-
[show abstract]
[hide abstract]
ABSTRACT: Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.
The Lancet 11/2001; 358(9288):1155-6. · 38.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A polymorphism of the human angiotensin-1-converting enzyme (ACE) gene has been identified in which the presence (insertion, I allele) of a 287-bp fragment rather than the absence (deletion, D allele) is associated with lower ACE activity. Several recent studies have shown an association of the I allele with endurance performance, it being found with excess frequency in elite distance runners, rowers and mountaineers. Other workers using heterogeneous cohorts of athletes from mixed sporting disciplines have found no such association. An increasing linear trend of I allele frequency with the distance run amongst Olympic runners and an excess of the D allele amongst sprinters led us to examine whether the ratio of I and D alleles in swimmers competing over different distances would also vary. Swimmers (n=120) from the European and Commonwealth championships and an American college team had their ACE genotype determined and their gene and allele frequencies compared with several control groups, the most closely age-matched of which were 1,248 military recruits. Of the 103 Caucasians, there was a significant excess of the D allele compared with this control group only in the truly elite swimmers of the European and Commonwealth championships (P=0.004). This association remained in those competing over shorter distances (P=0.005 for 400 m and below) but not in the longer events. These findings were confirmed in three further large control groups. A population association study testing whether a genetic marker (the ACE I/D polymorphism) occurs more frequently in cases (elite athletes) than in controls therefore requires a homogeneous cohort of subjects from the same sporting discipline.
Human Genetics 04/2001; 108(3):230-2. · 5.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.
Thrombosis and Haemostasis 03/2000; 83(3):397-403. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human physical performance is strongly influenced by genetic factors. A variation in the structure of the human angiotensin I-converting enzyme (ACE) gene has been reported in which the insertion (I) variant is associated with lower ACE levels than the deletion (D) gene. We have previously reported that the I variant was associated with improved endurance performance in high-altitude mountaineers and British Army recruits. We now examine this genotype distribution in 91 British Olympic-standard runners (79 Caucasians). DNA was extracted from the buccal cells contained in 10 ml of saline mouthwash donated by the subjects, and the I and D variants of the ACE gene were identified by PCR amplification of the polymorphic region. There was an increasing frequency of the I allele with distance run [0.35, 0.53, and 0.62 for </=200 m (n = 20), 400-3,000 m (n = 37), and >/=5,000 m (n = 34), respectively; P = 0.009 for linear trend]. Among 404 Olympic-standard athletes from 19 other mixed sporting disciplines (in which endurance performance was not necessarily a key factor), the I allele did not differ significantly from that found in control subjects: 0.50 vs. 0.49 (P = 0.526). These results support a positive association of the I allele with elite endurance performance.
Journal of Applied Physiology 11/1999; 87(4):1313-6. · 3.75 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Variation at the cholesteryl ester transfer protein (CETP) gene locus has been implicated in determining the levels and activity of CETP, apoAI and high-density lipoprotein (HDL) plasma concentration and the risk of developing coronary artery disease.
The effects of two common polymorphisms of CETP, TaqIB in intron 1 and isoleucine 405 to valine (I405-->V) in exon 14, were examined in a sample of 822 men age 18-28 years from 11 countries in Europe who had participated in a study (the European Atherosclerosis Research Study II) of the offspring of myocardial infarction sufferers before the age of 55 years and age-matched control subjects.
The frequency of the rare TaqIB allele (B2) and the rare V405 allele was 0.44 and 0.28 respectively and was the same in different regions of Europe. There was a moderate linkage disequilibrium between the two polymorphisms in all the regions (D' = +0.31, P < 0.001), explained by the preferential association between the two common alleles, B1 and I405. There was a statistically significant association of the rare alleles for both the polymorphisms with lower activity of CETP (P < 0.001), 11.2% lower for the TaqIB and 7.0% lower for the I405-->V polymorphism. The TaqIB polymorphism explained 9.1% (P < 0.001) and I405-->V explained 3.7% (P < 0.001) of the variance in CETP activity, and in combination these genotypes explained 12.0% of the variance (P < 0.001). Overall, subjects whose fathers had had an early coronary heart disease had 2.4% higher plasma CETP activity than those without such family history, which became statistically significant when adjusted for the effect of the genotypes (P = 0.015), but the significance disappeared after adjustment for the effect of lipids. There was a statistically significant effect of the TaqIB polymorphism on both plasma HDL cholesterol and apoAI level (P < 0.001), with those homozygous for the rare B2 allele having the highest level. Those individuals homozygous for the rare V405 allele had the highest HDL and apoAI levels, although these effects only reached statistical significance for HDL (P < 0.03).
