Biomedical subjects

Steven C Hunt

Publications and source records attributed to Steven C Hunt.

At least 19 recordsLinked to original sources

PubMed2007

Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study.

It remains unclear whether genetic factors contribute to the susceptibility to valve calcification. Accordingly, echocardiograms and genotyping were performed in 1871 hypertensive siblings who participated in the Hypertension Genetic Epidemiology Network Study. Genome-wide affected sibpair nonparametric linkage analysis was conducted using the allele-sharing method implemented in the Merlin computer program. A total of 1014 sibships from 858 families were evaluated for aortic valve sclerosis or mitral annular calcification. Of these, 78 sibships from 68 families contained > or =2 affected siblings with > or =1 type of valve calcification (142 affected siblings). All 3 of the traits showed a modest degree of familial aggregation, with sibling recurrence risk (SD) and sibling recurrence risk ratio (95% CI) being 0.25 (0.035) and 2.31 (1.72 to 3.11) for aortic valve sclerosis, 0.25 (0.035) and 1.78 (1.36 to 2.33) for mitral annular calcification, and 0.31 (0.030) and 1.52 (1.24 to 1.85) for aortic valve sclerosis and mitral annular calcification, respectively. Affected sibpair linkage analysis revealed the highest logarithm of odds score (3.14) in chromosome 16 at 105.6 cM for aortic valve sclerosis. Other chromosomal regions with logarithm of odds score > or =1.9 were found in chromosomes 19 (2.88), 16 (2.63), 1 (2.12), and 2 (2.03) for aortic valve sclerosis and chromosome 13 (2.12) for any valve calcification. There was no logarithm of odds score > or =1.9 for mitral annular calcification. Our study shows strong linkage of aortic valve sclerosis to chromosome 16q22.1-q22.3 and suggestive linkage to chromosome 19p13.11-p11 and identifies several other promising genomic regions that may contain specific susceptibility loci for valve calcification.

Adult↗

PubMed2007

Genotype-by-sex interaction on fasting insulin concentration: the HyperGEN study.

Recent studies have demonstrated the importance of sex effects on the underlying genetic architecture of insulin-related traits. To explore sex-specific genetic effects on fasting insulin, we tested for genotype-by-sex interaction and conducted linkage analysis of fasting insulin in Hypertension Genetic Epidemiology Network families. Hypertensive siblings and their first-degree relatives were recruited from five field centers. We performed a genome scan for quantitative trait loci influencing fasting insulin among 1,505 European Americans and 1,616 African Americans without diabetes. Sex-stratified linear regression models, adjusted for race, center, and age, were explored. The Mammalian Genotyping Service typed 391 microsatellite markers, spaced roughly 9 cM. Variance component linkage analysis was performed in SOLAR using ethnic-specific marker allele frequencies and multipoint IBDs calculated in MERLIN. We detected a quantitative trait locus influencing fasting insulin in female subjects (logarithm of odds [LOD] = 3.4) on chromosome 2 at 95 cM (between GATA69E12 and GATA71G04) but not in male subjects (LOD = 0.0, P for interaction = 0.007). This sex-specific signal at 2p13.2 was detected in both European-American (LOD = 2.1) and African-American (LOD = 1.2) female subjects. Our findings overlap with several other linkage reports of insulin-related traits and demonstrate the importance of considering complex context-dependent interactions in the search for insulin-related genes.

Alcohol Drinking↗

PubMed2006

Genome scan of glomerular filtration rate and albuminuria: the HyperGEN study.

