Endothelin-1 gene Lys198Asn polymorphism and blood pressure reactivity

The Lys198Asn polymorphism of the endothelin-1 gene has been associated with increased blood pressure levels in several studies involving European and Australian adults. The purpose of the present study was to examine the potential moderating influence of ethnicity, obesity, and socioeconomic status on associations between the ET-1/Lys198Asn polymorphism and hemodynamic function at rest and during two laboratory stressors (video game, forehead cold) in a sample of 161 black and 213 white American normotensive young adults (mean age, 18.5+/-2.7 years). Carrier status of the T allele was not associated with resting blood pressure or total peripheral resistance index. However, carriers of the T allele showed greater diastolic blood pressure increases to the video game (P<0.04), particularly among those who were obese (P<0.02). Carrier status also interacted with socioeconomic status such that T allele carriers who came from lower socioeconomic status backgrounds exhibited the greatest increases in systolic blood pressure to the video game challenge (P<0.05). In conclusion, the findings point out the importance of examining the impact of genetic polymorphisms on blood pressure control phenotypes within the context of potentiating environmental factors.     

The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people.

There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5' flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l'Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (P<0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index >/=26 kg/m2), while no significant effect was observed in lean subjects (body mass index <26 kg/m2). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (P<0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (P<0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people.     

Impact of endothelin-1 Lys198Asn polymorphism on coronary artery disease and endorgan damage in hypertensives

OBJECTIVE: Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages. METHODS: In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients. RESULTS: Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004). CONCLUSION: Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.     

Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene.

Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo.     

Endothelin-1 gene variant Lys198Asn and plasma endothelin level in obstructive sleep apnea

Obstructive sleep apnea (OSA) is a recognized risk factor for cardiovascular disorders. Thus, an association between endothelin-1 (EDN1) and OSA can be assumed. We investigated a cohort of 364 consecutive patients (age 57 +/- 10 years) with mild to severe OSA for the EDN1 variant Lys198Asn (G/T) and endothelin plasma levels and compared them with 57 controls. The Lys198Asn genotype was significantly associated with the apnea/hypopnea index (AHI) with a median of 30/h of sleep for GG, 27/h for GT and 59/h for TT genotype (p < 0.05). Further stratification of patients into 2 groups by body mass index (BMI) revealed a strong association between AHI and Lys198Asn polymorphism in 191 obese patients (p = 0.005), whereas in 173 nonobese patients, we observed no association. A substantial effect by BMI on OSA severity was seen with multiple linear regression (p < 0.001). However, this effect was modified by the Lys198Asn polymorphism and by gender: the AHI increase per unit of BMI was more pronounced in males than in females, and about 1.3 times greater in homozygous carriers of the mutant allele than in other carrier groups. EDN1 plasma levels of untreated OSA patients and of patients treated with nasal continuous positive airway pressure were not elevated compared with controls. Our results indicate that the Lys198Asn polymorphism is associated with the severity of OSA in obese subjects. The EDN1 plasma level cannot be used as a marker for OSA or its severity.     

内皮素-1基因Lys198Asn及TaqI多态性与原发性高血压关系的研究

目的探讨内皮素-1外显子5Lys198Asn多态性及内含子4TaqI基因多态性与原发性高血压的关系。方法对264例确诊为原发性高血压的患者及103例对照者抽取静脉血，以多聚酶链反应-限制性内切酶片段长度多态性（PCR-RFLP）分析ET-1基因中的外显子5Lys198Asn多态性及内含子4TaqI基因多态性。结果（1）高血压组与对照组ET-1的基因型和等位基因频率分布无明显差异（2）高血压组的吸烟人群中，ET-1外显子SLys198Asn位点的GT基因型人数比不吸烟组高，存在显著性差异。结论（1）内皮素-1外显子5Lys198Asn多态性及内含子4TaqI基因多态性与高血压的发病无显著相关；（2）ET-1外显子5Lys198Asn位点的T基因携带者可能对吸烟有较高反应性，增加高血压的患病率。     