These results suggest that the TaqIB and I405-->V polymorphisms represent two independent functional variations in the CETP gene that may affect the activity of CETP and thus plasma levels of HDL.
European Journal of Clinical Investigation 03/1999; 29(2):116-28. · 3.02 Impact Factor
-
H Montgomery,
P Clarkson,
M Barnard,
J Bell,
A Brynes,
C Dollery,
J Hajnal,
H Hemingway,
D Mercer,
P Jarman,
R Marshall,
K Prasad,
M Rayson,
N Saeed,
P Talmud,
L Thomas,
M Jubb,
M World, S Humphries
[show abstract]
[hide abstract]
ABSTRACT: The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems.
We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training.
Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype.
II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.
The Lancet 03/1999; 353(9152):541-5. · 38.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL-6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis.
Journal of Clinical Investigation 10/1998; 102(7):1369-76. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A common polymorphism has been described in the methylenetetrahydrofolate reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V allele results in a thermolabile enzyme with reduced activity. This polymorphism is easily detectable by PCR amplification and digestion with HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing of this polymorphism. Seven hundred and eighty five individuals participating in the European Atherosclerosis Research Study II (EARS II), aged 22-25 from 14 universities in 12 countries across Europe were genotyped for this polymorphism. The frequency of the V allele was 0.32 overall (95% CI; 0.30-0.35), but was significantly lower in the Baltic countries (0.23; 95% CI; 0.19-0.28) compared with the other regions of Europe (0.37; 95% CI; 0.32-0.38) (P < 0.001). Individuals homozygous for the V allele had statistically significant (P < 0.001) higher plasma homocysteine (16.5 micromol/l) compared with those heterozygous for an A allele (10.4 micromol/l) or homozygous for an A allele (10.0 micromol/l). This effect was seen in all countries and regions of Europe. Mean plasma homocysteine levels were significantly higher in the South compared to the Baltic, UK and Middle regions (P = 0.001), but this difference was not explained by the difference in the frequency of the V allele in the samples. This polymorphism explained 12.3% of the total sample variance in plasma homocysteine, other measured factors (smoking, alcohol consumption, systolic blood pressure, physical activity) explained 0.7%. This study demonstrates the large and consistent impact of the thermolabile MTHFR variant on plasma homocysteine levels in different European populations, and shows a regional difference in the levels of homocysteine that must be explained by other genetic or environmental factors.
Atherosclerosis 02/1998; 136(2):347-54. · 3.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. The matrix metalloproteinases are a family of at least 16 zinc-dependent endopeptidases possessing catalytic activity against extracellular matrix components. Some members of this family have been implicated in vascular matrix remodelling in the pathogenesis of atherosclerosis. 2. A common, naturally occurring variant has been identified in the promoter of the stromelysin gene with one allele having a run of five adenosines (5A) and the other having six adenosines (6A). Functional analyses have shown that the 6A allele has a lower promoter activity than the 5A allele, which is probably attributable to preferential binding of a putative transcriptional repressor protein. 3. In patients with coronary artery disease, the 6A allele has been found to be associated with progression of atherosclerosis assessed by sequential quantitative angiography. 4. In conclusion, the matrix metalloproteinases may be over-expressed in certain locations in atherosclerotic plaques, which might contribute to local destruction of connective tissue and thus plaque rupture. In the majority of lesional areas, however, matrix synthesis is likely to outstrip matrix degradation, because matrix accumulation is a major feature of most atheromas. This imbalance favouring matrix deposition is likely to be exacerbated in individuals with the 6A6A genotype in whom stromelysin expression is lower due to the weaker stromelysin promoter.
Clinical Science 02/1998; 94(2):103-10. · 4.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Familial clustering of microalbuminuria with cardiovascular disease suggests a possible common genetic antecedent. We have tested the hypothesis that the angiotensin-converting enzyme (ACE) DD genotype and the angiotensin II type I receptor (AT1R) gene C allele represent the common link between microalbuminuria and coronary heart disease. The frequency of polymorphisms of the ACE and AT1R genes were investigated in 509 nondiabetic white subjects and in 86 non-insulin-dependent diabetic white patients. There was no significant difference in albumin excretion rate between the genotypes in nondiabetic subjects on either a daytime or an overnight sample or in diabetic subjects expressed as a normalized albumin concentration on an untimed morning urine collection. We have found no evidence for an association between polymorphism of the ACE or AT1R genes and microalbuminuria in two groups of subjects without insulin-dependent diabetes.
