Biomedical subjects

Steven C Hunt

Publications and source records attributed to Steven C Hunt.

At least 37 records · Page 2Linked to original sources

PubMed2005

Meta-analysis of genome-wide linkage studies for quantitative lipid traits in African Americans.

Genetic influences on lipid traits have been suggested by numerous studies. In addition to heritability studies, over 50 genome scans have been performed to identify regions of linkage for quantitative lipid levels. Five of these scans have been performed in African Americans (four univariate and one bivariate linkage analysis), but with results that have been largely inconclusive. Linkage analyses are often limited by both sample size and heterogeneity, which may lead to nominal LOD scores or lack of evidence for linkage; the use of meta-analysis to combine linkage results from populations with similar ethnic backgrounds may help overcome some of these limitations. Thus, we performed a meta-analysis using data from four genome scans conducted in African American families to identify chromosomal regions showing evidence of linkage for total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). Significant evidence (i.e. P<0.00042) for linkage was found for LDL on chromosome 1q32.1-q41 (Pweighted=0.00014 and Punweighted=0.00007) and 1q41-q44 (Pweighted=0.00017 and Punweighted=0.00014). We found suggestive evidence (i.e. P<0.00847) for TG on 16p12.1-q11.2 and for HDL on 4p15.1-p11. We also assessed heterogeneity between studies and found significant evidence for low heterogeneity for both regions on chromosome 1q (P=0.0300 and P=0.0279, respectively) for LDL and chromosome 16 (P=0.0429) for TG. Statistically significant evidence for linkage and low heterogeneity on chromosome 1q therefore suggest that this region may harbor a gene underlying the inheritance of LDL in African Americans.

Black or African American↗

PubMed2005

Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides.

Positive evidence has been reported for linkage and association between the upstream stimulatory factor 1 gene (USF1) and familial combined hyperlipidemia (FCHL). We genotyped the two most positive single-nucleotide polymorphisms (SNPs) (usf1s1: rs3737787 and usf1s2: rs2073658) from previous studies in a large family sample. This sample included 2,195 subjects in 87 Utah pedigrees ascertained for early death due to coronary heart disease (CHD), early strokes, or early onset hypertension. There were a total of 262 relative pairs in these families with FCHL. In the full family sample, FCHL was associated with usf1s1 (P = 0.02). Triglyceride and LDL cholesterol defined qualitatively or quantitatively were also associated with usf1s1 (P = 0.02-0.05). Results were strengthened for qualitative and quantitative triglyceride and LDL cholesterol when data from males only was analyzed, revealing associations for usf1s1 (P = 0.001-0.02), usf1s2 (P = 0.02-0.05) and the haplotype of these two SNPs (P = 0.01-0.04). The strongest results were in the subset of subjects from families ascertained for premature stroke or hypertension, rather than those ascertained for premature CHD. This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL.

Age of Onset↗

PubMed2005

Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease.

OBJECTIVES: This study was designed to explore contributions of plasma total triglycerides (TGs) and type III hyperlipidemia to the risk of premature familial coronary artery disease (CAD). BACKGROUND: Although plasma TGs are recognized as a risk factor for CAD, the independence of this association from related risk factors remains controversial. Also, the degree of CAD risk conferred by excess remnants of TG-rich lipoproteins in type III hyperlipidemia remains unclear. METHODS: We analyzed lipids by ultracentrifugation in a series of 653 cases with premature familial CAD (myocardial infarction or revascularization by age 55 years in men or age 65 years in women, with similar onset in at least one other first-degree relative) and in 1,029 control subjects. The relationship of CAD risk to various strata of plasma TGs, high-density lipoprotein (HDL) cholesterol, and type III hyperlipidemia, and interactions among these variables were examined by multiple logistic regression, adjusting for other CAD risk factors. RESULTS: The odds ratio for CAD with elevated plasma TG rose progressively to 11.4 in those with TGs 500 to 799 mg/dl (95% confidence interval 3.4 to 38.0, p < 0.0001) compared with <100 mg/dl, even after correction for HDL cholesterol, other elements of the metabolic syndrome, and other CAD risk factors. Risk of CAD associated with type III hyperlipidemia (found in 3.4% of cases) was also markedly increased independent of other risk factors (odds ratios of 5 to 10 depending on the model, all with p < 0.002). CONCLUSIONS: The association between the plasma TG level and premature familial CAD is strong, graded, and independent. Risk of CAD is also strikingly elevated with type III hyperlipidemia.