吸烟者内皮素-1基因Lys198Asn多态性与冠心病关系的研究

目的探讨吸烟者内皮素-1(ET-1)基因Lys198Asn(G198T)多态性与中国汉族人群冠心病(CHD)的关系。方法将213例吸烟者和192例非吸烟者分为CHD组(198例)和对照组(207例),应用聚合酶链反应-单链构象多态性方法(PCR-SSCP)检测ET-1基因G198T多态性。按吸烟与否分析G198T多态性与CHD的关系。结果当ET-1基因G198T基因型为GG时,吸烟者的调整OR=2.35(95%CI:2.15–6.83,P=0.00);基因型为GT+TT时,不吸烟者的OR=2.05(95%CI:0.98-6.97,P=0.00),吸烟者的OR=5.65(95%CI:2.87–7.65,P=0.03);吸烟者的GT+TT型更可能患冠心病,风险是GG基因型的5.65倍(OR=5.65,95%CI:2.87–7.65,P=0.03)。结论吸烟者ET-1基因G198T多态性与中国汉族人群CHD的发病具有相关性,T等位基因可能是CHD的易感性标志。     

内皮素1 Lys198AsnT等位基因与冠心病关系的研究

目的 探讨内皮素1（ET-1）Lys198Asn （G198T）基因多态性与汉族人群冠心病的关系.方法 对160例冠心病（CHD）患者和健康对照者80名进行研究.应用ELISA试剂盒检测血清ET-1水平;用聚合酶链反应-引物特异性片断长度多态性（PCR-SSP）方法检测Lys198Asn 基因型,采用非条件多元逐步Logistic回归模型控制混杂因素.结果 冠心病组G198T GT＋TT基因型频率（19.375%）显著高于对照组（5.000%）,差异有统计学意义（χ2＝8.847,P＜0.05）,基因型频率的相对风险分析,GT＋TT基因型患冠心病的风险是GG基因型的4.566倍（OR＝4.566,95%CI：1.68,12.40）;两组等位基因频率差异也有统计学意义χ2＝9.659,P＜0.05,OR＝4.6364,95%CI：1.953～8.052）.冠心病组血清ET-1水平[（27.8±7.3）ng/L]高于对照组[（12.5±8.1）ng/L],差异有统计学意义（P＜0.01）;冠心病组GT＋TT基因型携带者的血清ET-1水平[（33.3±7.9）ng/L]显著高于同组GG基因型者[（24.2±7.5）ng/L,P＜0.01].经Logistic回归分析冠心病的危险因素显示,G198T基因多态性（T等位基因）为冠心病的独立危险因素.结论 ET-1基因Lys198Asn多态性与冠心病的发病具有相关关系,T等位基因可能是冠心病的易感性标志.     

Validation and use of the Finometer for blood pressure measurement in normal, hypertensive and pre-eclamptic pregnancy

OBJECTIVE: Although a large variety of automated blood pressure devices are available, only some have been validated for use in clinical practice. The British Hypertension Society (BHS) recommends separate validation of automated devices in special subgroups, e.g. the elderly and pregnant women. The aim of this study was to compare the Finometer (FM) and the earlier validated SpaceLabs 90207 (SL) with standard auscultatory blood pressure measurements in normal, pre-eclamptic and hypertensive pregnancy, following the guidelines of the BHS and the Association for the Advancement of Medical Instrumentation (AAMI). METHODS: The total study group consisted of 123 pregnant women, of whom were 54 normotensive, 31 pre-eclamptic and 38 hypertensive. Automated readings with the FM and SL were compared with auscultatory blood pressure measurements. Bland-Altman plots, BHS grades, mean pressure differences and 95% limits of agreement were used for analysis. RESULTS: Bland-Altman plots showed a wide scatter of the pressure differences between auscultatory and automated measurements. FM achieved BHS grades C/D, C/B, D/D and D/D in the total, normotensive, pre-eclamptic and hypertensive group, respectively. The AAMI criteria were only met for diastolic blood pressure in the normotensive group. For SL almost identical BHS grades and 95% limits of agreement as compared to our earlier study were found. CONCLUSIONS: The accuracy and precision of the Finometer are not sufficient for determination of absolute blood pressure levels in individual pregnant women. Our present findings on the SpaceLabs 90207 reconfirm our earlier results.     