Arteriosclerosis Thrombosis and Vascular Biology 11/1997; 17(10):2188-91. · 6.37 Impact Factor
-
H E Montgomery,
P Clarkson,
C M Dollery,
K Prasad,
M A Losi,
H Hemingway,
D Statters,
M Jubb,
M Girvain,
A Varnava,
M World,
J Deanfield,
P Talmud,
J R McEwan,
W J McKenna, S Humphries
[show abstract]
[hide abstract]
ABSTRACT: The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy.
Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001).
Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.
Circulation 08/1997; 96(3):741-7. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In a group of 705 healthy middle-aged men, we have examined the relationship between plasma levels of Factor VII (FVII) c and Factor VII antigen (FVIIag) and two polymorphisms in the FVII gene. One polymorphism alters arginine at position 353 to glutamine (R/Q), and the other is the result of a 10 base pair (bp) insertion in the promoter region at position -323 from the start of translation (0/10bp). The frequency for the Q allele was 0.105 (95% CI 0.09-0.12) and for the 10bp allele was 0.117 (95% CI 0.10-0.13). Men who were carriers of either of the rare alleles had levels of FVIIc and FVIIag that were approximately 20% lower than non-carriers, and both of these effects were highly statistically significant (p < 0.0001). Strong allelic association was observed between the two polymorphisms, with R and 0 bp being on the same chromosome in 96% of cases, and Q and 10 bp being on the same chromosome in 90% of cases where this could be determined unambiguously (Delta = 0.92, chi 2 = 1206, p < 0.0001). This strong allelic association created three major genotype groups which were found to have significantly different levels of FVIIc (p < 0.001). In the 547 men homozygous for both common alleles (R/R & 0/0), mean (SD) FVIIc was 101 (29) as compared with 85 (30) in the 20 men with the genotype R/R & 0/10 and 81 (23) in the 126 men with the genotype R/Q & 0/10, suggesting a larger lowering effect associated with the 10 bp allele (16%) compared to the Q allele (an additional 4%). The lowering effect on FVII associated with the 10 bp allele remained statistically significant after adjusting for the effect of the Q allele (p = 0.004 for FVIIc and p = 0.06 for FVIIag), but the effect associated with the Q allele was no longer significant after adjusting for the 10 bp allele, suggesting that the strongest effect on levels of FVIIc was associated with the 0/10 bp genotype. In the sample overall, plasma FVIIc was associated positively with serum triglyceride concentration and the slope of this relationship was significantly greater in those with the genotype R/R compared to the other groups combined (0.12 versus 0.02, p = 0.008) with differences of similar size seen in the 0/0 compared to 0/10 + 10/10 groups. However, using the combined genotype, the slope of this relationship in the R/R & 0/10 group was 0.38 and was significantly steeper (p = 0.01) than in the other two groups who did not differ in this respect (slopes 0.11 and 0.08). This effect was seen on four subsequent annual examinations, and was also evident in the relationship between FVIIag and triglyceride concentration (p = 0.003 for difference between groups measured at baseline only). These data suggest that part of the previously described effects on FVIIc levels associated with the R/Q polymorphism may be explained by genetic variation in the promoter region of the FVII gene.
Thrombosis and Haemostasis 04/1996; 75(4):567-72. · 5.04 Impact Factor
-
H E Montgomery,
P Clarkson,
O M Nwose,
D P Mikailidis,
I A Jagroop,
C Dollery,
J Moult,
F Benhizia,
J Deanfield,
M Jubb,
M World,
J R McEwan,
A Winder, S Humphries
[show abstract]
[hide abstract]
ABSTRACT: We have investigated the effects of chronic physical training and acute intensive exercise on plasma fibrinogen levels and the relationship of these responses to beta-fibrinogen G-453-A polymorphism genotype. One hundred fifty-six male British Army recruits were studied at the start of their 10-week basic training, which emphasizes physical fitness. Cohorts were restudied between 0.5 and 5 days after a major 2-day strenuous military exercise (ME) undertaken in their final week of training. Changes in fibrinogen concentration were adjusted for the effects of age, body mass index, and smoking history. Compared with baseline values, fibrinogen concentrations were significantly lower (11.9%, P=.04) at day 5 after ME, consistent with the beneficial effect of training. However, they were higher on days 1 through 3 after ME (suggesting an "acute-phase" response to strenuous exercise) and were maximal on days 1 and 2 (27.2%, P<.001 and 37.1%, P<.001 respectively). Fibrinogen genotype was available in 149 individuals. As expected from previous studies, men with one or more fibrinogen gene A-453 alleles had plasma fibrinogen concentration slightly but significantly higher at baseline (4.5%, P=.11). During the acute-phase response (days 2 and 3), however, the degree of rise was strongly related to the presence of the A allele, being 26.7+/-5.4% (mean+/-SE), 36.5+/-11.0%, and 89.2+/-30.7 for the GG, GA, and AA genotypes, respectively (P=.01). These results confirm that chronic exercise training lowers plasma fibrinogen levels, that intensive exercise generates an acute-phase rise in levels, and that this acute response is strongly influenced by the G/A polymorphism of the beta-fibrinogen gene.