Aged↗

PubMed2005

Utah's Family High Risk Program: bridging the gap between genomics and public health.

BACKGROUND: Family history is a simple yet powerful genomic tool that can identify individuals and entire populations at risk for diseases such as heart disease, cancer, and diabetes. Despite its use for predicting disease, family history has traditionally been underused in the public health setting. CONTEXT: A program for identifying families at risk for a variety of chronic diseases was implemented in Utah. Utah has population characteristics that are unique among the United States. Although the land area is large, most residents live within a relatively small geographic area. The religion of 70% of the residents encourages the recording of detailed family histories, and many families have access to records dating back to the 1800s. METHODS: From 1983 through 1999, the Utah Department of Health, local health departments, school districts, the University of Utah, and the Baylor College of Medicine implemented and conducted the Family High Risk Program, which identified families at risk for chronic diseases using the Health Family Tree Questionnaire in Utah high schools. CONSEQUENCES: The collection of family history is a cost-effective method for identifying and intervening with high-risk populations. More than 80% of eligible families consented to fully participate in the program. A total of 80,611 usable trees were collected. Of the 151,188 Utah families who participated, 8546 families identified as high-risk for disease(s) were offered follow-up interventions. INTERPRETATION: The program was revolutionary in design and demonstrated that family history can bridge the gap between genetic advances and public health practice.

Breast Neoplasms↗

PubMed2005

Linkage of the cholesterol 7alpha-hydroxylase gene and low-density lipoprotein cholesterol conditional on apolipoprotein E association: the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7alpha-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. METHODS: Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. RESULTS: The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly. CONCLUSION: Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.

Adult↗

PubMed2005

An evaluation of the metabolic syndrome in the HyperGEN study.

BACKGROUND: In 2001 the National Cholesterol Education Program (NCEP) provided a categorical definition for metabolic syndrome (c-MetS). We studied the extent to which two ethnic groups, Blacks and Whites were affected by c-MetS. The groups were members of the Hypertension Genetic Epidemiology Network (HyperGEN), a part of the Family Blood Pressure Program, supported by the NHLBI. Although the c-MetS definition is of special interest in particular to the clinicians, the quantitative latent traits of the metabolic syndrome (MetS) are also important in order to gain further understanding of its etiology. In this study, quantitative evaluation of the MetS latent traits (q-MetS) was based on the statistical multivariate method factor analysis (FA). RESULTS: The prevalence of the c-MetS was 34% in Blacks and 39% in Whites. c-MetS showed predominance of obesity, hypertension, and dyslipidemia. Three and four factor domains were identified through FA, classified as "Obesity," "Blood pressure," "Lipids," and "Central obesity." They explained approximately 60% of the variance in the 11 original variables. Two factors classified as "Obesity" and "Central Obesity" overlapped when FA was performed without rotation. All four factors in FA with Varimax rotation were consistent between Blacks and Whites, between genders and also after excluding type 2 diabetes (T2D) participants. Fasting insulin (INS) associated mainly with obesity and lipids factors. CONCLUSIONS: MetS in the HyperGEN study has a compound phenotype with separate domains for obesity, blood pressure, and lipids. Obesity and its relationship to lipids and insulin is clearly the dominant factor in MetS. Linkage analysis on factor scores for components of MetS, in familial studies such as HyperGEN, can assist in understanding the genetic pathways for MetS and their interactions with the environment, as a first step in identifying the underlying pathophysiological causes of this syndrome.

Journal Article↗

PubMed2005

Further evidence of a quantitative trait locus on chromosome 18 influencing postural change in systolic blood pressure: the Hypertension Genetic Epidemiology Network (HyperGEN) Study.

