Hyperalphalipoproteinemia 1

A number sign (#) is used with this entry because variation in high density lipoprotein (HDL) cholesterol levels, including hyperalphalipoproteinemia, can result from mutation in the cholesteryl ester transfer protein gene (CETP; 118470) on chromosome 16q21.

Another form of hyperalphalipoproteinemia (HALP2; 614028) results from loss-of-function mutations in the apolipoprotein C-III gene (APOC3; 107720).

Clinical Features

Glueck et al. (1975) described a family in which 3 generations contained persons with elevated levels of alpha-lipoprotein (HDL, the molecule deficient in Tangier disease (205400), or hypoalphalipoproteinemia). They referred to preliminary studies of 11 other kindreds. There was no instance of male-to-male transmission in the pedigree described in detail. The 'affected' persons showed no xanthomata or vascular or neurologic disease. On further studies in 18 kindreds, Glueck et al. (1975) found segregation among 84 offspring of 22 hyper-alpha X normo-alpha matings consistent with autosomal dominant inheritance. However, the distribution of alpha-lipoprotein cholesterol (HDLC) did not show bimodality in the kindreds and no parent-offspring correlation was found. The authors concluded that an environmental cause common to sibships might be responsible. Longevity analysis showed prolongation of life and a rarity of premature 'atherosclerotic events.' The last finding makes it particularly important to identify the postulated environmental factors. Glueck et al. (1977) identified a kindred with 4 affected generations through measurement of elevated levels of cord blood high-density lipoproteins in neonates.

In a study of 11 black and 15 white kindreds, Siervogel et al. (1980) found bimodality for HDL cholesterol only in whites: one mode at 46 mg per dl and the second at 69.

Koizumi et al. (1985) and Kurasawa et al. (1985) described 2 Japanese families with CETP deficiency. Koizumi et al. (1985) found a 58-year-old male and his 55-year-old sister with HDL cholesterol levels of 301 and 174 mg/dl, respectively. Both were asymptomatic without signs of atherosclerosis, and there was no unusual amount of cardiovascular disease in the family. Two other sibs and 4 offspring had levels of HDL cholesterol in the range of 54 to 83 mg/dl. Low density lipoprotein (LDL) cholesterol and triglyceride levels were low in the affected brother and sister. Both were shown to have a defect in the transfer of labeled cholesteryl ester from HDL to VLDL plus LDL. Studies of a 35-year-old Japanese male by Kurasawa et al. (1985) demonstrated an abnormally low triglyceride level in HDL, consistent with the concept that CETP exchanges cholesteryl ester in HDL for triglyceride in LDL or VLDL. Rats, dogs, and pigs with plasma CETP deficiency have been found to be relatively resistant to atherosclerosis.

Kronenberg et al. (2002) performed segregation analysis of HDLC values in 3,755 individuals from 560 randomly recruited Caucasian families and 522 Caucasian families with high family risk of coronary heart disease (CHD) in the NHLBI Family Heart Study. There was no evidence for an allele at a major gene locus responsible for low HDLC levels (604091). The best model for low HDLC was the environmental model. However, there was evidence for a major allele leading to higher-than-average HDLC values in the CHD group after adjustment for triglyceride concentrations. The environmental and dominant models were rejected, while the codominant and recessive models were not rejected. In both models, the means of those individuals inferred to be homozygous for the high HDLC allele and those without the high HDLC allele were separated by about 25 mg/dl HDLC. Because these results were unexpected, segregation analysis was repeated using data of 2,013 individuals from 85 large Utah pedigrees ascertained for early CHD deaths, early stroke deaths, and early hypertension. Similar results were obtained supporting the evidence for a major allele for high HDLC level in subjects ascertained for CHD risk.

Molecular Genetics

CETP Deficiency/Hyperalphalipoproteinemia

Saito (1984) described a family in which both parents were hyperlipoproteinemic. Among their progeny, 2 individuals showed extremely high levels of HDL-cholesterol (more than 150 mg/dl), suggesting that the affected parents were heterozygous and the exceptional progeny homozygous. The family reported by Saito (1984) was found by Inazu et al. (1990) to have deficiency of plasma cholesteryl-ester transfer protein; see 118470.0002.

In 3,469 men of Japanese ancestry in the Honolulu Heart Program, Zhong et al. (1996) found a high prevalence of 2 different CETP gene mutations: 5.1% for D442G (118470.0002) and 0.5% for the G-to-A substitution in the intron 14 donor site (118470.0001). The mutations were associated with decreased CETP (-35%) and increased HDL cholesterol levels (+10% for D442G). However, the overall prevalence of definite coronary heart disease was 21% in men with mutations and 16% in men without mutations.

Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, Borggreve et al. (2005) hypothesized that triglycerides modify the effect of the CETP -629C-A promoter polymorphism on HDL cholesterol. In 7083 nondiabetic subjects, the HDL cholesterol-raising effect of the CETP -629A allele was diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides. Neither central obesity nor insulin resistance modified the influence of the -629C-A polymorphism on HDL cholesterol.

Large-scale clinical trials in which inhibitors of 3-hydroxy-3-methylglutaryl-co enzyme A reductase (HMGCR; 142910) (statins) were used to reduce LDL cholesterol levels have shown marked improvements in clinical outcomes (Schaefer and Brousseau, 2000). Despite the favorable effects of statins on the risk of coronary heart disease, many cardiovascular events are not prevented by statin therapy. Brousseau et al. (2004) noted that decreased HDL cholesterol levels constitute a major risk factor for coronary heart disease, and investigated the effect of a novel CETP inhibitor, torcetrapib, on plasma lipoproteins in patients with low HDL cholesterol levels. They found that in patients with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

High Density Lipoprotein Cholesterol Level Quantitative Trait Locus 10

In an evaluation of the hypothesis that multiple HDL cholesterol levels reflect the cumulative contributions of multiple common DNA sequence variants, each of which has a small effect, Spirin et al. (2007) identified a single-nucleotide polymorphism (SNP) of the CETP gene (118470.0005) that acts in concert with other SNPs in the PLTP (172425.0001) and LPL (118470.0042) genes to affect plasma levels of HDL cholesterol.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs1800775 of CETP, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.

Aulchenko et al. (2009) reported the first genomewide association (GWA) study of loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. This study included a total of 17,797 to 22,562 individuals aged 18 to 104 years from geographic regions spanning from the Nordic countries to Southern Europe. Aulchenko et al. (2009) established 22 loci associated with serum lipid levels at a genomewide significance level (P less than 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The area near the CETP gene identified by rs1532624 was significantly associated with HDL cholesterol levels (P = 9.4 x 10(-94)).

Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators (e.g., CYP7A1, 118455; NPC1L1, 608010; SCARB1, 601040) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified several novel loci associated with plasma lipids that are also associated with coronary artery disease. Teslovich et al. (2010) identified rs3764261 near the CETP gene as having an effect on HDL cholesterol concentrations with an effect size of +3.39 mg per deciliter and a P value of 7 x 10(-380).

TaqI Polymorphism

Kondo et al. (1989) demonstrated an association between 1 allele of the CETP locus, as demonstrated by a TaqI polymorphism (rs708272), and plasma apoA-I concentrations. The effect of the CETP alleles was limited to nonsmokers in this study.

HDL cholesterol concentration is inversely related to the risk of coronary artery disease. CETP has a central role in the metabolism of this lipoprotein and might therefore alter the susceptibility to atherosclerosis. For this reason, Kuivenhoven et al. (1998) studied the DNA of 807 men with angiographically documented coronary atherosclerosis for the presence of a polymorphism in the CETP gene. The specific polymorphism studied was a restriction polymorphism TaqIB in intron 1 of the CETP gene (Kuivenhoven et al., 1997). The TaqIB polymorphism had been shown to be associated with an effect on lipid-transfer activity (Hannuksela et al., 1994) and on HDL cholesterol concentrations (Freeman et al., 1994). The presence of the DNA variation was referred to as B1 and its absence as B2. All 807 patients in the study participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for 2 years. The B1 variant of CETP was associated with both higher plasma CETP concentrations and lower HDL cholesterol concentrations. In addition, Kuivenhoven et al. (1998) observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group. This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers. This common DNA variant appeared to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis. In the total cohort, the B1 and B2 alleles were found at frequencies of 0.594 and 0.406, respectively. The observed frequencies were in Hardy-Weinberg equilibrium.

In commenting on the report by Kuivenhoven et al. (1998), Altshuler et al. (1998) expressed caution concerning the interpretation of studies of association between allelic variants and common diseases. The 2 issues they raised in urging caution were, first, population admixture, which can cause an artificial association if a study includes genetically distinct subpopulations, one of which coincidentally displays a higher frequency of disease and allelic variants. Consideration of the ethnic backgrounds of subjects and the use of multiple, independent populations can help avoid this problem. The most persuasive tests, however, such as the transmission disequilibrium test, involve family-based controls. In this test, if a given allele contributes to disease, then the probability that an affected person has inherited the allele from a heterozygous parent should vary from the expected mendelian ratio of 50:50; the association of a neutral polymorphism due to admixture displays no such deviation. A second source of concern is multiple-hypothesis testing, aggravated by publication bias. Authors who test a single genetic variant for an association with a single phenotype base statistical thresholds for significance on a single hypothesis. However, many laboratories search for associations using different variants. Each test represents an independent hypothesis, but only positive results are reported, leading to an overestimate of the significance of any positive associations. Statistical correction for multiple testing is possible, but the application of such thresholds result in loss of statistical power.

