D. Kaplan

The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis

BackgroundCholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample.MethodsThe polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography.ResultsNo differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 – 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed.ConclusionsNone of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.

Cholesteryl ester transfer protein gene mutations in Brazilian hyperalphalipoproteinemia

To the Editor: Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism and is a key protein in the reverse cholesterol transport (1, 2). CETP facilitates the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, and its deficiency is associated with hyperalphalipoproteinemia (HALP) (3, 4). Although the inverse association between HDL-cholesterol (HDL-C) concentrations and cardiovascular disease (CVD) is well established (5), the role of CETP in atherosclerosis remains controversial (6–8). Several mutations at the CETP gene locus have been described, which cause depletion of CETP activity and consequently high HDL-C in plasma (4, 9). HALP patients due to plasma CETP deficiency have been reported, mostly from Japan (3, 4, 8, 10), but there are some reports of CETP deficiency from German, Caucasian, and Asian populations (9). In this study, we investigated the prevalence of the most studied CETP gene mutations (intron 14 splicing defect, Int14A, and exon 15 missense mutation, D442G) in Brazilian HALP subjects (152 HALP and 139 controls, CTL). In addition, we evaluated the impact of each genetic mutation on the degree of carotid atherosclerosis, the concentrations of lipoproteins, the activities of CETP, phospholipid transfer protein (PLTP), and lipases in the plasma. For the identification of the CETP mutations, the genomic DNAs were extracted from peripheral leukocytes and analyzed by the polymerase chain reaction-restriction fragment length polymorphism method, as described previously (11–13). The Brazilian population is ethnically diverse, with a predominance of Afro-descendents. The frequency of the Int14A and D442G alleles in the HALP population was 0.023 and 0.0033, respectively. The prevalence of Int14A mutation was 4%, which was lower than that observed in the Japanese HALP population (32%) (14) but higher than that in the North-American HALP (0.7%) (9) and Japanese-American HALP (0.5%) subjects (6). The prevalence of the D442G mutation was far lower (0.7%) than that reported for the HALP (above 22%) and Japanese general population (4.5–7%) (4, 12) and for JapaneseAmerican subjects (5.1%) (6). Among the six Int14A mutation carriers (Table 1), we found one homozygote, a 61-yearold white woman, born from a non-consanguineous marriage, with family history of coronary artery disease (CAD), but no clinical cardiovascular damage. This is the first description of a homozygote Int14A CETP mutation outside Japan. Among the heterozygotes for Int14A, a 29-year-old male presented corneal arcus with established CAD and a 46-year-old female presented a carotid atheroma with no other manifestations of CVD. Both were whites, with no biochemical characteristics distinct from other mutation carriers. Three individuals had positive family histories of CAD. A 73-year-old male, from Asian origin and heterozygote for the D442G, presented results similar to the CTL group. Besides no personal or family register of CAD, he was the only one who presented increased intima-media thickness (IMT), possibly because he was the oldest. When we considered all mutation carriers together, higher HDL-C concentration (83%), lipoprotein lipase (LPL, 11%) and PLTP (60%) and lower CETP (36%) and hepatic lipase (HL, 26%) activities were observed. While the D442G carrier presented CETP, LPL, HL, and PLTP activities closer to the values from CTL group, the homozygote for Int14A mutation had an HL activity below the reference interval (2.5 and 97.5 percentiles of CTL), suggesting a double gene defect as described by Hirano et al. (7). The double deficiency of CETP and HL is Clin Genet 2006: 69: 455–457 # 2006 The Authors Printed in Singapore. All rights reserved Journal compilation # 2006 Blackwell Munksgaard

Moderate hyperalphalipoproteinaemia in a Brazilian population is related to lipoprotein lipase activity, apolipoprotein A-I concentration, age and body mass index

We investigated 95 Brazilian adults, aged 21-79 years, who were divided into two groups defined as having high-density lipoprotein (HDL)-cholesterol concentrations above [hyperalphalipoproteinaemia (HALP); n=48] or below (controls; n=47) the 90th percentile of a local population. The activities of lipid transfer proteins and enzymes involved in the plasma reverse cholesterol transport and the prevalence of factors that modulate HDL metabolism (alcohol consumption, ponderosity, physical exercise, menopause and use of hormone replacement treatment in women and smoking) were measured, as well as the prevalence of cardiovascular disease and of its various risk factors. The two groups showed no differences in their frequencies of cardiovascular disease. The HDL2/HDL3-cholesterol and triacylglycerol (triglyceride) ratios and the activities of the phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) were similar in both groups. Lipoprotein lipase (LPL) and hepatic lipase (HL) activities were 35% higher (P=0.0002) and 40% lower (P=0.0006) respectively, in HALP compared with control subjects. In a multivariate analysis, HDL-cholesterol and its subfractions were influenced by LPL, apolipoprotein A-I, age (negative relationship) and body mass index (negative relationship). Use of alcohol and ponderosity, as well as the interaction of these factors, explained the LPL activity. HL activity was modulated by smoking, and hormone-replacement therapy influenced the apolipoprotein A-I concentration. CETP activity was influenced by race and PLTP by age. The unique phenotype found in this Brazilian HALP population, namely low HL and high LPL activities, could be determined mostly by genetic components, on which future work will focus.