Hyperchylomicronemia

The lipoprotein lipase gene is highly polymorphic, and several common mutations have been associated with an increased atherogenic lipid profile. One of these, Asn291Ser, was also found to be associated with increased ischemic heart disease in women. More recently, this same mutation, present in approximately 5% of the population, was also associated with increased ischemic cerebrovascular disease risk. The magnitude of this increase is less than or equal to that attributed to other modifiable risk factors, such as hypertension, smoking, and hypercholesterolemia. A prudent diet and lifestyle should therefore attenuate the higher genetic predisposition to atherosclerosis observed in women carrying this mutation.

Atherosclerosis is a diff-use process that begins early in childhood, progresses throughout adult life, and culminates in symptomatic ischemic syndromes later in life. Vascular beds of different organs such as heart, brain, and peripheral arteries are influenced by similar risk factors. Therefore, patients identified with one kind of atherosclerotic disease are at high risk of developing others, as shown in the Framingham Heart Study.1,2

High total cholesterol and low-density lipoprotein cholesterol, hypertension, smoking, and diabetes mellitus have all been identified as major risk factors for coronary heart disease (CHD) and peripheral vascular disease. Coexistence of risk factors substantially increases the risk of premature atherosclerosis. Low high-density lipoprotein (HDL) cholesterol is a strong independent predictor of CHD, present in up to 30% of patients as the main risk factor.3,4 The role of plasma triglyceride (TG) levels as a CHD risk factor has been controversial. Primarily owing to the inverse correlation between TG and HDL levels, TG was removed as a risk factor in population studies after adjustment for HDL levels. The evidence continues to accumulate, however, in support of the concept that elevated TG levels are independent risk factors for cardiovascular disease, especially in women.5 Moreover, a recent prospective study6 showed that baseline TG level predicted subsequent cardiovascular disease mortality among relatives of familial hypertriglyceridemic probands.

Lipoprotein lipase (LPL) is the rate-limiting enzyme involved in the lipolysis of triglyceride-rich lipoproteins (TRL), providing free fatty acids as a source of energy for muscles and other tissues or for storage in adipose tissue (Figure 1). Adipose tissue and muscle parenchymal cells are the major sources of LPL. From those sites, LPL is secreted and transported to the vascular endothelium where it attaches to heparan sulfate proteoglycans. LPL is also synthesized and secreted by macrophages. The importance of this enzyme in the development of dyslipidemia and atherosclerosis is increasingly recognized. However, there is conflicting evidence as to whether increased LPL activity has proatherogenic or antiatherogenic properties (Table 1). Based on the current evidence, it is possible that the atherogenic role of LPL may be tissue specific. In the arterial wall, its action could be proatherogenic, whereas in adipose tissue and muscle it could have a protective role.7,8

The human LPL gene is approximately 30 kb in length and is located on chromosome 8q22. More than 90 mutations in the LPL gene have been identified.9 Some are rare and were identified owing to their causative role in familial hyperchylomicronemia, a disorder characterized by massive accumulation of chylomicrons in plasma. Other more common variants of the LPL gene have been shown in some studies to be associated with less dramatic alterations in plasma lipids. Both Asp9Asn (D9N) and Asn291 Ser (N291 S) occur at carrier frequencies of up to approximately 5% and have been associated with higher plasma triacylglycerol levels and lower HDL concentrations, effects that seem to be magnified in more obese individuals. The Gly188Glu (GI 88E) variant is less common and has been associated with the chylomicronemia syndrome. Another variant is Ser447Ter (S447X), with a carrier frequency of approximately 20%. Unlike carriers of N9 or S29 1, X447 carriers appear to have a more favorable lipid profile.10,11 It is important, however, to emphasize that individual studies examining the associations between LPL gene variants, plasma lipids, and CHD risk have yielded controversial results. Although similar trends were noted for most ofthem, the results have not always been significant. This is in part owing to the small sample sizes used in many of the studies, the multifactorial character of the regulation of plasma lipid levels and coronary heart disease, and the different genetic backgrounds of the subjects studied. Greater knowledge of the underlying mechanisms of these variations within the LPL gene may be of considerable importance in understanding genetic predisposition to atherosclerosis and heart disease.

A recent meta-analysis has assessed the effect of heterozygous G188E, D9N, N291S, and S447X alleles of LPL on lipid metabolism and the risk of ischemic heart disease (IHD). Twenty-nine studies that included 20,903 white subjects were screened for at least one of these substitutions. 12 In population-based studies, heterozygote frequencies were as shown in Table 2. Postheparin plasma LPL activity decreased with the G188E, D9N, and N291 S variants and was unchanged for the S447X variant. Plasma TG increased with the G188E, D9N, and N291S variants and decreased with the S447X variant, whereas the opposite effect was observed for HDL cholesterol. Odds ratios for IHD were significantly higher for the G188E allele and lower for the S447X allele. These studies suggest that, compared with noncarriers, carriers of the Gly188Glu, Asp9Asn, and Asn291 Ser substitutions have an atherogenic lipid profile, whereas carriers of the Ser447Ter substitution have a protective lipid profile. Accordingly, the risk of IHD in heterozygous carriers is higher for Gly188Glu carriers, the increase barely reached statistical significance for Asp9Asn and Asn291 Ser carriers, and the risk is possibly lower for Ser447Ter carriers. This meta-analysis, its strength being its large number of subjects, was able to give additional support to the concept that the LPL gene locus is an important determinant of the population variability in plasma lipid levels, as well as, more modestly, the IHD risk. These data also support the view that increases in TRL are associated with higher CHD risk, as has previously been shown for low-density lipoproteins.