BACKGROUND: Albuminuria and reduced glomerular filtration rate (GFR) are markers of renal dysfunction associated with hypertension. We performed genome-wide scans to detect loci impacting these parameters in 1251 African American (AAs) and 1129 European American (EAs) hypertensive siblings from the Hypertension Genetic Epidemiology Network study. METHODS: GFR, estimated by the Modification of Diet in Renal Disease equation, and albuminuria, measured as albumin to creatinine ratio (ACR), were adjusted for gender, age, centre, mean blood pressure, anti-hypertensive medication class and diabetes status using SOLAR. Since albuminuria and abnormal GFR often coexist, we conducted bivariate linkage analyses to investigate the presence of pleiotropy. RESULTS: The phenotypic correlation between ACR and GFR was not significant in EAs (r = 0.04) and significantly negative in AAs (r = -0.17). Univariate analyses of ACR showed suggestive evidence of linkage on chromosomes 8, 16 and 17 (LOD: 2-2.8) in AAs, on chromosomes 18 and 19 (LOD = 2) in EAs, and on chromosome 19 (LOD = 2.6) when combining AAs and EAs. For GFR, suggestive linkage was found on chromosomes 7, 14 and 19 (LOD: 2.2-2.9) in AAs and on chromosomes 14, 15 and 16 (LOD: 2.1-3.3) in the combined group. Also, bivariate analyses showed a LOD score of 3.4 at 133 cM on chromosome 7 in AAs. CONCLUSIONS: Suggestive evidence for linkage to GFR and ACR was observed at many loci. The findings are consistent with previous studies. Also, indication of a pleiotropic locus was detected in chromosome 7 in AAs.

Albumins↗

PubMed2006

Left ventricular hypertrophy in severe obesity: interactions among blood pressure, nocturnal hypoxemia, and body mass.

Obese subjects have a high prevalence of left ventricular (LV) hypertrophy. It is unclear to what extent LV hypertrophy results directly from obesity or from associated conditions, such as hypertension, impaired glucose homeostasis, or obstructive sleep apnea. We tested the hypothesis that LV hypertrophy in severe obesity is associated with additive effects from each of the major comorbidities. Echocardiography and laboratory testing were performed in 455 severely obese subjects with body mass index 35 to 92 kg/m(2) and 59 nonobese reference subjects. LV hypertrophy, defined by allometrically corrected (LV mass/height(2.7)), gender-specific criteria, was present in 78% of the obese subjects. Multivariable regression analyses showed that average nocturnal oxygen saturation <85% was the strongest independent predictor of LV hypertrophy (P<0.001), followed by systolic blood pressure (P<0.015) and then body mass index (P<0.05). With regard to LV mass, there were synergistic effects between hypertension and body mass index (P interaction <0.001) and between hypertension and reduced nocturnal oxygen saturation. Severely obese subjects had normal LV endocardial fractional shortening (35+/-6% versus 35+/-6%) but mildly decreased midwall fractional shortening (15+/-2% versus 17+/-2%; P<0.001), indicating subtle myocardial dysfunction. In conclusion, more severe nocturnal hypoxemia, increasing systolic blood pressure, and body mass index are all independently associated with increased LV mass. The effects of increased blood pressure seem to amplify those of sleep apnea and more severe obesity.

Adult↗

PubMed2006

Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study.

BACKGROUND: Bilirubin is an antioxidant that suppresses lipid oxidation and retards atherosclerosis formation. An inverse association between serum bilirubin and coronary heart disease has been reported. Linkage studies have identified a major locus at the chromosome 2q telomere that affects bilirubin concentrations. A candidate gene in the linkage region encodes hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1). The insertion of a TA in the TATAA box of the gene, an allele designated UGT1A1*28, decreases gene transcription. Individuals homozygous for UGT1A1*28 (genotype 7/7) have increased serum bilirubin levels compared with carriers of the 6 allele. To date, no significant association between UGT1A1*28 and cardiovascular disease (CVD) events has been reported. We performed an association study in the Framingham Heart Study population to investigate whether UGT1A1*28 is associated with the risk of CVD events. METHODS AND RESULTS: The study population included 1780 unrelated individuals from the Offspring cohort (49% males, mean age 36 years at entry) who had been followed up for 24 years. Individuals with genotype 7/7 had significantly higher bilirubin levels (mean+/-SD 1.14+/-0.44 mg/dL) than those with genotypes 6/6 and 6/7 (mean+/-SD 0.69+/-0.27 mg/dL, P<0.01). Using the Cox proportional hazards model, we found significant associations between the UGT1A1*28 allele and decreased risk of CVD. Individuals with genotype 7/7 (population frequency of 11%) had approximately one third the risk for CVD and coronary heart disease as carriers of the 6 allele, which resulted in a hazard ratio (95% confidence interval) of 0.36 (0.18 to 0.74) and 0.30 (0.12 to 0.74), respectively. CONCLUSIONS: Homozygote UGT1A1*28 allele carriers with higher serum bilirubin concentrations exhibit a strong association with lower risk of CVD.