BACKGROUND: Postural change in systolic blood pressure (SBP) is prospectively associated with several disease outcomes including hypertension, stroke, and coronary heart disease. The objective of this study was to characterize further a possible quantitative trait locus on chromosome 18q21 influencing SBP response to a postural challenge. METHODS: A prior genome scan of postural SBP response in 636 subjects of white ethnicity from 285 hypertensive sibships in the Hypertension Genetic Epidemiology Network (HyperGEN) indicated suggestive evidence for linkage on chromosome 18q21. This study included a de novo set of 452 African American pedigrees from the HyperGEN study and an expanded set of 372 white pedigrees. Variance components linkage analysis of postural SBP change was conducted using microsatellite markers on chromosome 18, and association studies were performed with a common single nucleotide polymorphism (variant 13) in the gene encoding NEDD4L, a key regulator of fine sodium reabsorption in the distal nephron. RESULTS: Combined analysis of all white and African American pedigrees yielded a LOD score of 4.25 at 80 cM on chromosome 18q21, with at least nominal evidence of linkage at this position in both white (LOD: 3.43) and African American (LOD: 1.14) subjects. Postural SBP response was associated with variant 13 of the NEDD4L in a subset of white subjects taking medications effective in treating sodium volume-dependent hypertension (alpha1-blockers, calcium channel blockers, and/or diuretics). CONCLUSION: These data provide further evidence for a quantitative trait locus on chromosome 18q21 influencing postural change in SBP.

Adult↗

PubMed2005

A summary of the effects of antihypertensive medications on measured blood pressure.

BACKGROUND: Epidemiologic analysis of family data on blood pressure (BP) is often compromised by the effects of antihypertensive medications. A review of numerous clinical trials that investigated the effects of BP-lowering medications is summarized here. METHODS: Published clinical trials, including 137 clinical trials with monodrug therapies and 28 clinical trials of combination drug therapies with a total of 11,739 participants, were reviewed from PubMed. Six major classes/groups of antihypertensive medications were categorized by ethnicity, including angiotensin-converting enzyme (ACE) inhibitors, alpha1-blockers, cardioselective beta-blockers (beta1-blockers), calcium channel blockers, thiazide and thiazide-like diuretics, and loop diuretics. RESULTS: Using sitting or supine BP, for ethnic groups combined, monodrug therapy with ACE inhibitors showed a weighted average effect of lowering the systolic and diastolic BP by 12.5/9.5 mm Hg; alpha1-blockers by 15.5/11.7 mm Hg; beta1-blockers by 14.8/12.2 mm Hg; calcium channel blockers by 15.3/10.5 mm Hg; thiazide diuretics by 15.3/9.8 mm Hg; and loop diuretics by 15.8/8.2 mm Hg. However, ACE inhibitors, alpha1-blockers, and beta1-blockers were less effective in African Americans than in non-African Americans, whereas calcium channel blockers, thiazide diuretics, and loop diuretics were more effective in African Americans than in non-African Americans. For two-drug combination therapy with ethnic groups combined, the BP-lowering effect of the second medication, when compared to its effect as monodrug therapy, was 84% and 65% for systolic and diastolic BP, respectively. CONCLUSIONS: The BP-lowering effects reported here may be used to impute the pretreatment BP levels, which can improve the information content and hence the power of epidemiologic analysis in studies where use of antihypertensive medications is a confounding factor in the BP measurements.

Adult↗

PubMed2005

Design and rationale of the Utah obesity study. A study to assess morbidity following gastric bypass surgery.

