A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families

Gaukrodger, N; Mayosi, Bongani M.; Imrie, Helen; Avery, Peter; Baker, Michelle; Connell, John; Watkins, Hugh; Farrall, Martin; Keavney, Bernard

doi:10.1136/jmg.2004.027631

Cited by 44 publications

(41 citation statements)

References 35 publications

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“…Jiang et al 18 found that five SNPs positioned beyond the defined promoter region of the LEP gene showed strong association with human obesity and was transmitted to obese offspring. A recent study 19 demonstrated a strong association between a rare polymorphism in the 3 0 untranslated region of LEP and pulse pressure and carotid intimamedial thickness; the effects were not related to BMI or plasma leptin levels. Thus, differences in subject's enrolment and the presence of other variants within the LEP gene (different from the LEP-tet) should be considered to explain the relationship between LEP gene and cardiovascular risk factors.…”

Section: Discussionmentioning

confidence: 94%

Microsatellite polymorphism of the human leptin gene (LEP) and risk of cardiovascular disease

et al. 2005

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Background: No data have been so far reported on the relationship between polymorphisms of LEP gene and cardiovascular disease. Patients and methods: We genotyped a tetranucleotide repeat mapped in the 3 0 UTR of the LEP gene (LEP-tet) in 109 subjects with cardiovascular events and in 109 control subjects. Results: Univariate analysis and multivariate logistic regression analysis adjusted for age, gender, smoking status, history of hyperlipidemia, hypertension or diabetes showed not significant association between the genotype of the LEP-tet and cardiovascular diseases. Moreover, no differences were observed in the plasma leptin concentrations between cases and control subjects (22719 vs 22714 ng/ml, P ¼ 0.52) and in relation to the LEP-tet classes or carriage of specific allelels (P ¼ 0.76 for the association between LEP-tet classes and leptin levels in overall analysis). Conclusions: In conclusion, our data do not support an association between the LEP-tet microsatellite polymorphism of the human LEP gene and cardiovascular diseases.

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Section: Discussionmentioning

confidence: 94%

Microsatellite polymorphism of the human leptin gene (LEP) and risk of cardiovascular disease

et al. 2005

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“…The population collection strategy has been previously described in detail (Gaukrodger et al, 2005). In brief, families were ascertained via a hypertensive proband between 1993 and 1996, and any sibship in the family (in the generation of the proband or his/her offspring) greater than three members quantitatively assessable for blood pressure was collected.…”

Section: Study Populations and Ace Phenotypingmentioning

confidence: 99%

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

Terao

Bayoumi

McKenzie

et al. 2013

Annals of Human Genetics

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SummaryAngiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.

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“…Blood pressure was measured using ambulatory monitoring for a period of 24 h in all subjects willing to undergo monitoring, using the A&D TM2421 monitor (Takeda Medical) according to a previously described protocol (8). A full clinical history was taken that included the subject's medical history and lifestyle factors, including consumption of alcohol and tobacco and habitual physical exercise.…”

Section: Methodsmentioning

confidence: 99%

Plasma potassium level is associated with common genetic variation in the β-subunit of the epithelial sodium channel

Gaukrodger¹,

Avery²,

Keavney³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Gaukrodger N, Avery PJ, Keavney B. Plasma potassium level is associated with common genetic variation in the ␤-subunit of the epithelial sodium channel. Am J Physiol Regul Integr Comp Physiol 294: R1068-R1072, 2008. First published January 9, 2008 doi:10.1152/ajpregu.00732.2007.-Plasma potassium is a moderately heritable phenotype, but no robust associations between common single nucleotide polymorphisms (SNPs) and plasma potassium have previously been described. Genetic influences on renal potassium handling could be important in the etiology of hypertension. We have tested whether common genetic variation in the gene encoding the ␤-subunit of the epithelial sodium channel (SCNN1B) affects plasma potassium and blood pressure level in a study of 1,425 members of 248 families ascertained on a proband with hypertension. We characterized family members for blood pressure using ambulatory monitoring, measured plasma potassium in venous blood samples, and genotyped four SNPs that spanned the SCNN1B gene. We found highly significant association between genotype at the SCNN1B rs889299 SNP situated in intron 4 of the gene and plasma potassium. Homozygotes for the rarer T allele had on average a 0.15 mM lower plasma potassium than homozygotes for the common C allele, with an intermediate value for heterozygotes (trend, P ϭ 0.0003). Genotype at rs889299 accounted for ϳ1% of the total variability in plasma potassium, or around 3% of the total heritable fraction. There was no association between genotype at any SCNN1B SNP and blood pressure considered as a quantitative trait, or with hypertension affection status. We have shown a modest sized but highly significant effect of common genetic variation in the SCNN1B gene on plasma potassium. Interaction between the rs889299 SNP and functional SNPs in other genes influencing aldosterone-responsive distal tubular electrolyte transport may be important in the etiology of essential hypertension.aldosterone; electrolyte; heritability; genetics THE EPITHELIAL SODIUM CHANNEL (ENaC) plays a key role in the maintenance of blood pressure and electrolyte homeostasis in the distal nephron. ENaC consists of three subunits ␣, ␤, and ␥, which combine in a 1-to-1-to-1 ratio to form the functional channel (15). Activating mutations in the ␤-and ␥-subunits of ENaC (encoded by the SCNN1B and SCNN1G genes, respectively) give rise to Liddle's syndrome, an autosomal dominant condition involving amiloride-sensitive hypertension, hypokalemia, and metabolic alkalosis (10,20). Conversely, loss of function mutations in the ␣-, ␤-, or ␥-subunits of ENaC leads to recessive pseudohypoaldosteronism type I, a childhood condition characterized by severe salt wasting and hyperkalemia (6). A number of groups have investigated the role of common polymorphisms in the genes encoding the ENaC subunits as potential susceptibility alleles influencing the risk of essential hypertension to a moderate degree. However, no common single nucleotide polymorphism in any subunit of ENaC has been consistently identified as c...

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A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families

Cited by 44 publications

References 35 publications

Microsatellite polymorphism of the human leptin gene (LEP) and risk of cardiovascular disease

Microsatellite polymorphism of the human leptin gene (LEP) and risk of cardiovascular disease

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

Plasma potassium level is associated with common genetic variation in the β-subunit of the epithelial sodium channel

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