Adult↗

PubMed2006

TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition.

The molecular etiology of obesity predisposition is largely unknown. Here, we present evidence that genetic variation in TBC1D1 confers risk for severe obesity in females. We identified a coding variant (R125W) in TBC1D1 that segregated with the disease in 4p15-14-linked obesity pedigrees. In cases derived from pedigrees with the strongest linkage evidence, the variant was significantly associated with obesity (P=0.000007) and chromosomes carrying R125W accounted for the majority of the evidence that originally linked 4p15-14 with the disease. In addition, by selecting families that segregated R125W with obesity, we were able to generate highly significant linkage evidence for an obesity predisposition locus at 4q34-35. This result provides additional and confirming evidence that R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34-35 and identifies a gene/gene interaction that influences the risk for obesity predisposition. Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin-mediated Glut4 translocation.

Chromosomes, Human, Pair 4↗

PubMed2006

Alcohol consumption and plasma atrial natriuretic peptide (from the HyperGEN study).

Although moderate alcohol consumption has been associated with a lower risk of cardiovascular disease, underlying physiologic mechanisms are not fully understood. Data relating alcohol intake to atrial natriuretic peptide (ANP) have been inconsistent. We evaluated whether alcohol consumption was associated with plasma ANP in 1,345 participants from the Hypertension Genetic Epidemiology Network (HyperGEN) study. We used random effect models to estimate the adjusted means of logarithmic transformed ANP. The mean age was 35.8 +/- 8.6 years, 91% were normotensive, 46% were men, and 40% and 60% were African-Americans and whites, respectively. In a model adjusting for age, body mass index, field center, education, gender, race, and serum albumin, alcohol consumption was positively associated with ANP in men (p < 0.0001 for trend) and women (p = 0.0014) and in African-Americans (p = 0.006) and whites (p < 0.0001). The adjusted mean of log-transformed ANP was 3.68, 3.67, 3.77, 3.76, 3.86, and 3.91 pg/ml in lifetime abstainers, former drinkers, and current drinkers of 1 to 6, 7 to 12, 13 to 24, and > 24 g/d, respectively. Controlling for additional factors, including left atrial size, ejection fraction, left ventricular mass, end-diastolic volume, systolic blood pressure, smoking, lipids, and serum creatinine did not change the results. Restriction to normotensive subjects yielded similar results. Alcohol intake was associated positively with systolic and diastolic blood pressure (p < 0.0001 each for trend). In conclusion, our data have shown a positive and linear association between alcohol consumption and ANP in men and women, irrespective of race.

Adolescent↗

PubMed2006

Influence of saturated fat and linolenic acid on the association between intake of dairy products and blood pressure.

Data on the association between dairy consumption and blood pressure have been inconsistent. We sought to examine the relation between dairy consumption and prevalent hypertension (HTN) among 4797 participants of the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized estimating equations to estimate prevalence odds ratios of HTN across categories of dairy consumption. From the lowest to the highest sex-, age-, and energy-adjusted quartile of dairy consumption, there was an inverse association between dairy intake and prevalent HTN: odds ratios (95% CIs) were 1.0 (reference), 0.82 (0.64 to 1.05), 0.68 (0.53 to 0.89), and 0.62 (0.45 to 0.84), respectively, in a model adjusting for age, sex, energy intake, field center, body mass index, dietary linolenic acid, saturated and monounsaturated fat, sodium intake, potassium, caffeine, fiber, and fruits and vegetables (P for trend = 0.002). This association was independent of calcium intake and was mainly observed among subjects consuming fewer calories from saturated fat (P for interaction = 0.014). Dairy consumption was inversely associated with systolic (P for trend = 0.003) but not diastolic (P for trend = 0.09) blood pressure. Although subjects consuming > or = 2 servings per day of dairy products and higher total linolenic acid had the lowest prevalence odds of HTN, there was no evidence for interaction between linolenic acid and dairy consumption on HTN (P for interaction = 0.65). In conclusion, our data indicate an inverse association between dairy consumption and prevalent HTN that was independent of dietary calcium, mainly among individuals consuming less saturated fat. This suggests that consumption of low-fat dairy products might be more beneficial for preventing HTN.