PURPOSE: This paper details the design and baseline characteristics of a study on the morbidity associated with Roux-en-Y gastric bypass surgery (GBP) in severely obese adults. This study is designed to assess the effectiveness of GBP in reducing morbidity and maintaining weight loss. A wide array of clinical tests and psycho-behavioral questionnaires are included as part of the study. METHODS: Three groups (n=1156 severely obese) have been recruited for this study: cases who were approved for and participated in surgery (n=415), a control group of GBP seeking individuals who were denied surgery (n=420) and a control group that was randomly chosen from a population of severely obese participants who were not seeking GBP (n=321). Clinical measures include: a physician interview and detailed medical history, resting electro- and echocardiograms, a submaximal exercise treadmill test and electrocardiogram, pulmonary function, limited polysomnography, resting metabolic rate, anthropometrics, resting and exercise blood pressure, comprehensive blood chemistry and urinalysis and dietary, quality of life and physical activity questionnaires. Most participants (76%) were tested following an overnight stay in a clinical research center. Remaining participants underwent less extensive testing in an outpatient clinic. RESULTS: Baseline characteristics of the 1156 participants are available for selected measures. Mean+/-S.D. for BMI was 46+/-7.5 kg/m(2) (range=33 to 92) and for age was 44+/-11.4 years (range=18 to 72). The prevalence of diabetes and hypertension was 19% and 35%, respectively. Of the participants who had an echocardiogram or polysomnogram, 92% had left-ventricular hypertrophy and 85% had mild to severe sleep apnea. The two control groups were similar to the surgical group. At approximately 24 months, all participants will have a second clinical examination. Statistical comparisons of changes in morbidity variables will be made between the surgical and control groups. CONCLUSIONS: This study design facilitates assessment of risks and benefits of GBP to perform recommendations on whether or not to perform surgery on the severely obese patient. Baseline and 2-year exams provide valuable data for comparison to future long-term follow-up data that can be collected at 5 and 10 years.

Adolescent↗

PubMed2005

Quantitative trait loci for metabolic syndrome in the Hypertension Genetic Epidemiology Network study.

As part of the Hypertension Genetic Epidemiology Network study, genome scans were performed in two ethnicities on the categorical metabolic syndrome (MetS). Genome scans were performed also on the factor scores produced by factor analysis (quantitative MetS). Heritabilities were highest for the obesity-insulin (INS) factor and lowest for blood pressure (BP) and central obesity. Seventeen unique putative quantitative trait loci (QTLs) yielded logarithm of the odds ratio (LOD) scores in excess of 1.7, 8 for blacks and 9 for whites. Important QTL findings in whites included an LOD score of 3.19 on chromosome 15q15 for the BP factor, 3.08 on chromosome 8p23 for the lipids-INS factor, and 3.07 on chromosome 3p26 for the obesity-INS factor. In blacks, after excluding type 2 diabetics, important QTLs were identified, including an LOD score of 2.77 on 13p12 for the obesity-INS factor and 2.63 on chromosome 11q24 for the lipids-INS factor. Categorical MetS had lower results than quantitative MetS. Notably, several loci identified overlap with those identified in other studies for a single or group of traits. The most promising candidate loci on 11q24 for lipids-INS and 13p12 for obesity-INS in blacks, 8p23 for lipids-INS, 14q24 for obesity-INS, and 15q15 for BP in whites warrant further investigation.

Black People↗

PubMed2005

Interarm differences in seated systolic and diastolic blood pressure: the Hypertension Genetic Epidemiology Network study.

OBJECTIVE: To examine whether blood pressure (BP) differs between arms in hypertensive siblings and randomly selected volunteers, and whether this difference is explained by cardiovascular risk factors. METHODS: The Hypertension Genetic Epidemiology Network recruited 2395 hypertensive siblings and 854 volunteers. BP was measured six times (three measurements per arm) in seated participants using a Dinamap monitor. The average of three measurements was calculated per arm and the difference taken between arms (i.e. interarm BP differences). RESULTS: The mean age of the subjects was 56 years, and about one-half of the sample was male. More than one-half of the sample was African-American. The mean diastolic BP was equal in the two arms in the random sample (68.8 versus 68.7 mmHg) and in hypertensive siblings (73.4 versus 73.1 mmHg), as was systolic BP (random, 119.6 versus 119.3 mmHg; hypertensives, 130.8 versus 130.7 mmHg). The mean interarm diastolic and systolic BP differences were 2.96 +/- 2.51 and 4.61 +/- 4.10 mmHg, respectively, in the random sample and were 3.09 +/- 2.73 and 5.35 +/- 4.98 mmHg, respectively, in hypertensive siblings. Few (random, 1.6%; hypertensives, 2.8%) had interarm diastolic BP differences > 10 mmHg, but 9.2% of the random sample and 14.2% of hypertensive siblings had systolic BP differences > 10 mmHg. Obesity, higher heart rate, and higher systolic BP were associated with larger interarm BP differences. These results have implications for blood pressure measurement in research settings and in screening programs.

