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ABSTRACT: Nearly one-third of adults in the United States have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment study and using a case-only design, we examined whether single-nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure (HF) in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca(+2) in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on HF, the strongest of which was for rs877087, with the smallest P-value=0.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3058 CHD cases and 1940 HF cases show that a hypertensive patient's genetic profile may help predict which medication(s) might better lower CVD risk.The Pharmacogenomics Journal advance online publication, 5 June 2012; doi:10.1038/tpj.2012.22.
The Pharmacogenomics Journal 06/2012; · 4.54 Impact Factor
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ABSTRACT: Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (angiotensin-converting enzyme (ACE) insertion/deletion (I/D); angiotensinogen (AGT) -6G-A, M235T, -20A-C) in the renin-angiotensin system on left ventricular mass (LVM) among hypertensive participants in the Hypertension Genetic Epidemiology Network study. Included were 2156 participants aged 20-87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: adjusted mean LVM (gm(-2.7)) increased with 'G' allele copy number ('AA':41.2, 'AG':42.3, 'GG':44.0; P=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction P=0.03): among ACE 'DD' participants, AGT -20A-C 'C' allele carriers had lower mean LVM than 'AA' homozygotes ('DD/CC':39.2, 'DD/AC':39.9, 'DD/AA':43.9), with no similar significant effect among ACE 'I' allele carriers ('ID/CC':47.2, 'ID/AC':43.4, 'ID/AA':42.6; 'II/CC': NA, 'II/AC':41.3, 'II/AA':43.1). These findings indicate that renin-angiotensin system variants in at least two genes may interact to modulate LVM.
Journal of human hypertension 01/2011; 26(2):133-40. · 2.80 Impact Factor
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Paul Adams,
James C Barton,
Gordon D McLaren,
Ronald T Acton,
Mark Speechley,
Christine E McLaren,
David M Reboussin,
Catherine Leiendecker-Foster,
Emily L Harris,
Beverly M Snively,
Thomas Vogt,
Phyliss Sholinsky,
Elizabeth Thomson,
Fitzroy W Dawkins,
Victor R Gordeuk, John H Eckfeldt
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ABSTRACT: The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.
A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.
Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects.
Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 11/2009; 23(11):769-72. · 1.21 Impact Factor
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ABSTRACT: Hemoglobin (Hb) levels and mean corpuscular volume (MCV) are abnormal in some persons with hemochromatosis or thyroid disorders. We sought to determine whether serum free thyroxine (T4) affects erythrocyte measures in euthyroid adults with or without C282Y homozygosity. We evaluated 488 white HFE C282Y homozygotes and controls (no HFE C282Y or H63D; normal serum iron measures) identified in screening; we excluded those with thyroid disorders, anemia, erythrocytosis, or serum ferritin (SF) <34 pmol/l. In the remaining 141 C282Y homozygotes and 243 controls, we evaluated correlations of log(10) free T4 with Hb, RBC, MCV, and red blood cell distribution width (RDW). C282Y homozygotes had lower mean age, higher mean Hb, MCV, and log(10) SF, and lower mean RBC and RDW than controls; mean log(10) free T4 did not differ significantly. In HFE C282Y homozygotes, there was no significant correlation of log(10) T4 with erythrocyte measures. In controls, there was a positive correlation of log(10) T4 with Hb (P = 0.0096) and a negative correlation with RDW (P = 0.0286). Among euthyroid white adults without iron deficiency, there are significant correlations of log(10) free T4 with Hb and RDW in controls, but not in HFE C282Y homozygotes.