Fumeron et al. (1995) reported that alcohol intake modulates the effect of the TaqIB polymorphism on plasma HDL and the risk of myocardial infarction. They found that HDL cholesterol was increased in subjects with the B2B2 genotype only when they ingested at least 25 g of alcohol per day. The cardioprotective effect of the B2B2 CETP genotype was restricted to subjects who consumed the highest amounts of alcohol. In a study of patients with insulin-dependent diabetes, Dullaart et al. (1997) found that the ratio of very low density lipoprotein cholesterol plus LDL cholesterol to HDL cholesterol fell in response to a linoleic acid-enriched, low-cholesterol diet in B1B1 homozygotes but not in B1B2 heterozygotes.

In 276 unrelated patients with statin-treated familial hypercholesterolemia, Mohrschladt et al. (2005) found that the relative risk for cardiovascular disease events was 1.8 for B2B2 carriers compared to B1 allele carriers, despite the fact that B2B2 patients had higher baseline HDL cholesterol levels. Mohrschladt et al. (2005) noted that their findings were consistent with those of Kuivenhoven et al. (1998).

Durlach et al. (1999) studied the B polymorphism of the CETP gene in 406 type II diabetic (125853) patients aged 59.5 +/- 10.8 years, with a body mass index of 28.9 +/- 5.3 kg/m2, and glycosylated hemoglobin of 8.2 +/- 1.9%. Patients were separated into 2 groups, 231 males (78 B1B1, 108 B1B2, and 45 B2B2) and 175 females (48 B1B1, 94 B1B2, and 33 B2B2), and were compared on the basis of their lipid parameters (total cholesterol, triglycerides, HDL cholesterol (HDLC), APOA1 (107680)/APOB (107730), and LDL cholesterol) and their micro- and macrovascular complications. HDLC was significantly higher in men with the B2B2 genotype, together with a lower incidence of coronary heart disease. Women displayed a higher HDLC than men and an equally high incidence of coronary heart disease in B2 homozygotes as in other genotypes. The authors concluded that in type II diabetic patients, the B polymorphism exerts a modulating role in males only and that this may contribute to the loss of macrovascular protection in type II diabetic females.

CETP Promoter Polymorphisms

In 709 males with coronary artery disease (CAD), Klerkx et al. (2003) investigated phenotypic associations of 5 tightly linked polymorphisms in the CETP gene: -2708G-A, 784CCC-A, -971G-A, -629C-A, and TaqIB. All polymorphisms were associated with CETP concentration and HDL cholesterol, except for the -971G-A polymorphism with HDL cholesterol. Detailed haplotype analysis revealed that a 3-polymorphism haplotype model consisting of the -2708G-A, -629C-A, and -971G-A polymorphisms best explained the variation in CETP concentration.

Frisdal et al. (2005) reported that a -1337C-T polymorphism in CETP (C allele frequency, 0.684), was significantly associated with plasma HDL cholesterol and CETP levels (P = 0.0001 and P less than 0.0001, respectively). Transient transfection of liver cells with a reporter gene construct containing the CETP promoter from nucleotides -1707 to +28 revealed that the -1337T allele was expressed to a significantly lower degree (34%, P less than 0.0001) than the -1337C allele. The -971G-A polymorphism was functional, and its functionality was intimately linked to the presence of the -1337C-T SNP. In vitro evaluation of potential interaction between -1337C-T and the variants -971G-A and -629C-A demonstrated that these 3 functional CETP promoter polymorphisms could interact to determine the overall activity of the CETP gene and thus contribute significantly to variation in plasma CETP mass concentration.

Animal Model

Paigen et al. (1987) described a mouse mutation, Ath1, which phenotypically resembles the human disorder familial hyperalphalipoproteinemia. In the mouse, HDL-cholesterol levels and susceptibility to atherosclerosis appear to be determined by the same gene (or by two closely linked genetic factors that could not be more than 1.7 cM apart). Ath1 was found to map on mouse chromosome 1 near Alp2 (APOA2; 107670), a gene that determines the structure of apolipoprotein A-II, one of the 2 major proteins found in HDL. The 2 loci were separated by a distance of about 6.0 cM.