Heterozygous Lipoprotein Lipase Deficiency
Frequency in the General Population, Effect on Plasma Lipid Levels, and Risk of Ischemic Heart Disease
Background Patients with mutations on both alleles of the lipoprotein lipase gene resulting in complete lipoprotein lipase deficiency exhibit the chylomicronemia syndrome with severe hypertriglyceridemia and increased risk of pancreatitis and possibly of ischemic heart disease. This study examined frequency, lipid levels, and risk of ischemic heart disease for heterozygous carriers of lipoprotein lipase mutations known to cause the chylomicronemia syndrome in the homozygous state.
Methods and Results Two mutations were screened for in 9259 individuals in a general population sample and in 948 patients with verified ischemic heart disease. The percent frequencies of heterozygous individuals with the Gly188→Glu and Ile194→Thr substitutions in the general population were 0.06% (95% CI, 0.04% to 0.23%) and 0% (95% CI, 0.00% to 0.12%), respectively. The Gly188→Glu substitution was associated with an increase in plasma triglycerides of 0.8±0.3 mmol/L (mean±SEM) and a decrease in plasma HDL cholesterol, apo A-I, and glucose levels of 0.45±0.07 mmol/L, 17±6 mg/dL, and 1.1±0.2 mmol/L, respectively. On multiple logistic regression analysis allowing for age, sex, plasma cholesterol, plasma lipoprotein (a), hypertension, diabetes mellitus, smoking, and body mass index, both plasma triglycerides and HDL cholesterol levels were independent predictors of ischemic heart disease. Finally, the Gly188→Glu substitution was more common among patients with verified ischemic heart disease (percent frequency of heterozygous individuals, 0.32%) than among individuals from the general population (odds ratio, 4.9; 95% CI, 1.2 to 19.6). The effects of the Gly188→Glu substitution were more pronounced than those of the common Asn291→Ser substitution.
Conclusions Heterozygous lipoprotein lipase deficiency due to the Gly188→Glu substitution appears to increase plasma triglycerides and reduce HDL levels and may thereby predispose carriers to ischemic heart disease.
The enzyme LPL plays a crucial role in the catabolism of triglycerides contained in chylomicrons and large VLDLs.1 If these particles are converted into chylomicron remnants and smaller VLDLs or IDLs, plasma triglyceride levels are decreased.
In studies of patients with severe hypertriglyceridemia, the so-called chylomicronemia syndrome, more than 40 different structural mutations in the homozygous or compound heterozygous state have been described in the LPL gene over the past few years.1 As a result of such mutations, the enzyme is either not produced or becomes catalytically defective, and these patients typically exhibit severe chylomicronemia, hepatosplenomegaly, episodes of abdominal pain, pancreatitis, and eruptive xanthomas but in most cases not ischemic heart disease. It has recently been shown, however, that ischemic heart disease may be seen in some patients with either homozygous or compound heterozygous forms of LPL mutations.2 The majority of the mutations have been located to exons 4, 5, and 6 in the LPL gene and have been described in only a single or very few probands; phylogenetically, these exons are the most conserved regions of the LPL gene and probably contain the catalytic site, a triad of Ser132, Asp156, and His241.1 Two single-base mutations in exon 5, however, the Gly188→Glu and Ile194→Thr substitutions, respectively, have both been described in several kindreds of mainly European descendance.1 3 4 5 6 This opens up the possibility for a search within the general populations of European heritage for individuals with these mutations in the heterozygous state to determine the frequency of the mutations as well as the associated phenotype.
Obligate heterozygotes for LPL deficiency have decreased LPL activity and mass and, in some families, increased plasma cholesterol and/or increased plasma triglycerides.7 Another study suggested that obligate heterozygotes for the Gly188→Glu substitution in the LPL protein have only elevated plasma triglycerides rather than elevations of both plasma cholesterol and triglycerides8 ; in this study, however, there was evidence for another putative gene causing increased triglycerides on the maternal side. Therefore, the exact phenotype associated with LPL mutations in the heterozygous state remains unclear, particularly because only obligate heterozygotes have been studied so far and no information is available on carriers found in the general population. Furthermore, it is still unknown whether such LPL mutations in the heterozygous state predispose carriers to ischemic heart disease.