International journal of laboratory hematology 09/2009; 32(3):282-7. · 1.30 Impact Factor
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P C Adams,
D M Reboussin,
J C Barton,
R T Acton,
M Speechley,
C Leiendecker-Foster,
R Meenan,
L Passmore,
C E McLaren,
G D McLaren,
V Gordeuk,
F Dawkins, J H Eckfeldt
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ABSTRACT: Hemochromatosis has often been associated with progressive iron overload, but the natural history of iron accumulation in untreated C282Y homozygotes has been reported infrequently. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101 168 primary care participants for iron overload using transferrin saturation, unbound iron-binding capacity, Serum ferritin (SF), and HFE C282Y and H63D genotyping. SF was measured at initial screening (IS) and again when selected participants returned for a clinical examination (CE). The change in SF over the observation period (defined as ferritin rate of change) was analyzed according to age, gender, initial SF, initial SF/age, transferrin saturation, and iron removed by phlebotomy in C282Y homozygotes. Seventy-four male and 133 female untreated C282Y homozygotes were observed over a median of 112 days (34-924 days) between IS and CE. In men, SF increased in 54% and decreased in 46%. In women, SF increased in 50% and decreased in 50%. The significant variables affecting the SF rate were initial log SF (P = 0.0027) and transferrin saturation (P < 0.0001). Male C282Y homozygotes with higher SF rates (n = 27, upper 50th percentile) had significantly greater iron removed by phlebotomy (mean 4.93 g, range 1.0-17 g) than those with lower SF rates (n = 26, lower 50th percentile) (mean 2.6 g, 0.42-7.1, P < 0.05). SF was as likely to decrease as increase in untreated C282Y homozygotes over this relatively brief observation period. Incremental increases in SF are not inevitable in untreated C282Y homozygotes.
International Journal of Laboratory Hematology 09/2008; 30(4):300-5. · 1.18 Impact Factor
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J B Wilk,
J M Laramie,
J C Latourelle,
S Williamson,
M W Nagle,
J E Tobin,
C L Foster, J H Eckfeldt,
M A Province,
I B Borecki,
R H Myers
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ABSTRACT: The NHLBI Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q with a logarithm of odds score of 4.9 for body mass index (BMI).
We report the results of fine mapping the linkage peak using 1020 single nucleotide polymorphisms (SNPs) to test for association to obesity in families exhibiting linkage to chromosome 7. Association observed in linked families (284 obese cases/381 controls) was examined in an independent set of unrelated FHS participants (172 obese cases/308 controls) to validate the observed association. Two dichotomous obesity phenotypes were studied based on clinical BMI cutoffs and the sex-specific distribution of both BMI and leptin levels.
Using a P-value of 0.01 as criteria for association in the linked families, a P-value of 0.05 as criteria for association in the unrelated sample, and requiring consistency in the direction of the effect of the minor allele between the two samples, we identified two coding SNPs in the NYD-SP18 gene with minor alleles increasing the risk of obesity. Adjustment for exercise, smoking and FTO genotype did not influence the result in linked families, but improved the result in the unrelated sample. Carrying a minor allele of the nonsynonymous SNP rs6971091 conferred an odds ratio of at least 2 for obesity defined by both BMI and leptin levels.
The effect of the NYD-SP18 SNP on obesity was larger than the effect of FTO in FHS families. Publicly available results from genome-wide association studies support the association between NYD-SP18 and BMI. The NYD-SP18 gene is described as testes development related, but little is known about the gene's function or the mechanism by which it may influence risk for obesity.
International journal of obesity (2005) 07/2008; 32(6):930-5. · 4.34 Impact Factor
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ABSTRACT: Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age-sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD)=3.5 at 78 cM, P=0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD=1.8 at 128 cM, P=0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.