Arteriosclerosis Thrombosis and Vascular Biology 03/1996; 16(3):386-91. · 6.37 Impact Factor
-
A Lane,
F Green,
P Y Scarabin,
V Nicaud,
L Bara, S Humphries,
A Evans,
G Luc,
J P Cambou,
D Arveiler,
F Cambien
[show abstract]
[hide abstract]
ABSTRACT: This paper describes the relationship of factor VII coagulant activity (FVIIc), FVII Arg/Gln353 genotype and risk of myocardial infarction (MI) in the ECTIM (Etude Cas Témoin sur l'Infarctus du Myocarde) study, a multi-centre case-control study on MI. FVIIc was significantly higher in controls from all four centres: Belfast, Lille, Strasbourg and Toulouse, perhaps because elevated FVIIc may predispose to fatal rather than non-fatal MI. Major influences on FVIIc were FVII Arg/Gln353 genotype, triglyceride and cholesterol levels. There was no significant effect of genotype on MI risk however there was a non-significant trend towards increased MI risk in FVII Arg353 homozygotes. Confirming previous observations, FVIIc was highest in FVII Arg353 homozygotes, intermediate in heterozygotes and lowest in FVII Gln353 homozygotes (except Toulouse cases) these differences being highly statistically significant (except Strasbourg cases P = 0.1). In Belfast, consistent with previous findings, there was significant interaction between FVII Arg/Gln353 genotype and triglyceride level in determining FVIIc, whilst this was absent in the French centres. In conclusion, FVII Arg/Gln353 genotype strongly determines FVIIc although neither factor has a strong impact on MI risk in the ECTIM study.
Atherosclerosis 02/1996; 119(1):119-27. · 3.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A recent study (1) reported variation among men in clotting factor VIIc levels is associated with a genetic polymorphism detected by the restriction enzyme Msp I. The present study determined the Msp I genotype (Arg353, Gln353 alleles) for 189 women (mean age 53) who were subjects in the Healthy Women Study, a population study of CHD risk factor change at menopause. Women with the Arg/Arg genotype (n = 147) had an 16% higher (geometric) mean FVIIc level than those with the Arg/Gln (n = 41) genotype (1.21 vs 1.04 U/ml, p < 0.01), while the one subject with the Gln/Gln genotype had an FVIIc level of 1.00 U/ml. These results are consistent with those previously found in healthy men (1). In addition, women carrying the Gln allele did not exhibit the elevation in FVIIc with menopause and use of hormone therapy found among those with the Arg allele, suggesting that genotype may modify the observed rise in factor VIIc at menopause. Possibly because of the small sample size this interaction did not reach conventional levels of statistical significance. Results of multiple linear regression analyses controlling for age, hormone use, obesity, (ln) triglyceride levels, and family history of CHD found FVIIc levels to be significantly (p < 0.001) related to genotype. Thus, genotype appears to be a major determinant of FVIIc levels among women.
Thrombosis and Haemostasis 04/1995; 73(4):623-5. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have examined the effect on plasma lipid levels of a single base change in exon 8 of the LDL receptor gene that causes an amino acid change Ala 370 to Thr in a sample of 318 Icelandic individuals selected at random from the general population. The change destroys a StuI restriction site and was detected by digestion of pooled samples in groups of 5. The frequency of the loss of the cutting site was 0.05 (95% CI = 0.014-0.054). In men, those with the Thr allele (n = 18) had 8.3% higher total cholesterol, 11.8% higher LDL cholesterol and 10.3% higher apolipoprotein B than those with the common Ala allele, whereas in women those with the Thr allele (n = 12) had levels lower by 7.4%, 13.3% and 10.1% respectively. These differences reached statistical significance only in the men (p < 0.05). Functional analysis of CHO cells transfected with constructs of the LDL receptor cDNA carrying the Ala370 and Thr370 alleles showed that within the limits of the assays there was no difference in function of the LDL receptor protein as measured by uptake and degradation of LDL. The data raise the possibility that amino acid substitutions that could affect LDL receptor function below the limits of detection by conventional assays, may have an effect on plasma lipid levels in the general population.
