Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11 beta hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus. All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P < 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-beta hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P ‫؍‬ 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation. Diabetes 54: 2492-2496, 2005A bdominal obesity is a major risk factor for type 2 diabetes, coronary heart disease (CHD), colon cancer, and several other common and serious conditions. Although the definition of obesity typically relies on BMI, several studies suggest that, with respect to risk stratification, measurement of the waist-to-hip ratio (WHR) may be a superior predictor both of type 2 diabetes and CHD, possibly because of specific metabolic abnormalities accompanying central, rather than generalized, obesity (1,2). Both WHR and BMI are heritable traits, and various studies suggest that genes account for 25-70% of the observed variability (3,4).Melanocortin signaling in the hypothalamus plays a central role in the control of energy homeostasis. The proopiomelanocortin (POMC) gene is expressed in response to leptin signaling by neurons of the hypothalamic arcuate nucleus. Intracellular posttranslational processing of the POMC propeptide by prohormone convertase 2 leads to the production in these neurons of ␣-, ␤-, and ␥-melanocyte-stimulating hormones. These peptides signal to downstream target neurons in the lateral hypothalamus that express the melanocortin receptors MC3R and MC4R with resultant decrease in food intake and increase in energy expenditure (5). Rare mutations in the POMC gene cause monogenic, severe, early-onset obesity in humans; however, the influence of common polymorphisms in POMC on obesity phenotypes in less extreme individuals is unclear (6). POMC is also a precursor of adrenocorticotrophic hormone (ACTH); pathological ACTH excess results in severe central obesity. We have investigated the role of common polymorphisms of the POMC gene on abdominal obesity in a large family study. RESEARCH DESIGN AND METHODSSubject collection and phenotyping. The collect...

Background: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. Results: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 39 untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3-5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.

Background and Purpose-Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) Ϫ174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to Ϫ174G/C polymorphism. Methods-We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. Results-The heritability of carotid IMT was 24%. Under a recessive model (GGϩGC versus CC), there was significant evidence of association between IL-6 to the Ϫ174G/C genotype and adjusted log e maximal carotid IMT (Fϭ5.469; Pϭ0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association ( 2 1 ϭ0.469; Pϭ0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT (Pϭ0.0014). Conclusions-The genotype at the IL-6 to Ϫ174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small. [3][4][5][6][7][8][9] Accurate information regarding the heritability of a trait is a prerequisite for the design of adequately powered genetic studies.Interleukin-6 (IL-6) is a cytokine that plays a key role in driving the acute phase response by orchestrating the production of C-reactive protein and fibrinogen. 10 IL-6 has been associated with several markers of endothelial dysfunction, and, as such, may play a role in the pathogenesis of atherosclerotic vascular disease by direct endothelial activation or indirectly through stimulation of C-reactive protein and fibrinogen synthesis. Several groups have provided evidence indicating that the promoter polymorphism at position Ϫ174 of the IL-6 gene (Ϫ174G/C) may itself be a functional change that affects the affinity of nuclear proteins involved in the transcription of the gene, 11,12 raising the possibility that the polymorphism may be a genetic risk factor for vascular inflammation and, thus, atherosclerosis. Four studies to date have examined the association of the IL-6 to Ϫ174G/C polymorphism and carotid IMT. 10,[13][14][15] Only 1 of these studies has reported a significant association of the IL-6 to Ϫ174G/C polymorphism and carotid IMT in the whole sample, 13 whereas the other 3 studies found sig...

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...

Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping of over 3300 Mycobacterium tuberculosis isolates from the north of England has identified large clusters of strains which share common profiles. However, many apparent clusters identified when typed using the existing 15 loci lack clear epidemiological links. This study seeks to discover whether or not six additional VNTR loci can increasethe discriminatory power of the existing MIRU-VNTR 15-loci technique. Two hundred and six M. tuberculosis isolates were genotyped, including 57 isolates from 20 epidemiologically linked clusters and 149 from unlinked patients belonging to six large MIRU-VNTR-defined clusters. The discriminatory power of the six additional loci was high (Hunter Gaston Discriminatory Index [HGDI]: 0.952). Five of the six loci were highly discriminative (h > 0.6); however, locus 2401 was less discriminative (h = 0.5). The additional VNTR loci were able to subtype all six unlinked common MIRU-VNTR clusters into 56 subclusters, significantly differentiating unrelated strains in a set previously incorrectly clustered using 15 MIRU-VNTR loci. The largest cluster size was 14 (9.3%) when typed using the six additional VNTR loci, compared to 30 (20%) when typed using the original 15 MIRU-VNTR loci. The same loci were also found to be stable as a result of their inability to subdivide any of the epidemiologically linked clusters. This study has demonstrated that expanding the MIRU-VNTR panel beyond the 15 previously used loci significantly increases the discriminatory power of the technique and thus provides a valuable tool in the epidemiological monitoring of this disease.

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