We screened for the mutations in the LPL gene causing the Gly188→Glu and Ile194→Thr substitutions in 9259 individuals from a general population sample, the Copenhagen City Heart Study, and in 948 patients with verified ischemic heart disease. This enabled us to determine the frequency in the general population. By comparing lipid levels as well as other clinical and biochemical characteristics of the probands with the age- and sex-matched percentiles in the total general population sample, we were also able to examine the phenotypic expression of these mutations in vivo, which gave us some insight into whether these mutations predispose heterozygous carriers to ischemic heart disease or not. Finally, we compared the effects of heterozygosity for the Gly188→Glu substitution with those of the common Asn291→Ser substitution in LPL.9
First, a general population sample (the Copenhagen City Heart Study) with an almost equal number of men and women stratified into age groups from 20 to ≥80 years was drawn from the Copenhagen Central Population Register with the aim of obtaining a sample representing the Danish general population.10 Fewer than 1% were nonwhite, and 98.8% had Danish citizenship, ie, for practical purposes were of Danish descent. The sample was collected in 1991 through 1994: of the 17 180 individuals invited, 10 049 participated, and among these, 9259 individuals gave blood.
Second, 992 consecutive patients from the greater Copenhagen area were referred for coronary angiography in the period 1991 to 1993. Among these, 948 (26% women) had ischemic heart disease with characteristic symptoms plus at least one of the following characteristics: severe stenosis on coronary angiography (n=767) (ie, >70% stenosis of at least one coronary artery or >50% stenosis of the left main coronary artery), a previous myocardial infarction, or a positive exercise ECG. Fewer than 1% were nonwhite, and >98% had Danish citizenship, ie, for practical purposes were of Danish descent.
The present studies were approved by Danish ethical committees: No. 100.2039/91 Copenhagen and Frederiksberg committee and No. KA 93125 Copenhagen County committee.
From each individual, total genomic DNA was isolated from a whole-blood sample as described.11 For the purpose of rapid screening, whole blood was pooled from 10 or 20 individuals (from heart patients and the general population, respectively): 200 μL of whole blood from each individual was pooled, the blood was mixed thoroughly, and DNA was isolated with a commercially available kit (QIAamp Blood Kit, QIAGEN GmbH).
Screening for the Gly188→Glu Substitution
This substitution is caused by a G→A missense mutation in codon 188 (GGG→GAG) of the LPL gene.3 Initially, DNA from the 948 patients with ischemic heart disease was first screened individually by AvaII restriction enzyme digestion of PCR-amplified DNA; presence of the mutation causes loss of an AvaII site. Part of intron 4 and most of exon 5 of the LPL gene were amplified in a PCR assay with an automated thermocycler (Omnigene Thermal Cycler, Hybaid Ltd). The 100-μL PCR assay contained 1 μmol/L sense (5′-GAGCAGTGACATGCGAATGT-3′) and antisense (5′-CTCCAAGTCCTCTCTCTGCA-3′) primers (DNA Technology Aps); 190 μmol/L each of d′ATP, d′TTP, d′GTP, and d′CTP; 1.5 mmol/L MgCl2; 1 U Taq DNA polymerase; 1× PCR amplification buffer (all from Life Technologies Inc); and 5 μL DNA sample (0.1 to 0.2 μg DNA). The thermal cycling procedure was as follows: 1 cycle of 5 minutes at 94°C, 30 seconds at 50°C, and 60 seconds at 72°C; 30 cycles of 30 seconds at 94°C, 30 seconds at 50°C, and 60 seconds at 72°C; and finally 1 cycle of 30 seconds at 94°C, 30 seconds at 50°C, and 5 minutes at 72°C. The PCR product was digested overnight with 1 U AvaII (Biolabs) at 37°C and was diagnosed in a 4% agarose gel as undigested (305 bp), two normal alleles (131, 88, and 86 bp), or one normal and one mutated allele (219, 131, 88, and 86 bp).