Adult↗

PubMed2004

Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies.

We have analyzed genetic data for 326 microsatellite markers that were typed uniformly in a large multiethnic population-based sample of individuals as part of a study of the genetics of hypertension (Family Blood Pressure Program). Subjects identified themselves as belonging to one of four major racial/ethnic groups (white, African American, East Asian, and Hispanic) and were recruited from 15 different geographic locales within the United States and Taiwan. Genetic cluster analysis of the microsatellite markers produced four major clusters, which showed near-perfect correspondence with the four self-reported race/ethnicity categories. Of 3,636 subjects of varying race/ethnicity, only 5 (0.14%) showed genetic cluster membership different from their self-identified race/ethnicity. On the other hand, we detected only modest genetic differentiation between different current geographic locales within each race/ethnicity group. Thus, ancient geographic ancestry, which is highly correlated with self-identified race/ethnicity--as opposed to current residence--is the major determinant of genetic structure in the U.S. population. Implications of this genetic structure for case-control association studies are discussed.

Case-Control Studies↗

PubMed2004

Evidence for a gene on chromosome 13 influencing postural systolic blood pressure change and body mass index.

Previous analysis in the Hypertension Genetic Epidemiology Network (HyperGEN) of the National Heart Lung and Blood Institute (NHLBI) Family Blood Pressure Program, a multicenter study of genetic and environmental factors related to hypertension, indicated regions of linkage for blood pressure traits together with several coincident regions for phenotypically correlated traits, including systolic blood pressure (SBP) response to a postural challenge and body mass index (BMI). Motivated by these findings and by our desire to better understand the physiology of these traits, we conducted bivariate linkage analysis of postural SBP change and BMI. Sibships in HyperGEN were recruited from 5 field centers in Massachusetts, North Carolina, Minnesota, Utah, and Alabama. All available affected siblings, their parents, and selected nonmedicated offspring were recruited. Among 1636 whites and 1747 blacks, we performed a maximum likelihood bivariate genome scan for quantitative trait loci influencing postural SBP change and BMI, similarly adjusted for race, study center, sex, age, and age-by-sex interactions. Genome scans were performed using SOLAR (version 2.0) and race-specific marker allele frequencies derived from founders. The maximum genome-wide logarithm of odds (LOD) score of 3.2 was detected on chromosome 13 at 24 cM. This marker (D13S493) lies within 20 cM of a marker previously linked to BMI in the Family Heart Study and is substantially higher than the univariate linkage for each trait (LOD scores for BMI and postural SBP change were 2.4 and 0.9, respectively). These findings suggest that a gene(s) on chromosome 13q jointly regulates the SBP response to postural change and BMI.

Adult↗

PubMed2004

Positional identification of hypertension susceptibility genes on chromosome 2.

Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.

Chromosomes, Human, Pair 2↗

PubMed2004

Identification of a congenic mouse line with obesity and body length phenotypes.

Our primary objective was to discover simplified mouse models corresponding to human obesity linkages. We used the B10.UW- H3(b) we Pax1(un) a(t)/Sn (B10.UW) congenic strain, a subcongenic strain with a reduced UW strain donor region, and their C57BL/10SnJ background strain. The congenic and subcongenic UW strain donor regions are on mouse Chr 2. We measured body length [anal-nasal (AN) length], summed fat depot weights normalized for body weight (Adiposity Index, AI), and percentage of body weight that is lipid. The B10.UW congenic and subcongenic strains have significantly smaller AN lengths ( p < 0.0001) and have a significantly lower AI and percentage of body weight as fat than the background strain ( p < 0.0001). In an F(2) intercross of the congenic and background strains, AN and AI were both linked to the distal half of the donor region with LOD scores greater than 19 and 5, respectively. F(2) haplotypes identified a minimal region for AN linkage of 0.8 megabases (Mb) that is estimated to express four genes in the current Celera mouse genome assembly. We narrowed the most likely location of the obesity gene to 15 Mb whose homologous genes are all located on human Chr 20 in the region surrounding the centromere. Since a previous study identified human obesity linkage peaking near the centromere, then the B10.UW mice may exhibit obesity due to the homologous gene.