Wittrup et al.13 recently reported, in the largest individual population sampled so far, that the Asn291 Ser mutation in the LPL gene raises plasma TG levels and increases the risk of IHD in women but not in men. Considering the reported comorbidity of IHD with ischemic cerebrovascular disease (ICVD), therefore, these authors took the logical step of following this initial observation with further analyses examining ICVD risk in relation to this genetic variant. 14

These authors examined two populations for the presence of the Asn291 Ser mutation and its association with ischemic stroke. The first set was from a cross-sectional study involving 9215 subjects (Copenhagen City Heart Study).13 From this pool, the authors extracted 205 (83 women and 122 men) with ICVD and 1210 (498 women and 712 men) age- and sex-matched controls. The second study population consisted of 260 (97 women and 163 men) ICVD cases who were referred to the National University Hospital in Copenhagen because of their neurologic symptoms and who had equal to or greater than 50% carotid artery stenosis. The control group for this subset consisted of 1560 (582 women and 978 men) age- and sex-matched controls sampled from the general population who showed no evidence of ICVD.

When all subjects were analyzed, the investigators found that the risk of ICVD was not associated with the presence of the 291 Ser allele. After carrying out genderspecific analyses, however, they observed that women with the 291 Ser allele had a risk of ICVD that was approximately twice that of women who were homozygous for the more frequent 291 Asn allele (Figure 2). Men with the 291 Ser allele did not have an increased risk of ICVD as compared with the reference group (subjects with the lower tertile of age, cholesterol, lipoprotein(a), triglycerides, and body mass index, the upper tertile of HDL-C and the normal Asn 291 Ser genotype). In fact, a nonsignificant protective trend was found for the 291 Ser allele in men (odds ratio [OR] 0.8; Figure 2).

These findings support the concept that coronary and peripheral ischemic diseases share common risk factors, including some of genetic origin such as the LPL locus; when these results are examined in the context of their clinical relevance, however, we should keep in mind the inconsistency of the findings observed in individual studies. Even in the current study,14 the results were not homogenous between the two populations examined. Whereas significant associations were observed in subjects who attended the National University Hospital and were selected on the basis of having >=50% carotid artery stenosis, no such significance could be obtained from the population cross-sectional sample (Copenhagen City Heart Study).

Even though this study may appear to have sufficient statistical power by using a large cross-sectional study of almost 10,000 subjects and a large case/control study, the reality is that owing to the selection and matching conditions and the low frequency of the genetic variant examined, all conclusions are based on the presence of 10 women with ICVD plus carotid stenosis who were carriers of the rare Ser291 allele. Therefore, one cannot ignore that these findings were obtained by chance (as the authors recognize in the discussion section of their paper). Nevertheless, if further research confirms that this mutation is a risk factor for both ischemic heart and cerebrovascular diseases, this knowledge will provide some practical applications, the most obvious being the use of this polymorphism as a screening tool for heart disease and stroke risk, especially in women. It is important to emphasize that the study of individual mutations at single gene loci to assess individual genetic risk will provide very little information. Useful assessment of genetic risk will be possible only after careful design of"cardiovascular risk panels" incorporating multiple markers representing variation at a large number of candidate gene loci.

The results of this study should also stimulate further basic research to understand the role of hormones regulating the synthesis of LPL and the tissue specificity of this effect. It is generally accepted that TG levels are a better predictor of atherosclerosis in women than in men. Our group showed that this is also the case when examining remnant lipoproteins, which have been hypothesized to represent the atherogenic component of triglyceriderich lipoproteins.15 This polymorphism, therefore, which has been shown to increase TG levels, may also induce a greater progression of atherosclerosis in women, who tend to be more affected by this risk factor than do men. Moreover, it is important to emphasize that LPL is hormonally regulated. A recent report demonstrated that estrogen suppresses transcription of the LPL gene.16 Therefore, one can hypothesize that this mutation reduces lipolytic activity in both men and women, but that in women this effect is enhanced by their estrogen levels. Conversely, in men, testosterone could compensate for the lower LPL activity observed in carriers of this mutation.17

In summary, the authors have expanded their initial female-specific association between this polymorphism and IHD owing to a similar association with ICVD. However, this association needs further verification in other studies. Moreover, we should keep in perspective that the impact of this genetic effect is lower than that of other, classical risk factors such as elevated cholesterol, high blood pressure, and smoking, all of which are modifiable risk factors (Figure 2). Therefore, the potentially higher genetic risk contributed by this mutation could be easily neutralized by proper behavioral, dietary, or pharmacologic interventions to reduce the nongenetic risk factors.

Acknowledgments. This work was supported by grant HL54776 and contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department ofAgriculture Research Service.

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This review was prepared by Jose M. Ordovas, Ph.D., Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.

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