Adult↗

PubMed2006

Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study.

Recent epidemiological studies have indicated that baseline C-reactive protein (CRP) levels may have value in prediction of cardiovascular risk. Using six tag single-nucleotide polymorphisms (SNPs) selected from our complete list of SNPs on the CRP gene, we investigated the association of CRP genotypes with plasma CRP levels and cardiovascular risk in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study cohort (1,296 Caucasians, 48.5% male, 54.7 +/- 12.8 yr old). There was a significant trend toward association of CRP haplotypes with CRP levels (P = 0.045). SNP analysis indicated a highly significant association of SNP -757 (rs3093059, P = 0.0004) and SNP -286 (rs3091244, P = 0.0065) and a borderline association of SNP -7180 (rs1341665, P = 0.06) with CRP levels. Neither CRP haplotypes nor individual SNP genotypes were associated with intima-media thickness of the common carotid or internal carotid artery or the bifurcation of the carotid arteries. These results indicated a strong impact of local SNPs of the CRP gene on plasma CRP levels, but there was no direct evidence that these genetically controlled CRP elevations by local CRP SNPs contributed to cardiovascular disease phenotypes.

Adult↗

PubMed2006

Association of coronary artery calcified plaque with clinical coronary heart disease in the National Heart, Lung, and Blood Institute's Family Heart Study.

The presence of calcified coronary artery plaque has shown variable association with clinical coronary heart disease (CHD), particularly after adjustment for other risk factors. From 2002 to 2004, as part of the National Heart, Lung, and Blood Institute's Family Heart Study, coronary artery calcium (CAC) scans by 4-slice multidetector computed tomography were performed in 3,359 subjects, including 389 with clinically diagnosed CHD. Among these was a cohort of 2,254 patients who had been asymptomatic at an initial examination 7 to 9 years previously (1994 to 1996), with 111 who had developed newly diagnosed, nonfatal CHD since the initial examination. In cross-sectional analyses, we examined associations between CAC and CHD in the entire group and in the subgroup seen at the initial examination. In the 2 sets of analyses, odds ratios for CHD ranged from approximately 4 in those with CAC scores of 100 to 199 (p <0.01) to >20 in those with CAC scores >/=1,000 (p <0.0001) compared with those with no measurable CAC. This steep gradient of risk persisted after adjustment for risk factors. A quantitative CHD family history score was significantly associated with CHD even after adjusting for all standard risk factors and including CAC in the model. In conclusion, CAC was strongly associated with CHD even after adjustment for standard risk factors and family history contributed independently to CHD risk.

Adult↗

PubMed2006

Evidence for a gene influencing heart rate on chromosome 5p13-14 in a meta-analysis of genome-wide scans from the NHLBI Family Blood Pressure Program.

BACKGROUND: Elevated resting heart rate has been shown in multiple studies to be a strong predictor of cardiovascular disease. Previous family studies have shown a significant heritable component to heart rate with several groups conducting genomic linkage scans to identify quantitative trait loci. METHODS: We performed a genome-wide linkage scan to identify quantitative trait loci influencing resting heart rate among 3,282 Caucasians and 3,989 African-Americans in three independent networks comprising the Family Blood Pressure Program (FBPP) using 368 microsatellite markers. Mean heart rate measurements were used in a regression model including covariates for age, body mass index, pack-years, currently drinking alcohol (yes/no), hypertension status and medication usage to create a standardized residual for each gender/ethnic group within each study network. This residual was used in a nonparametric variance component model to generate a LOD score and a corresponding P value for each ethnic group within each study network. P values from each ethnic group and study network were merged using an adjusted Fisher's combining P values method and the resulting P values were converted to LOD scores. The entire analysis was redone after individuals currently taking beta-blocker medication were removed. RESULTS: We identified significant evidence of linkage (LOD = 4.62) to chromosome 10 near 142.78 cM in the Caucasian group of HyperGEN. Between race and network groups we identified a LOD score of 1.86 on chromosome 5 (between 39.99 and 45.34 cM) in African-Americans in the GENOA network and the same region produced a LOD score of 1.12 among Caucasians within a different network (HyperGEN). Combining all network and race groups we identified a LOD score of 1.92 (P = 0.0013) on chromosome 5p13-14. We assessed heterogeneity for this locus between networks and ethnic groups and found significant evidence for low heterogeneity (P < or = 0.05). CONCLUSION: We found replication (LOD > 1) between ethnic groups and between study networks with low heterogeneity on chromosome 5p13-14 suggesting that a gene in this region influences resting heart rate.