Genes and Immunity 01/2008; 8(8):684-90. · 3.87 Impact Factor
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ABSTRACT: Research suggests pulse pressure (PP) is a predictor of cardiovascular disease, and genes likely influence PP levels. Additionally, gender may be an effect modifier between PP and cardiovascular disease. This study addresses whether two renin-angiotensin-aldosterone system (RAAS) variants are associated with PP in a sex-specific manner (genotype-by-sex interaction). Subjects comprised 35,048 GenHAT study participants over 55 years old, approximately half were women and half non-Hispanic white. Blood pressure measurements were obtained 6 months after randomization to one of four antihypertensive medications. The polymorphisms considered were AGT-6 and ACE-I/D. We employed linear regression to assess the interaction. AGT-6 showed a significant (p < 0.001) genotype-by-sex interaction. Men with the 'G/G' genotype had a higher PP (0.6 mm HG) than men carrying an 'A' allele, while 'G/G' women had a lower PP (0.7 mm Hg) than women carrying an 'A' allele. Three of the four treatment groups (chlorthalidone, amlodipine and lisinopril) suggested a consistent interaction in sub-group analyses (only amlodipine was statistically significant, p < 0.001), whereas doxazosin did not. The interaction was evident among non-Hispanic participants but not among Hispanic participants. For ACE-I/D no evidence for a genotype-by-sex interaction was detected. This finding of genotype-by-sex interaction on PP helps our understanding of the complexity of genetic effects on blood pressure.
Annals of Human Genetics 12/2007; 71(Pt 6):735-45. · 2.57 Impact Factor
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R T Acton,
B M Snively,
J C Barton,
C E McLaren,
P C Adams,
S S Rich, J H Eckfeldt,
R D Press,
P Sholinsky,
C Leiendecker-Foster,
G D McLaren,
M R Speechley,
E L Harris,
F W Dawkins,
V R Gordeuk
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ABSTRACT: Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.
Clinical Genetics 06/2007; 71(6):518-29. · 3.13 Impact Factor
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ABSTRACT: In a double-blind, outcome trial conducted in hypertensive patients randomized to chlorthalidone (C), amlodipine (A), lisinopril (L), or doxazosin (D), the alpha-adducin Gly460Trp polymorphism was typed (n=36 913). Mean follow-up was 4.9 years. Relative risks (RRs) of chlorthalidone versus other treatments were compared between genotypes (Gly/Gly+Gly/Trp versus Trp/Trp). Primary outcome was coronary heart disease (CHD). Coronary heart disease incidence did not differ among treatments or genotypes nor was there any interaction between treatment and genotype (P=0.660). Subgroup analyses indicated that Trp allele carriers had greater CHD risk with C versus A+L in women (RR=1.31) but not men (RR=0.91) with no RR gender differences for non-carriers (gender-gene-treatment interaction, P=0.002). The alpha-adducin gene is not an important modifier of antihypertensive treatment on cardiovascular risk, but women Trp allele carriers may have increased CHD risk if treated with C versus A or L. This must be confirmed to have implications for hypertension treatment.
The Pharmacogenomics Journal 05/2007; 7(2):112-22. · 4.54 Impact Factor
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ABSTRACT: To prospectively investigate the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid (FA) composition with incidence of coronary heart disease (CHD).
3,591 white participants in the Minneapolis field center of the Atherosclerosis Risk in Communities Study, aged 45-64 years, were studied. Plasma FA composition of CEs and PLs was quantified using gas-liquid chromatography and expressed as percentage of total FAs. Incident CHD was identified during 10.7 years of follow-up. In both CE and PL fractions, the proportions of stearic (18:0) acid, dihomo-gamma-linolenic (20:3n6) acid and total saturated fatty acids (SFAs) were significantly higher while arachidonic (20:4n6) acid and total polyunsaturated fatty acids (PUFAs) were significantly lower among participants who developed incident CHD (n = 282). After adjusting for age, gender, smoking, alcohol drinking, sports activity, and non-FA dietary factors, the incidence of CHD was significantly and positively associated with the proportion of dihomo-gamma-linolenic acid but inversely associated with arachiadonic acid. The multiply-adjusted rate ratios (RRs) of CHD incidence for the highest versus the lowest quintile were 1.31 in CE and 1.44 in PL for dihomo-gamma-linolenic acid (p for trend: 0.05 and 0.017, respectively), 0.59 in CE and 0.65 in PL for arachidonic acid (p: 0.016 and 0.024, respectively). Also significantly and positively associated with incident CHD were PL stearic acid and CE linolenic (18:3n3) acid. Only a borderline significant positive association was observed for total SFAs in CE (multivariate RRs across quintiles: 1.00, 1.15, 1.40, 1.62, 1.32; p = 0.07). Total PUFAs or monounsaturated FA were not independently associated with CHD.