Association between plasma endothelin-1 levels and Cheyne-Stokes respiration in patients with congestive heart failure

STUDY OBJECTIVES: Elevated plasma endothelin-1 (ET-1) levels have been reported in association with hypoxia and congestive heart failure (CHF). Furthermore, Cheyne-Stokes respiration-central sleep apnea (CSR-CSA) has been found to correlate with the degree of pulmonary hypertension and the severity of CHF; however, the association between ET-1 levels and CSR-CSA has not been investigated previously. SETTING: Veterans Affairs Medical Center. INTERVENTIONS: We studied 46 consecutive patients with CHF (left ventricular function < or = 40%) who underwent right-heart catheterization and overnight polysomnography. Thirty-nine patients completed the study. Sixteen patients (41%) had CSR-CSA, 5 patients (13%) had obstructive apnea, and 18 patients (46%) had no sleep-disordered breathing. Circulating plasma ET-1 levels were assayed in patients with CSR-CSA and in patients with no sleep-disordered breathing using commercially available enzyme-linked immunosorbent assay kits. RESULTS: ET-1 levels were significantly elevated in patients with CSR-CSA (mean +/- SD, 5.4 +/- 1.3 pg/mL) compared to those without central apnea (3.9 +/- 1.1 pg/mL; p < 0.01), and correlated with mean pulmonary artery pressure (r = 0.66, p < 0.01), pulmonary capillary wedge pressure (r = 0.56, p < 0.03), and central apnea frequency (r = 0.66, p < 0.01). In multivariate analysis, the severity of CSR-CSA was the only variable independently associated with plasma ET-1. CONCLUSIONS: We conclude that elevated plasma ET-1 levels are linked to the severity of CSR-CSA. Whether ET-1 represents an important pathogenic factor in CSR-CSA or marker of its occurrence requires further evaluation.     

乙醛脱氢酶2基因Glu487Lys多态性与冠心病相关性的研究

目的观察汉族人群中,乙醛脱氢酶2(ALDH2)基因Glu487Lys多态性与罹患冠心病危险性之间的关联。方法收集经冠脉造影检查明确诊断且冠脉狭窄≥50%的490名冠心病患者(冠心病组)及明确排除的433名非冠心病患者(对照组),共923例纳入本项研究。ALDH2的Glu487Lys基因多态性由TaqManPCR技术测得,比较ALDH2各基因型在冠心病组与对照组的分布,并根据冠心病危险因素,对该研究进行了亚组分析。结果在所有研究对象中,ALDH2各基因型在冠心病组和对照组分布差异无统计学意义(P=0.22)。但亚组分析显示,在无饮酒史,无吸烟史,无高血压史,BMI<25(kg/m2)4个亚组中,ALDH2各基因型的分布在冠心病组和对照组中差异有统计学意义(P<0.05)。结论 ALDH2基因多态性与中国人群罹患冠心病无显著关系,在单纯无饮酒史,无吸烟史,无高血压史或BMI正常的中国汉族人群中,ALDH2基因AA型与其罹患冠心病可能存在关联。     

乙醛脱氢酶2基因Glu487Lys多态性与冠心病相关的研究

目的 观察汉族人群中,乙醛脱氢酶2 (ALDH2)基因Glu487Lys多态性与罹患冠心病危险性之间的关联.方法 收集经冠脉造影检查明确诊断且冠脉狭窄> 50%的490名冠心病患者(冠心病组)及明确排除的433名非冠心病患者(对照组),共923例纳入本项研究.ALDH2的Glu487Lys基因多态性由TagManPCR技术测得,比较ALDH2各基因型在冠心病组与对照组的分布,并根据冠心病危险因素,对该研究进行了亚组分析.结果 在所有研究对象中,ALDH2各基因型在冠心病组和对照组分布差异无统计学意义(P=0.22).但亚组分析显示,在无饮酒史,无吸烟史,无高血压史,BMI<25 (kg/m2) 4个亚组中,ALDH12各基因型的分布在冠心病组和对照组中差异有统计学意义(P<0.05).结论 ALDH12基因多态性与中国人群罹患冠心病无显著关系,在单纯无饮酒史,无吸烟史,无高血压史或BMI正常的中国汉族人群中,ALDH2基因AA型与其罹患冠心病可能存在关联.     

Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men

BACKGROUND: Lipin 1 plays a role in abdominal obesity, insulin resistance, and hypertriglyceridemia. The gene is located at 2p25.1, a susceptibility locus for hypertension. We studied the association of tagging single-nucleotide polymorphisms (SNPs) in the lipin 1 (LPIN1) gene with hypertension and blood pressure. METHODS: Twelve tagging SNPs from the HapMap database were genotyped using Sequenom MassArray in 268 hypertensive subjects and 407 normotensive controls, of whom 268 matched the cases in age and sex. RESULTS: None of the tagging SNPs were found to be associated with hypertension after correcting for multiple testing, although carriers of the minor allele of rs10520097 had nominally lower odds for hypertension (P = 0.014). After excluding subjects who were on antihypertensive medications, the minor allele of rs10495584 was nominally associated with lower mean systolic and diastolic blood pressures in men (121.1 +/- 14.2 and 76.3 +/- 10.2 mm Hg vs. 127.4 +/- 15.2 and 80.1 +/- 10.5 mm Hg, P = 0.002 and 0.007, respectively), but not in women (P > 0.05). The association of rs10495584 with systolic blood pressure in men remained significant after correcting for multiple testing and adjustment for age, waist circumference, insulin resistance, triglyceride, and high-density lipoprotein (HDL) cholesterol (beta = -0.158, P = 0.005). An analysis of statistically similar SNPs (ssSNPs) in the regions surrounding rs10495584 suggested that its effect may be caused by its high linkage disequilibrium (LD) with the SNP, rs11524, in which the major allele forms an exonic splicing silencer sequence. CONCLUSION: Our study provides further evidence that lipin 1 may play a role in blood pressure regulation, especially in men.     

The effect of regulation of high blood pressure on plasma endothelin-1 levels in blacks with hypertension

Plasma concentrations of immunoreactive endothelin-1 (irET-1) are significantly elevated in blacks with hypertension. In the present study, we investigated the effect of the regulation of high blood pressure on plasma irET-1 levels in black hypertensive individuals. After the initial blood samples were collected from 20 black patients with uncontrolled high blood pressure (Day 1), an intensive antihypertensive treatment was initiated, and the blood pressure and plasma irET-1 levels were monitored on days 2, 8, and 22. When the high blood pressure was brought under control with commonly used antihypertensive medications, plasma irET-1 concentrations dropped dramatically, suggesting that ET-1 concentrations rise as a consequence of high blood pressure in this study group.     

Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the alpha2-, beta2-, and beta3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the alpha2A(Lys418Asn)-, beta2(Arg16Gly, Gln27Glu)-, and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of > or =mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in > or =10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.     

Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy

Ghrelin, an endogenous ligand for the growth hormone secretagogues, was originally isolated from rat stomach. It stimulates the release of growth hormone from primary pituitary cell cultures. We investigated the plasma concentration of ghrelin peptide in 16 nonpregnant women, 18 normal pregnant women, 20 patients with pregnancy-induced hypertension, and 10 postpartum women. The plasma concentration of ghrelin in nonpregnant women was 239.5+/-16.9 fmol/mL. The plasma concentration of ghrelin in normal pregnant women at the third trimester was 127.1+/-5.6 fmol/mL. There was negative correlation between plasma ghrelin concentration and systemic blood pressure in normal pregnant women (systolic: r=-0.564, P<0.05; diastolic: r=-0.610, P<0.01). Pregnant women with pregnancy-induced hypertension (177.9+/-14.6 fmol/mL, P<0.05) also had significantly higher levels of ghrelin compared with those of normal pregnant women. In addition, there was a significant correlation between plasma ghrelin levels and systemic blood pressure (systolic: r=-0.482, P<0.05; diastolic: r=-0.466, P<0.05). These results suggest for the first time that ghrelin might have some role in cardiovascular control during normal pregnancy and in pathophysiological conditions in pregnancy, such as pregnancy-induced hypertension.     

Osteoprotegerin Lys3Asn polymorphism and the risk of fracture in older women

CONTEXT: Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator nuclear factor kappa-beta that blocks osteoclastic bone resorption. OBJECTIVE: We investigated the association between a Lys3Asn polymorphism in the OPG gene and bone mineral density (BMD), and the risk of fracture in 6695 women aged 65 yr and older participating in the Study of Osteoporotic Fractures. DESIGN: BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer; Dove Medical Group, Los Angeles, CA) or dual-energy x-ray absorptiometry (Hologic QDR 1000; Hologic, Inc., Bedford, MA). Incident fractures were confirmed by physician adjudication of radiology reports. Genotyping was performed using an immobilized probe-based assay. RESULTS: Women who were homozygous for the minor G (Lys) allele had significantly lower BMD at the intertrochanter, distal radius, lumbar spine, and calcaneus than those with the C (Asn) allele. There were 701 incident hip fractures during 13.6-yr follow-up (91,249 person-years), including 362 femoral neck and 333 intertrochanteric hip fractures. Women with the C/C (Asn-Asn) genotype had a 51% higher risk of femoral neck fracture (95% confidence interval, 1.13-2.02) and 26% higher risk of hip fracture (95% confidence interval, 1.02-1.54) than those with the G/G (Lys-Lys) genotype. These associations were independent of BMD. Intertrochanteric fractures were not associated with the Lys3Asn polymorphism. CONCLUSION: These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.     