Subsequently, whole blood from 1 of the 3 probands found with the Gly188→Glu substitution was used to construct a “mutation-positive” pool of 20 individuals, as described above. This DNA pool served as a positive control in an allele-specific PCR assay. The design of this assay was similar to that described above, except that the antisense primer (5′-CCAAGTCCTCTCTCTGCAATCAGG-3′) had a concentration of 0.05 μmol/L as opposed to 1 μmol/L for the sense (5′-GGCCTCGATCCAGCTGGACC-3′) and mutation-specific antisense (mutation in italics and underlined) (5′-AATGCTTCGACCAGGGCACT 3′) primers. In the mutation-specific primer, an extra base change was introduced 3 bases downstream from the mutation (underlined only), causing a C-to-C mismatch. These modifications ensured that the allele-specific primer, under the conditions used, would anneal only when the mutation was present and that in such a case, amplification of the mutation-specific PCR product (123 bp) would be favored compared with the normal PCR product (233 bp). The thermal cycling was identical to that described above except for an annealing temperature of 60°C. The DNA products were diagnosed in a 3% agarose gel.
The allele-specific PCR assay detected three and six DNA pools to be positive for the mutation among patients with ischemic heart disease and among individuals in the general population sample, respectively. DNA from each of the 10 or 20 individuals in each of these DNA pools were then tested individually with the allele-specific PCR assay; among heart patients, the same 3 individuals as initially identified with the AvaII restriction enzyme assay were found to be mutation positive. The AvaII restriction enzyme assay was used for final confirmation of the diagnosis.
Screening for the Ile194→Thr Substitution
This substitution is caused by a T→C missense mutation in codon 194 (ATT→ACT) of the LPL gene.5 DNA from a heterozygous proband (kindly provided by H.E. Henderson, University of Cape Town, South Africa) was used to construct a “mutation-positive” pool of 20 individuals. This pool served as the positive control in the assay screening pooled DNA samples. The composition and thermal cycling of the allele-specific PCR assay were similar to that described above, except for a different mutation-specific antisense primer (mutation in italics and underlined) (5′-CCAACTGGTTTCTGGATTACAG-3′) causing an additional A-to-G mismatch 3 bases downstream from the mutation (underlined only); this yielded a 233-bp normal PCR product and a 143-bp mutation-specific PCR product.
Colorimetric and turbidimetric assays were used to measure nonfasting (general population) or fasting (heart patients) plasma levels of total cholesterol, HDL cholesterol, triglycerides, glucose, apo B, apo A-I (CHOD-PAP, precipitation of apo B–containing lipoproteins followed by CHOD-PAP, GPO-PAP, hexokinase method, sheep anti-human apo B, and sheep anti-human apo A-I, respectively; all from Boehringer Mannheim), and lipoprotein (a) [rabbit anti-human lipoprotein (a), DAKO A/S]. Body mass index and blood pressure were determined as described previously,10 as was apo E genotyping.12 Waist-to-hip ratio was the body circumference measured midway between the lower rib margin and the iliac crest divided by the maximum circumference over the buttocks.
Analysis of Results
To examine the effect of mutations on phenotype, all values for each proband were converted to their respective percentiles in the total general population sample13 ; percentiles for the proband’s own sex group and 10-year age group were used at increments of 1%. These percentiles were converted to standardized normal deviations (z scores), and for a given parameter (eg, HDL cholesterol), z-score distribution was examined by comparing the mean z score with the standard gaussian distribution.14 The variances of the z scores were tested for differences compared with the general population variance of 1 by χ2 distribution.14 In addition, to compare effects of the Gly188→Glu substitution with those of the Asn291→Ser substitution, plasma triglycerides, apo A-I, and HDL cholesterol levels were adjusted by ANCOVA (see “Results”).