Our study found a weak positive association of SFAs with incident CHD. Our findings also confirm that FA metabolism in the body, such as the activity of delta-5 desaturase, which converts dihomo-gamma-linolenic acid to arachidonic acid, may affect the development of CHD.
Nutrition Metabolism and Cardiovascular Diseases 11/2003; 13(5):256-66. · 3.73 Impact Factor
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ABSTRACT: Full genome scans were performed for quantitative lipid measurements in 622 African American and 649 white sibling pairs not taking lipid-lowering medications who were ascertained through the Hypertension Genetic Epidemiology Network (HyperGEN) of the National Heart, Lung, and Blood Institute (NHLBI) Family Blood Pressure Program. Genotypes for 391 markers spaced roughly equally throughout the genome were typed by the NHLBI Mammalian Genotyping Service. Each of the phenotypes was adjusted for covariates within sex and race and then subjected to variance components linkage analysis, which was performed separately within race by using race-specific marker allele frequencies from additional random samples. The highest lod score detected was 2.77 for logarithmically transformed triglyceride (TG) on chromosome 20 (at 28.6 cM) in the African American sibling pairs. The highest score detected in the white sibling pairs was 2.74 for high density lipoprotein cholesterol on chromosome 5 (at 48.2 cM). Although no scores >3.0 were obtained, positive scores were found in several regions that have been reported in other genome scans in the literature. For example, a score of 1.91 for TG was found on chromosome 15 (at 28.8 cM) in white sibling pairs. This score overlaps the positive findings for TG in 2 other genome scans.
Arteriosclerosis Thrombosis and Vascular Biology 01/2002; 21(12):1969-76. · 6.37 Impact Factor
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ABSTRACT: Epidemiologic studies suggest that a higher consumption of eicosapentaenoic acid and docosahexaenoic acid is associated with a reduced risk of cardiovascular disease. Studies in humans and animals also reported an inverse association between alpha-linolenic acid and cardiovascular disease morbidity and mortality.
We examined the relation between dietary linolenic acid and prevalent coronary artery disease (CAD).
We studied 4584 participants with a mean (+/-SD) age of 52.1 +/- 13.7 y in the National Heart, Lung, and Blood Institute Family Heart Study in a cross-sectional design. Participants' diets were assessed with a semiquantitative food-frequency questionnaire. For each sex, we created age- and energy-adjusted quintiles of linolenic acid, and we used logistic regression to estimate prevalent odds ratios for CAD.
From the lowest to the highest quintile of linolenic acid, the prevalence odds ratios of CAD were 1.0, 0.77, 0.61, 0.58, and 0.60 for the men (P for trend = 0.012) and 1.0, 0.57, 0.52, 0.30, and 0.42 for the women (P for trend = 0.014) after adjustment for age, linoleic acid, and anthropometric, lifestyle, and metabolic factors. Linoleic acid was also inversely related to the prevalence odds ratios of CAD in the multivariate model (0.60 and 0.61 in the second and third tertiles, respectively) after adjustment for linolenic acid. The combined effect of linoleic and linolenic acids was stronger than the individual effects of either fatty acid.
A higher intake of either linolenic or linoleic acid was inversely related to the prevalence odds ratio of CAD. The 2 fatty acids had synergistic effects on the prevalence odds ratio of CAD.