Association between the TaqIB polymorphism in the cholesteryl ester transfer protein gene locus and plasma lipoprotein levels in familial hypercholesterolemia

Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides (TG) and cholesteryl ester between lipoprotein particles. Subjects with familial hypercholesterolemia (FH) have been reported to have higher CETP activities, which could contribute to the lower high-density lipoprotein-cholesterol (HDL-C) levels and increased cardiovascular risk observed in some of these patients. Several polymorphisms have been reported in the CETP locus; the common TaqlB polymorphism is associated, in normolipidemic subjects, with decreased CETP activity and levels and with increased HDL-C levels. No data is available on the influence of this polymorphism in FH subjects. We have examined the TaqIB polymorphism in a group of 101 FH heterozygotes from Valencia, Spain. We have observed a frequency of 0.43 for the B2 allele, similar to those reported in the general population. Based on analysis of variance (ANOVA), we found significant associations between the presence of the B2 allele and increased plasma HDL-C (P <.04) and apolipoprotein A-I (apoA-I) levels (P <.01). An opposite association was observed for low-density lipoprotein-cholesterol (LDL-C) levels, with the B2/B2 subjects having lower levels than B1/B1 and B1/B2 subjects. The plasma apoB levels followed the same trend as those for LDL-C. In addition, the response to a National Cholesterol Education Program (NCEP)-I diet was studied in 77 of these subjects. The TaqlB polymorphism did not have a significant effect over the individual dietary response for any of the variables examined, as demonstrated by the lack of significant gene by diet interactions. In summary, the CETP TaqlB polymorphism is associated with a less atherogenic lipid profile, consisting of lower LDL-C, higher HDL-C levels, and a lower LDL-C/HDL-C ratio in heterozygous FH subjects. Moreover, the B2 allele was associated with a lower appearance of arcus cornealis, xanthomata, and clinical arteriosclerotic disease in these subjects.     

Influence of Lys656Asn polymorphism of the leptin receptor gene on insulin resistance in nondiabetic obese patients

BACKGROUND: Alterations of the normal leptin receptor (LEPR) gene may be involved in the development of obesity. Leptin has been shown to be able to modulate insulin secretion. Different polymorphisms in the LEPR gene have been studied, albeit with unclear results. The polymorphism on codon 656 produces a change in charge, making this change possibly functional. OBJECTIVE: The objective of this study was to investigate the influence of Lys656Asn polymorphism in the LEPR gene on serum insulin, glucose values, and insulin resistance in the fasted state among obese men and women without diabetes mellitus. DESIGN: Two hundred thirty-three (body mass index, >30 kg/m(2)) nondiabetic obese patients were analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure determination, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. Statistical analysis was performed for Lys656/Asn656 and Asn656/Asn656 jointly as a mutant allelic group and for Lys656/Lys656 as a wild allelic group. RESULTS: The subjects' (67 males and 166 females) mean age and mean body mass index were 43.6+/-16.6 years and 35.3+/-5.6 kg/m(2), respectively. One hundred forty-three patients (61.9%) had the genotype Lys656/Lys656 (wild group), whereas 88 (38.1%) had either the genotype Lys656/Asn656 (n=81; 30.7%) or the genotype Asn656/Asn656 (n=7; 7.4%) (mutant group). Age and sex distribution were similar in both groups. No difference was detected between the mutant and wild allelic groups in anthropometric parameters and dietary intakes. Homeostasis model assessment (HOMA; 2.8+/-1.7 vs. 5.6+/-4.8; P<.05) and insulin (18.1+/-10.7 vs. 32.1+/-25 mUI/ml; P<.05) levels were higher in males with the genotypes Lys656/Asn656 and Asn656/Asn656 than in males with the genotype Lys656/Lys656. Leptin levels were higher in males with a mutant genotype than in males with a wild genotype (39.3+/-23 vs. 63.5+/-28 ng/ml; P<.05). CONCLUSION: The novel findings of our study are those of the association of the Lys656/Asn656 and Asn656/Asn656 genotypes with higher levels of insulin, HOMA, and leptin in males and the lack of such an association in females.