R.T. Nakamura

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

Association of postalimentary lipemia with atherosclerotic manifestations

We identified different lipemic and metabolic responses after the ingestion of a standardized meal by healthy adults and related them to atherosclerotic markers. Samples from 60 normolipidemic adults were collected before and after a liquid meal (40 g fat/m2 body surface) at 0, 2, 4, 6, and 8 h for measurements of lipids, free fatty acids (FFA), insulin, cholesteryl ester transfer protein (CETP), autoantibodies to epitopes of oxidized LDL (oxLDL Ab), lipolytic activities, and apolipoprotein E polymorphism. Mean carotid intima-media thickness (cIMT) was determined by Doppler ultrasound. The volunteers were classified into early (N = 39) and late (N = 31) triacylglycerol (TAG) responders to the test meal. Late responders showed lower HDL cholesterol concentration at fasting and in the TAG peak, lower insulin and higher FFA concentrations compared to early responders. Multivariate regression analyses showed that mean cIMT was associated with gender (male) and age in early responders and by cholesterol levels at the 6th hour in late responders. oxLDL Ab were explained by lipoprotein lipase and negatively by hepatic lipase and oxLDL Ab (fasting period) by CETP (negative) and FFA (positive). This study is the first to identify a postalimentary insulin resistance state, combined with a reduced CETP response exclusively among late responders, and the identification of the regulators of postalimentary atherogenicity. Further research is required to determine the metabolic mechanisms described in the different postalimentary phenotypes observed in this study, as well as in different pathological states, as currently investigated in our laboratory.