Multivariate logistic regression analysis with forced entry15 was performed to investigate whether plasma triglycerides, HDL cholesterol, and apo A-I were independent predictors of ischemic heart disease when conventional cardiovascular risk factors were allowed for; plasma glucose was not available for patients with ischemic heart disease and therefore could not be tested. To approach linearity in the logit, square-root, logarithmic, or inverse transformations were used for some but not all covariates. Because individuals >70 years old are unlikely to be referred to coronary angiography in Denmark, only individuals <70 years old were included in the logistic regression analysis. The ability to predict ischemic heart disease was expressed as an odds ratio (eβ) with 95% CIs (eβ±1.96×SEM), for an increase of 1 SD in the variable. The likelihood ratio test between models including and excluding the parameter of interest was the test of significance.
Student’s t test and calculation of odds ratios were also performed15 ; Fisher’s exact test was used as a test of independence. Statistical tests were two-tailed, with the level of significance chosen as P<.05.
Frequency in the General Population
The Gly188→Glu and Ile194→Thr substitutions in the LPL protein were identified in 6 and 0 individuals, respectively, from among 9259 individuals in a general population sample. Accordingly, the 95% CIs for the percent frequencies of heterozygous individuals with these two mutations in the Danish population are 0.04% to 0.23% and 0.00% to 0.12%, respectively. Among the 948 patients with ischemic heart disease, 3 (0.32%) and 0 (0%) carried the Gly188→Glu and Ile194→Thr substitutions, respectively.
Gly188→Glu Substitution and Phenotypic Characteristics
Characteristics in terms of absolute values for the 9 unrelated probands heterozygous for the Gly188→Glu substitution in the LPL protein are shown in Table 1⇓. For comparison, mean values for the total general population sample and for all patients with ischemic heart diseases are likewise shown in Table 1⇓; the predictors of ischemic heart disease are consistent with findings from numerous previous studies. At the time of investigation, none of the probands were being treated with lipid-lowering, antidiabetic, or antihypertensive drugs, except proband 6, who received the calcium antagonist verapamil, and proband 8, who received bezafibrate at a low dose when plasma apo B, apo A-I, and lipoprotein (a) were measured. The 24-year-old woman (proband 1) took oral contraceptives.
Because all continuous characteristics were measured simultaneously in all other participants of the Copenhagen City Heart Study, it was possible to assign each proband to a percentile in the relevant sex group and 10-year age group (Figs 1⇓ and 2⇓). When all 9 probands were examined, plasma triglycerides were significantly increased and plasma HDL cholesterol, apo A-I, and glucose significantly reduced; however, patients with ischemic heart disease were fasting at the time of examination and individuals in the general population cohort were not. The same conclusions were nevertheless drawn for plasma triglycerides, HDL cholesterol, and plasma glucose when the 6 probands identified in the general population were examined separately (P=.02, P=.01, and P=.05, respectively), whereas plasma apo A-I was then no longer significantly reduced (P=.14). There was no evidence that the variances of the phenotypic characteristics shown in Figs 1⇓ and 2⇓ were different from the equivalent variances in the general population (all comparisons, P>.05), except that plasma triglycerides had a smaller variance among probands than in the general population sample (P<.05).
The effect of the Gly188→Glu substitution was an increase in plasma triglycerides of 0.8±0.3 mmol/L (mean±SEM) and a decrease in plasma HDL cholesterol, apo A-I, and glucose levels of 0.45±0.07 mmol/L, 17±6 mg/dL, and 1.1±0.2 mmol/L, respectively; when the 6 probands from the general population sample were considered alone, the increase in plasma triglycerides and decrease in plasma HDL cholesterol, apo A-I, and glucose were 0.9±0.4 mmol/L, 0.41±0.10 mmol/L, 16±7 mg/dL, and 0.9±0.2 mmol/L, respectively. This effect of the Gly188→Glu substitution was calculated as the absolute difference between the proband’s own value and the mean value for the matched sex group and 10-year age group, thus allowing for the effect of age and sex.