Animals↗

PubMed2004

Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in Utah pedigrees.

BACKGROUND: Serum creatinine and creatinine clearance are used as indicators of renal function and may indicate a propensity for development of end-stage renal disease. Identifying genes related to future decreases in renal function could be important in assessing risk and defining abnormal mechanisms amenable to preventive measures. Although creatinine clearance is a better measure of renal function than serum creatinine, proper and complete urine collections in large population studies are sometimes problematic. This can lead to a loss in power to detect linkage. Therefore, in this study we also investigated serum creatinine and estimated glomerular filtration rates (GFR), both of which are more reliably measured. METHODS: Linkage was tested in a genome scan using 49 large Utah pedigrees examined three times over 10 years to detect regions harboring genes related to reduced renal function. RESULTS: Heritability of serum creatinine ranged from 25% to 31% across three examinations, and heritability of GFR ranged from 37% to 42%. The highest log of the odds (LOD) score for serum creatinine was found on chromosome 2 at 145 cM on the Marshfield map (D2S1334). Consistent nonparametric linkage for serum creatinine was found for all three examinations (LOD = 3.15, 2.75, and 2.00, respectively). Estimates of GFR also showed linkage to this region. CONCLUSIONS: The consistency of linkage to chromosome 2 over longitudinally repeated measurements increases the likelihood that this region harbors a gene influencing phenotypic variation in serum creatinine and GFR. Identification of this gene could help to predict which individuals are most likely to progress to renal disease.

Adult↗

PubMed2004

Genome-wide linkage analyses for age at diagnosis of hypertension and early-onset hypertension in the HyperGEN study.

A genome-wide scan was performed to identify chromosomal regions related to age at diagnosis of hypertension and to early-onset hypertension in white and African American families from the Hypertension Genetic Epidemiology Network (HyperGEN). Age at diagnosis of hypertension was reported by participants at recruitment and standardized residuals adjusted for sex, study center, and body mass index were created. Participants were classified as having early-onset hypertension if their reported age at diagnosis was before 45 years in whites or before 35 years in African Americans. Variance component linkage analysis was performed for age at diagnosis and an affected sibpair linkage analysis was performed for early-onset hypertension, both implemented in GENEHUNTER. In whites, the heritability of diagnosis age was estimated to be 35% and the maximum LOD score was found on chromosome 1 at 123 cM (LOD = 1.48). The maximum LOD score for early-onset hypertension was located on chromosome 18 at 69 cM (LOD = 1.21). In African Americans, the heritability of age of diagnosis was estimated to be 42% and the maximum LOD scores were found on chromosome 4 at 120 cM (LOD = 2.44) and on chromosome 15 at 60 cM (LOD = 2.31). The maximum LOD for early-onset hypertension in African Americans was also on chromosome 4 at 153 cM (LOD = 2.05) and overlies the mineralocorticoid receptor. Although these results report modest LOD scores, several of these loci have been previously reported to be linked to hypertension and blood pressure, lending further support that genes related to the risk of hypertension may be at these loci.

Adult↗

PubMed2004

TXNIP gene not associated with familial combined hyperlipidemia in the NHLBI Family Heart Study.

Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, and is implicated in up to 20% of cases of premature coronary heart disease. Positive linkage to chromosome 1q was found in FCHL families participating in the NHLBI Family Heart Study (FHS), replicating linkage found in other studies. The HcB-19 mouse, which shares phenotypes with FCHL, was shown in other studies to have a nonsense mutation in the thioredoxin interacting protein gene (txnip). txnip is a gene on mouse chromosome 3 in a region syntenic with the 1q human FCHL linkage region. We re-sequenced the human homolog of mouse txnip in the FHS sample and identified nine single nucleotide polymorphisms (SNPs). We did not observe the nonsense mutation found in the HcB-19 mouse, and only three of the SNPs discovered were sufficiently polymorphic for analysis. No association between FCHL and the TXNIP gene was found. Within FCHL cases, presence of variants also did not significantly affect body mass index or levels of lipids, insulin, or glucose. Our results suggest that in this sample, TXNIP does not play a major role in FCHL or related traits, and is unlikely to account for the positive evidence of linkage in this region.

Adult↗