American Journal of Clinical Nutrition 12/2001; 74(5):612-9. · 6.67 Impact Factor
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ABSTRACT: Recent prospective studies have demonstrated that elevated C-reactive protein (CRP) is a marker of increased risk of atherothrombotic clinical events. We examined in a large, cross-sectional family-based study (n = 875 men, 948 women) whether serum CRP was associated with prevalent coronary heart disease (CHD), the ankle/brachial blood pressure index, or carotid intima-media thickness, an indicator of subclinical atherosclerosis as assessed by B-mode ultrasound. CRP was associated with many other cardiovascular risk factors, particularly markers of obesity and insulin resistance, markers of inflammation and acute phase reaction, and hormone replacement therapy. Adjusted for age and family type, there was a weak positive association of CRP with carotid intima-media thickness in both genders and with prevalent CHD in women. However, adjustment for other risk factors completely eliminated the associations. For example, among women, the risk factor-adjusted mean values of intima-media thickness across quartiles of CRP were 0.76, 0.74, 0.75, and 0.76 mm (p >0.5). In men there was a weak inverse association between CRP and ankle/brachial blood pressure index, independent of other risk factors, but no such association in women. Our findings indicate that CRP is not strongly and independently associated with prevalent atherosclerosis. Because CRP has been associated with clinical events, it could be that elevated CRP may be a stronger marker of thrombotic risk than of the degree of atherosclerosis.
The American Journal of Cardiology 08/2001; 88(2):112-7. · 3.37 Impact Factor
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ABSTRACT: A common mutation in methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is associated with reduced enzyme activity, a thermolabile enzyme and mild hyperhomocysteinemia, a risk factor for vascular disease. Recently, a second common mutation (1298A-->C; glutamate to alanine) was reported, but this mutation was suggested to increase homocysteine only in individuals who carried the bp677 variant. To evaluate the functional consequences of this mutation, we performed site-directed mutagenesis and in vitro expression. For in vivo assessment of clinical impact, we examined the 1298A-->C genotypes and plasma homocysteine in 198 individuals from the NHLBI Family Heart Study that had previously been assessed for the 677 substitution. Site-directed mutagenesis of the human cDNA was performed to generate enzymes containing each of the two mutations, as well as an enzyme containing both substitutions. Enzyme activity and thermolability were assessed in bacterial extracts. The activity of the wild-type cDNA was designated as 100%; mutant enzymes containing the 1298 and 677 mutations separately had 68% (+/-5.0) and 45% (+/-10.8), respectively, of control activity while the enzyme containing both mutations had 41% (+/-12.8) of control activity. The 1298 mutation was not associated with a thermolabile enzyme. In the Family Heart Study, fasting homocysteine was significantly higher (P<0.05) in individuals heterozygous for both substitutions, compared to individuals who carried only the 677C-->T variant. This study suggests that two variants in MTHFR should be assessed as genetic risk factors for hyperhomocysteinemia.
Atherosclerosis 06/2001; 156(2):409-15. · 3.79 Impact Factor
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ABSTRACT: Increased iron stores may play a role in the development of coronary heart disease (CHD) by increasing lipoprotein oxidation. Recently, mutations have been discovered in the gene (HFE) for hereditary hemochromatosis, an autosomal recessive condition of disordered iron metabolism, absorption, and storage. It is possible that people who carry HFE mutations have increased risk of CHD. We used a prospective case-cohort design (243 CHD cases and 535 non-cases) to determine whether the HFE C282Y mutation was associated with incident CHD in a population-based sample of middle-aged men and women. The frequencies of homozygosity and heterozygosity for the C282Y mutation in the ARIC study population were 0.2% (one homozygous person) and 6%, respectively. The C282Y mutation was associated with nonsignificantly increased risk of CHD (relative risk=1.60, 95% CI 0.9-2.9). After adjusting for other confounding risk factors (age, race, gender, ARIC community, smoking status, diabetes status, hypertension status, LDL cholesterol, HDL cholesterol, and triglycerides), the association became stronger (relative risk=2.70, 95% CI 1.2-6.1). However, a sensitivity analysis showed that this estimate of relative risk was somewhat unstable due to few subjects in some strata. Our prospective findings suggest that individuals carrying the HFE C282Y mutation may be at increased risk of CHD.