Triglycerides, HDL Cholesterol, and Risk of Ischemic Heart Disease
On univariate analysis, plasma triglyceride, HDL cholesterol, and apo A-I levels all were predictors of ischemic heart disease (Table 1⇑). Furthermore, on multiple logistic regression analyses allowing for age, sex, plasma cholesterol, plasma lipoprotein (a), hypertension, diabetes mellitus, smoking, and body mass index, both plasma triglycerides and HDL cholesterol levels were still predictors of ischemic heart disease (Table 2⇓).
Gly188→Glu Substitution and Risk of Ischemic Heart Disease
The Gly188→Glu substitution in the LPL protein was found more frequently among patients with verified ischemic heart disease than among individuals in the general population (odds ratio, 4.9; 95% CI, 1.2 to 19.6) (Table 3⇓). When the comparison was limited to age 40 to 75 years or to men only, comprising 94% and 74%, respectively, of patients with verified ischemic heart disease and 72% and 45% of individuals in the general population sample, the odds ratios were 7.5 (95% CI, 1.5 to 37.0) and 4.4 (95% CI, 1.0 to 19.9), respectively. This mutation was also more common among patients with severe stenosis on coronary angiography than in the general population sample (odds ratio, 6.1; 95% CI, 1.5 to 24.3).
The 3 probands identified among patients with verified ischemic heart disease developed angina pectoris between the ages of 46 and 58 years (Table 1⇑). Among probands identified in the general population sample, only 1 developed ischemic heart disease, but among the remaining 5 individuals, 3 were <50 years old, and the 72-year-old man was thin, with a body mass index of only 19.
Comparison of the Gly188→Glu and Asn291→Ser Substitutions
Heterozygous carriers of the Gly188→Glu substitution were rare, whereas heterozygous carriers of the Asn291→Ser substitution were common, in the Danish general population (Fig 3⇓); no individual carried both substitutions. The observed effects on plasma triglycerides, apo A-I, and HDL cholesterol levels, however, were more pronounced in individuals heterozygous for the Gly188→Glu substitution than in those heterozygous for the Asn291→Ser substitution. Furthermore, the odds ratio for ischemic heart disease was larger for Gly188→Glu heterozygotes than for Asn291→Ser heterozygotes.
A new observation in the present study is the observed percent frequency of heterozygous carriers of the Gly188→Glu and Ile194→Thr substitutions in LPL in the Danish general population of 0.06% and 0%, respectively; <1% of the individuals screened were nonwhite, and >98% had Danish citizenship, ie, for practical purposes were of Danish descent.
The importance of a given mutation for phenotypic expression is often evaluated by examining characteristics of index patients and their relatives. Because index patients as a rule are identified among patients with a characteristic phenotype (eg, hyperlipidemia or ischemic heart disease) and not among individuals in the general population, this approach would tend to overestimate the effect of the mutation, even among obligate heterozygotes; other genes or environmental factors of importance for the phenotype may cluster in such families. Alternatively, in vitro expression systems have been used to measure the effect of a given mutation on the expression of the protein coded for, but some of these effects could be modulated in vivo. Transgenic animals have also been used to study effects of mutations relative to the wild-type protein, with the limitation that these effects may not represent those in humans. Our present approach of identifying unrelated individuals with the same mutation within the general population and comparing the characteristics of the individuals identified with those for age- and sex-matched individuals in the general population may give a better estimate of the “true” phenotype of a given mutation in humans.