Adult↗

PubMed2006

Relationship of ghrelin and leptin hormones with body mass index and waist circumference in a random sample of adults.

OBJECTIVE: To evaluate the relationship of ghrelin and leptin hormones with body mass index (BMI) and waist circumference in a population-based random sample of adult men and women subsequently categorized from normal weight to severely obese based on BMI criteria. The relationship between total ghrelin and leptin was also evaluated. DESIGN: A cross-sectional study was conducted on adults. METHODS: Two-hundred thirty-three men (n=107) and women (n=126) between the ages of 23 and 75 years were randomly selected from a database of over 600,000 adults who had previously participated in a population-based study conducted by the University of Utah Cardiovascular Genetics Program. Items collected included height, weight, waist circumference, and fasting blood samples. Blood samples were later thawed, and plasma leptin and total ghrelin levels were analyzed with radioimmunoassay kits. RESULTS: Leptin levels were directly associated with BMI (r=0.72, P=0.001) and waist circumference (r=0.71, P=0.0001), whereas total ghrelin was inversely associated with BMI (r=-0.39, P=0.001) and waist circumference (r=-0.37, P=0.001). There were also statistically significant linear changes in means across the BMI categories for both hormones. After controlling for BMI and waist circumference, the highly significant correlation of leptin with ghrelin (r=-0.39) was reduced but still significant (r=-0.17, P=0.01). CONCLUSION: Leptin increases and ghrelin decreases were linear over the five BMI categories, suggesting there is no threshold of BMI where the hormone levels change abruptly. There remain other factors beyond current BMI and waist circumference that induce a correlation of these two hormones. Further understanding of the role that each of these hormones has in influencing appetite and body weight may provide insight into mechanisms involved with obesity.

Adult↗

PubMed2006

Dietary linolenic acid and fasting glucose and insulin: the National Heart, Lung, and Blood Institute Family Heart Study.

OBJECTIVE: To assess whether dietary linolenic acid is associated with fasting insulin and glucose. RESEARCH METHODS AND PROCEDURES: In a cross-sectional design, we studied 3993 non-diabetic participants of the National Heart, Lung, and Blood Institute Family Heart Study 25 to 93 years of age. Linolenic acid was assessed through a food frequency questionnaire, and laboratory data were obtained after at least a 12-hour fast. We used generalized linear models to calculate adjusted means of insulin and glucose across quartiles of dietary linolenic acid. RESULTS: From the lowest to the highest sex-specific quartile of dietary linolenic acid, means +/- standard error for logarithmic transformed fasting insulin were 4.06 +/- 0.02 (reference), 4.09 +/- 0.02, 4.13 +/- 0.02, and 4.17 +/- 0.02 pM, respectively (trend, p < 0.0001), after adjustment for age, sex, energy intake, waist-to-hip ratio, smoking, and high-density lipoprotein-cholesterol. When dietary linolenic acid was used as a continuous variable, the multivariable adjusted regression coefficient was 0.42 +/- 0.08. There was no association between dietary linolenic acid and fasting glucose (trend p = 0.82). DISCUSSION: Our data suggest that higher consumption of dietary linolenic acid is associated with higher plasma insulin, but not glucose levels, in non-diabetic subjects. Additional studies are needed to assess whether higher intake of linolenic acid results in an increased insulin secretion and improved glucose use in vivo.

Adult↗

PubMed2006

Lack of association of glutamate decarboxylase 2 gene polymorphisms with severe obesity in utah.