Atherosclerosis 03/2001; 154(3):739-46. · 3.79 Impact Factor
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ABSTRACT: Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35-40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13-30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.
Atherosclerosis 03/2001; 154(3):681-9. · 3.79 Impact Factor
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ABSTRACT: Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 micromol/l) and 140 females (9.3 micromol/l, P<0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio=0.93 for a 1 micromol/l increase in bilirubin, P=0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect (h2=0.33, P=0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.
Atherosclerosis 02/2001; 154(3):747-54. · 3.79 Impact Factor
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ABSTRACT: Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.
Blood Coagulation and Fibrinolysis 10/2000; 11(6):551-8. · 1.24 Impact Factor
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R R Williams,
D C Rao,
R C Ellison,
D K Arnett,
G Heiss,
A Oberman, J H Eckfeldt,
M F Leppert,
M A Province,
S C Mockrin,
S C Hunt
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ABSTRACT: Hypertension is a common precursor of serious disorders including stroke, myocardial infarction, congestive heart failure, and renal failure in whites and to a greater extent in African Americans. Large genetic-epidemiological studies of hypertension are needed to gain information that will improve future methods for diagnosis, treatment, and prevention of hypertension, a major contributor to cardiovascular morbidity and mortality.
We report successful implementation of a new structure of research collaboration involving four NHLBI "Networks," coordinated under the Family Blood Pressure Program. The Hypertension Genetic Epidemiology Network (HyperGEN) involves scientists from six universities and the NHLBI who seek to identify and characterize genes promoting hypertension. Blood samples and clinical data were projected to be collected from a sample of 2244 hypertensive siblings diagnosed before age 60 from 960 sibships (half African-American) with two or more affected persons. Nonparametric sibship linkage analysis of over one million genotype determinations (20 candidate loci and 387 anonymous marker loci) was projected to have sufficient power for detecting genetic loci promoting hypertension. For loci showing evidence for linkage in this study and for loci reported linked or associated with hypertension by other groups, genotypes are compared in hypertensive cases versus population-based controls to identify or confirm genetic variants associated with hypertension. For some of these genetic variants associated with hypertension, detailed physiological and biochemical characterization of untreated adult offspring carriers versus non-carriers may help elucidate the pathophysiological mechanisms that promote hypertension.
The projected sample size of 2244 hypertensive participants was surpassed, as 2407 hypertensive individuals (1262 African-Americans and 1145 whites) from 917 sibships were examined. Detailed consent forms were designed to offer participants several options for DNA testing; 94% of participants gave permission for DNA testing now or in the future for any confidential medical research, with only 6% requesting restrictions for tests performed on their DNA. Since this is a family study, participants also are asked to list all first degree relatives (along with names, addresses, and phone numbers) and to indicate for each relative whether they were willing to allow study staff to make a contact. Seventy percent gave permission to contact some relatives; about 30% gave permission to contact all first degree relatives; and less than 1% asked that no relatives be contacted. Successes after the first four years of this study include: 1) productive collaboration of eight centers from six different locations; 2) early achievement of recruitment goals for study participants including African-Americans; 3) an encouraging rate of consent for DNA testing (including future testing) and relative contacting; 4) completed analyses of genetic linkage and association for several candidate gene markers and polymorphisms; 5) completed genotyping of random markers for over half of the full sample; and 6) early sharing of results among the four Family Blood Pressure Program networks for candidate and genome search analyses.
Experience after four years of this five-year program (1995-2000) suggests that the newly initiated NHLBI Network Program mechanism is fulfilling many of the expectations for which it was designed. It may serve as a paradigm for future genetic research that can benefit from large sample sizes, frequent sharing of ideas among laboratories, and prompt independent confirmation of early findings, which are required in the search for common genes with relatively small effects such as those that predispose to human hypertension.
Annals of Epidemiology 09/2000; 10(6):389-400. · 3.21 Impact Factor