The present finding of an increase in nonfasting plasma triglycerides among unrelated heterozygous carriers of the Gly188→Glu substitution is in accordance with previous findings in obligate heterozygous carriers of the same or other mutations in the LPL gene in the postprandial or fasting state.1 4 7 8 16 17 18 19 20 21 22 23 24 Also in support of this finding, the Gly188→Glu substitution was found in 6 of 95 unrelated Canadians with type IV hyperlipidemia, ie, with elevated levels of triglycerides due to VLDL elevations, but not among normotriglyceridemic subjects.25 The HDL cholesterol–reducing effect of heterozygous LPL deficiency found in the present study is also in agreement with previous observations in obligate heterozygous individuals,7 8 18 23 24 as is the present finding of reduced apo A-I levels among carriers.23 Obligate heterozygous carriers have on one occasion been shown to have elevated plasma apo B levels,7 a finding that was not confirmed in the present study, although a similar trend was observed (Fig 1⇑; two-tailed P=.11, one-tailed P=.054). The previously reported elevation of systolic blood pressure among obligate heterozygous carriers24 was not confirmed in the present study (Fig 2⇑).
Because the Gly188→Glu substitution in LPL appears to cause a moderate elevation in plasma triglycerides and a reduction in HDL levels and because these two cardiovascular risk factors have been found to be independent predictors of ischemic heart disease in the present and former studies,26 27 the data seem to suggest that this substitution represents a susceptibility mutation for ischemic heart disease. In support of this, we observed a higher frequency of the Gly188→Glu substitution among patients with ischemic heart disease than among individuals in the general population; there is, however, a 4% probability that the observed distribution is a chance finding. The present data also suggest that this mutation represents only a relatively weak susceptibility mutation, because the 4 carriers with ischemic heart disease had their initial disease manifestations in the age range of 46 to 67 years and because 2 male probands 59 and 72 years old had not yet experienced manifestations of ischemic heart disease.
An unexpected new observation is the plasma glucose–lowering effect of heterozygous LPL deficiency, which could easily represent a chance observation. Former studies in Gly188→Glu heterozygotes found no plasma glucose–reducing effect,8 16 and our observation therefore needs to be confirmed by other groups.
A number of potential limitations of the present study should be considered: (1) Were there any false-positives? This possibility can be excluded because each proband was diagnosed by two different methods. (2) Were there any false-negatives? To examine this possibility, we tested all 948 patients with verified ischemic heart disease by both detection methods and found complete concordance. (3) Individuals in the general population sample had blood samples drawn in the nonfasting state, whereas the patients’ blood was drawn in the fasting state. This could potentially be a problem for values of plasma glucose and triglycerides; however, plasma glucose was reduced and plasma triglycerides were increased when all probands were examined as well as when only the 6 probands identified within the general population cohort were considered. As an estimate of the variation in plasma lipids due to the nonfasting state, the Copenhagen City Heart Study has previously determined average levels of triglycerides and cholesterol as a function of the period after the last meal before blood sampling: 1 to 30 minutes (n=766), 30 minutes to 1 hour (n=2630), 1 to 3 hours (n=8004), or >3 hours (n=2468); average triglyceride levels for these four categories were (mean±SEM) 1.80±0.05, 1.82±0.02, 1.77±0.01, and 1.66±0.02 mmol/L, respec- tively. The equivalent values for plasma cholesterol were 5.95±0.04, 6.00±0.02, 6.14±0.01, and 6.21±0.03 mmol/L, respectively. (4) Finally, the samples examined (general population sample and patients with verified ischemic heart disease) may not truly represent the general population and patients with ischemic heart disease because of bias due to nonresponders or selection bias.28 If the Gly188→Glu substitution in fact is a susceptibility mutation for ischemic heart disease, a disease that could increase the likelihood that invited individuals did not respond to the Copenhagen City Heart Study, this substitution could be underrepresented among responders in the Copenhagen City Heart Study, and thereby the observed odds ratio for ischemic heart disease for heterozygous carriers could be overestimated.