Clinical Genetics 03/1995; 47(2):68-74. · 3.13 Impact Factor
-
Thrombosis and Haemostasis 03/1995; 73(2):325. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have examined the effect on plasma lipid levels of a single base change in exon 8 of the LDL receptor gene that causes an amino acid change Ala 370 to Thr in a sample of 318 Icelandic individuals selected at random from the general population. The change destroys a StuI restriction site and was detected by digestion of pooled samples in groups of 5. The frequency of the loss of the cutting site was 0.05 (95%CI=0.014-0.054). In men, those with the Thr allele (n=18) had 8.3% higher total cholesterol, 11.8% higher LDL cholesterol and 10.3% higher apolipoprotein B than those with the common Ala allele, whereas in women those with the Thr allele (n=12) had levels lower by 7.4%, 13.3% and 10.1% respectively. These differences reached statistical significance only in the men (p<0.05). Functional analysis of CHO cells transfected with constructs of the LDL receptor cDNA carrying the Ala370 and Thr370 alleles showed that within the limits of the assays there was no difference in function of the LDL receptor protein as measured by uptake and degradation of LDL. The data raise the possibility that amino acid substitutions that could affect LDL receptor function below the limits of detection by conventional assays, may have an effect on plasma lipid levels in the general population.
Clinical Genetics 01/1995; 47(2):68 - 74. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: By using chemical cleavage mismatch analysis and the single strand conformation polymorphism technique, DNA fragments of the apo CIII gene, including the 5' flanking region and all the exons, were screened for sequence changes underlying the observed association between familial combined hyperlipidaemia (FCHL) and the apo AI-CIII-AIV gene cluster in affected individuals from eight FCHL families. A C1100-T transition in the wobble position of codon 14 in exon 3 and a T3206-G transversion in the non-translated region of exon 4 were identified, occurring in four and all probands, respectively. Using these variants and the G-75-A transition in the apo AI promoter, co-segregation of the gene cluster with hyperlipidaemia could be excluded in all eight families (lod score - infinity at theta = 0). No support for co-segregation was obtained using the affected pedigree member method of linkage analysis (overall T = -0.77 for f(p) = 1 [symbol: see text] p). The frequencies of T1100 and G3206 in a group of 55 patients with combined hyperlipidaemia were 0.35 and 0.52, respectively, which were significantly higher compared to 360 controls (0.21, p < 0.01 and 0.35, p < 0.005 respectively). In patients homozygous for the T1100 allele, levels of plasma triglyceride were 2.5-fold higher (868 mg/dl) than those homozygous for the C1100 allele (337 mg/dl), while patients heterozygous for the polymorphism had intermediate values (443 mg/dl) (p < 0.01). A similar association was seen in controls (p < 0.04). The three polymorphisms studied were in strong linkage disequilibrium in both the group of CHL patients and the unrelated individuals. This study confirms the association between common variation in the gene cluster and differences in plasma lipid levels in the general population and in patients with combined hyperlipidaemia, but fails to confirm co-segregation with FCHL, suggesting the role of other genetic or environmental factors in the aetiology of FCHL.
Clinical Genetics 12/1994; 46(6):385-97. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A genetic polymorphism (Arg/Gln353) of coagulation factor VII was recently identified and shown to be associated with differences in basal factor VII coagulant activity. Postprandial lipaemia seems to exert an acute but evanescent effect on the activity of factor VII, and the influence of the Arg/Gln353 polymorphism on factor VII activation during postprandial lipaemia was therefore studied in male post-infarction patients [age 48.8 +/- 3.3 years (mean +/- SD)] with Arg/Arg (n = 23) and Arg/Gln (n = 8) genotypes. Factor VII antigen (VIIag) and activity along with plasma lipoproteins were determined before and after intake of a mixed meal-type of oral fat load. Patients with the Arg/Gln genotype had basal VIIag and activated factor VII (VIIa) levels 75% and 48%, respectively, of those of patients homozygous for the Arg allele. In absolute terms, VIIa increased more in homozygotes for the Arg allele (delta 0-6 h VIIa 1.76 +/- 1.48 ng/ml) than in heterozygotes (0.60 +/- 0.27 ng/ml) in response to fat intake, but the percentage increase in VIIa molecules did not differ significantly between subjects with Arg/Arg and Arg/Gln genotypes (37 +/- 32% versus 27 +/- 15%). This suggests that the influence of the Arg/Gln polymorphism on factor VII activity is mainly accounted for by differences in the basal factor VII protein level between genotypes. Since most of our lives are spent in the postprandial state, possession of the factor VII-Gln353 allele is likely to confer protection against coronary heart disease by reducing the amount of VIIa produced in response to fat intake.
Thrombosis and Haemostasis 12/1994; 72(5):734-9. · 5.04 Impact Factor
