast to the present findings for hepatic lipase. Thus, within a group of people with the same apolipoprotein E genotype, the association between hepatic lipase genotype and risk of IHD will not be masked by contradictory variability from apolipoprotein E.

Study limitations.   Although we observed a clear gene dosage effect from wild-type to triple heterozygotes to triple mutation homozygotes on levels of HDL cholesterol and apolipoprotein AI, this was not the case for risk of IHD, except in the subgroup of individuals with apolipoprotein E 43 genotype. There are several possible explanations for such a discrepancy: 1) our observation of increased risk of IHD is a chance finding; 2) absence of increased IHD risk among triple heterozygous individuals may be a chance event; 3) the effect on risk of IHD is recessive rather than co-dominant; and 4) the statistical power is much less for the end point IHD than for levels of intermediate variables like lipoproteins.

Lack of significant associations with IHD risk in some strata also represent a potential limitation. Interpretations of this phenomenon include 1) that triple mutation homozygosity versus wild-type is associated with increased risk of IHD in women (but not in men), and in 43 carriers (but not in those with 32 or 33); 2) that some strata like those with 32 genotype lack statistical power; and 3) that play of chance determines that, for example, women but not men demonstrate significant associations.

Study implications.   The present study presents new evidence that common SNPs in the hepatic lipase promoter gene result, despite a rise in HDL, in an increased risk of IHD, particularly in the setting of apolipoprotein E 43 genotype. This finding has implications beyond the genetic and metabolic finding, as it indicates that elevated HDL levels may actually be associated with increased risk of IHD in certain situations, as has previously been reported for mutations in the cholesteryl ester transfer protein (3,16,17,19), another important enzyme in reverse cholesterol transport (1). Therefore, the study is of relevance to both research scientists and clinicians.

Implications of the findings include that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk, and that our assessments of HDL levels do not directly measure reverse cholesterol transport. Thus, although the average person with high HDL levels is protected against IHD, a subgroup of such individuals where the opposite is true may also exist. Therefore, some patients with high HDL levels, particularly those with manifest IHD, need both aggressive lipid-lowering medication and other preventive measures against atherosclerosis and IHD.

	Acknowledgments

 
We thank laboratory technicians Pia Taaning Petersen and Marianne Lodahl for their expert technical assistance.

	Footnotes

 
Supported by the Danish Heart Foundation, the Danish Medical Research Council, and Chief Physician Johan Boserup and Lise Boserup’s Fund.

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