Nevertheless, mechanistically it is plausible that heterozygous LPL deficiency could lead to an increased risk of ischemic heart disease. Individuals heterozygous for the Gly188→Glu substitution have an ≈50% reduction in LPL activity,8 16 which may explain the observed increase in plasma triglycerides and reduction in HDL cholesterol. LPL normally removes triglycerides from chylomicrons and VLDLs, and as a byproduct, HDL particles are formed from the generated excess surface material of these large, triglyceride-rich lipoproteins.1 In observational epidemiological studies, both elevated plasma triglycerides and decreased plasma HDL cholesterol levels have been associated with an increased risk of ischemic heart disease,26 27 exactly as was also found in the present study. A modest increase in plasma triglycerides, such as that associated with heterozygous LPL deficiency, implies that more cholesterol in plasma is carried in IDL, small VLDL, or chylomicron remnant particles rather than in LDL particles only. These triglyceride-rich lipoproteins may be retained selectively in the arterial intima,29 leading to increased development of atherosclerosis and eventually to ischemic heart disease; triglyceride-rich lipoprotein particles have been shown in vitro to be taken up directly by macrophages to produce foam cells,30 31 a key cell type in the atherosclerotic plaque. It is worth noting that only the relatively smaller chylomicron remnants and VLDL and IDL particles may be involved, because large chylomicrons and VLDLs with a diameter >75 nm (like those present in the plasma of patients with complete LPL deficiency1 ) are excluded from the intima.32 A decrease in plasma HDL cholesterol levels may be an indicator of reduced ability to remove cholesterol from the arterial intima, potentially leading to more atherosclerosis and ischemic heart disease.33 Finally, elevated plasma triglycerides have been shown to be associated with a subclass of small, dense LDL particles that by themselves may promote atherogenesis.26 The present data suggest that neither diabetes mellitus, hypertension, obesity, elevated plasma lipoprotein (a) levels, nor the apo E4 genotype is necessary for Gly188→Glu carriers to develop ischemic heart disease.
The potential total impact of heterozygous LPL deficiency on risk of ischemic heart disease in countries with affluent lifestyles can currently only be guessed. Assuming that all LPL mutations known to cause the chylomicronemia syndrome in the homozygous or compound heterozygous state (frequency, 1 per million1 ) predispose heterozygous carriers to ischemic heart disease, a total of 2000 per million individuals may be at increased risk of ischemic heart disease due to such LPL mutations in the heterozygous state. However, two common LPL mutations causing the Asp9→Asn and Asn291→Ser substitutions may also be important. The presence of the Asn291→Ser substitution in the heterozygous state is associated with a decrease in postheparin plasma LPL activity of ≈30%,34 35 an increase in plasma triglycerides,9 25 35 36 37 38 39 and a decrease in HDL levels,9 34 35 36 38 39 as well as with an increased odds ratio for ischemic heart disease in women9 ; these effects were less pronounced for the Asn291→Ser substitution than for the Gly188→Glu substitution (Fig 3⇑). The Asp9→Asn substitution is associated with elevated plasma triglycerides,40 41 reduced HDL levels,42 and increased progression of coronary atherosclerosis.42 Finally, mutations in the LPL promoter43 may also affect plasma lipid levels and risk of ischemic heart disease, although evidence for this is still lacking.
Selected Abbreviations and Acronyms
|PCR||=||polymerase chain reaction|
This study was supported by the Danish Heart Foundation and the Danish foundation Lægeforeningens Forskningsfond. Thanks to Jørgen Hilden for in-depth statistical advice.
Reprint requests to Børge G. Nordestgaard, MD, DMSc (Dr med), Department of Clinical Biochemistry, 54 M1, Herlev University Hospital, DK-2730 Herlev, Denmark.
Drs Abildgaard and Wittrup contributed equally to this article.
- Received February 12, 1997.
- Revision received April 8, 1997.
- Accepted April 18, 1997.
- Copyright © 1997 by American Heart Association
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