Three polymorphisms of the glutamate decarboxylase 2 gene, which encodes the glutamic acid decarboxylase enzyme, have been associated with severe obesity in a large French cohort. One of these polymorphisms was shown to have functional consequences on promoter expression. Another polymorphism was associated with insulin levels and secretion. These associations were examined in 855 severely obese Utah subjects (mean BMI = 48 kg/m(2)) and a normal-weight and normoglycemic subset (N = 130, mean BMI = 22 kg/m(2)) of a random sample of the Utah population (N = 462). Comparisons of the normal-weight random group with the severely obese group did not result in significant genotype or allele frequency differences for any of the three polymorphisms, C61450A, T83897A, or A-243G (all p > or = 0.18). Haplotypes were also not related to severe obesity (p = 0.10). None of the polymorphisms was significantly related to fasting glucose, insulin levels, or homeostasis model assessment insulin resistance or secretion indices. This study of normal-weight and severely obese subjects from Utah does not provide evidence for involvement of the three genotyped polymorphisms in the glutamate decarboxylase 2 gene with obesity or with insulin- and glucose-related measures associated with obesity.

Adult↗

PubMed2006

The ATGL gene is associated with free fatty acids, triglycerides, and type 2 diabetes.

Adipose triglyceride lipase (ATGL) was recently described to predominantly perform the initial step in triglyceride hydrolysis and therefore seems to play a pivotal role in the lipolytic catabolism of stored fat in adipose tissue. In the first study investigating genetic variations within the ATGL gene in humans, 12 polymorphisms identified via sequencing and database search were studied in 2,434 individuals of European ancestry from Utah. These polymorphisms and their haplotypes were analyzed in subjects not taking diabetes medication for association with plasma free fatty acids (FFAs) as primary analysis, as well as triglycerides and glucose as a secondary analysis (n = 1,701, 2,193, or 2,190, respectively). Furthermore, type 2 diabetes (n = 342 of 2,434) was analyzed as an outcome. FFA concentrations were significantly associated with several single nucleotide polymorphisms (SNPs) of ATGL (P values from 0.015 to 0.00003), consistent with additive inheritance. The pattern was similar when considering triglyceride concentrations. Furthermore, two SNPs showed associations with glucose levels (P < 0.00001) and risk of type 2 diabetes (P < 0.05). Haplotype analysis supported and extended the shown SNP association analyses. These results complement previous findings of functional studies in mammals and elucidate a potential role of ATGL in pathways involved in components of the metabolic syndrome.

Adult↗

PubMed2006

Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study.

Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.

Black People↗

PubMed2005

Sodium bicarbonate cotransporter polymorphisms are associated with baseline and 10-year follow-up blood pressures.

The NaHCO3 cotransporter gene (SLC4A5) on chromosome 2 encodes a protein that transports sodium and bicarbonate across the cell membrane and regulates cellular pH. The National Heart, Lung, and Blood Institute Family Blood Pressure Program found linkage of blood pressure-related traits to the chromosomal region containing SLC4A5 and phenotype associations with single nucleotide polymorphisms (SNPs) in this gene. However, the results were inconsistent over various phenotypes and SNPs. Nevertheless, the evidence was strong enough to propose this gene as a blood pressure-related gene. To extend these findings, SLC4A5 SNPs were genotyped in an independent set of 96 Utah pedigrees of 1040 adult subjects at baseline, 760 of whom were followed longitudinally for 10 years. After adjusting for age, gender, body mass index, and polygenic correlations within pedigrees, SNP hcv1137534 was significantly associated with both systolic blood pressure and diastolic blood pressure (DBP) at baseline (unadjusted P=0.009 and P=0.043; respectively) and at 10-year follow-up (P=0.008 and P=0.007; respectively). In secondary tests of association of baseline-stressed blood pressure, hcv1137534 was borderline or significantly associated with DBP change during an isometric handgrip test (P=0.054), DBP change from supine to standing (P=0.020), and DBP change after a 50 degrees tilt (P=0.034). There was no evidence for compensation of abnormal SLC4A5 sodium transport by genotype-specific differences in sodium-lithium countertransport, lithium-potassium cotransport, altered plasma sodium, chloride, or CO2 levels. Therefore, in these Utah pedigrees, the SLC4A5 gene was significantly associated with blood pressure and persisted after 10 years of follow-up. These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear.

Adult↗

PubMed2005

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Black or African American↗