Biomedical subjects

Eric Boerwinkle

Publications and source records attributed to Eric Boerwinkle.

At least 37 records · Page 2Linked to original sources

PubMed2006

Family-based association study of matrix metalloproteinase-3 and -9 haplotypes with susceptibility to ischemic white matter injury.

Susceptibility to ischemic damage to the subcortical white matter of the brain has a strong genetic basis. Dysregulation of matrix metalloproteinases (MMPs) contributes to loss of cerebrovascular integrity and white matter injury. We investigated whether sequence variation in the genes encoding MMP3 and MMP9 is associated with variation in leukoaraiosis volume, determined by magnetic resonance imaging, in non-Hispanic whites and African-Americans using family-based association tests. Seven hundred and fifty-six white and 671 African-American individuals from sibships ascertained through two or more siblings with hypertension were genotyped for 7 and 8 haplotype-tagging polymorphisms in the MMP3 and MMP9 genes, respectively. MMP3 sequence variation was significantly associated with variation in leukoaraiosis volume in Whites. Two common haplotypes with opposing relationships to leukoaraiosis volume were identified. MMP9 sequence variation was also significantly associated with variation in leukoaraiosis volume in both African-Americans and Whites. Different haplotypes contributed to these associations in the two racial groups. These findings add to the growing body of evidence from animal models and human clinical studies suggesting a role of MMPs in ischemic white matter injury. They provide the basis for further investigation of the role of these genes in susceptibility and/or progression to clinical disease.

Black or African American↗

PubMed2006

Measuring marker information content by the ambiguity of block boundaries observed in dense SNP data.

Recent studies have noted that the boundary of common haplotype blocks in hapmap constructions involve a certain degree of ambiguity, and so do the resulting "tagSNPs". Here, we report how to address this issue at the level of individual SNP markers. We introduce a measure called the marker ambiguity score (MAS), and evaluate its utility by simulation studies based on a real dataset of 2949 SNPs spanning a region of 56.1M bp. We show that the MAS method can be used to assess the level of boundary ambiguity caused by varying ethnic background, sample sizes for hapmap construction, and disease aggregation. We find a striking difference in overall patterns of block boundary distributions in two ethnic groups (blacks and whites), and subtle changes in block structures that agree with the evolutionary history of the two populations. Our analyses suggest that a sample size of 200 or more subjects is probably needed for "stable" hapmap constructions. In addition, we demonstrate that there are subtle changes in block boundaries in hapmaps constructed in disease populations versus normal controls. This approach can quantify the information content of individual markers in the context of highly dense SNP data, which may have important implications in designing efficient genome-wide association mapping projects.

Computer Simulation↗

PubMed2006

Apolipoprotein E genotype and gallbladder disease risk in a large population-based cohort.

PURPOSE: The aim of the study is to describe the association between apolipoprotein E (apoE) genotype and gallbladder disease incidence. METHODS: Cases of incident hospitalized gallbladder disease were ascertained in nearly 13,000 middle-aged men and women participating in the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort study in four US communities. RESULTS: Between the ARIC baseline examination (1987 to 1989) and December 31, 2001, a total of 639 participants were hospitalized for gallbladder disease. After adjustment for age, sex, race, obesity, plasma lipid level, and diabetes, the relative risk for hospitalized gallbladder disease associated with the presence of an epsilon4 allele (i.e., genotypes E4/4, E3/4, and E2/4 versus other genotypes) was 0.72 (95% confidence interval [CI], 0.60-0.87). Stratification by race showed that the inverse association with epsilon4 was stronger in whites (relative risk, 0.69; 95% CI, 0.56-0.85) than African Americans (relative risk, 0.86; 95% CI, 0.58-1.30). The presence of the other rare isoform, epsilon2 (i.e., genotypes E2/2, E2/3, and E2/4 versus others) was associated with a modest increased risk for gallbladder disease (relative risk, 1.28; 95% CI, 1.05-1.57). CONCLUSIONS: These results suggest that independent of traditional risk factors, apoE genotype may influence gallbladder disease risk, particularly in whites. The exact biologic mechanism for such an association remains unclear and requires further investigation.

Apolipoproteins E↗

PubMed2006

Genome-wide linkage scans for loci affecting total cholesterol, HDL-C, and triglycerides: the Family Blood Pressure Program.

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD=3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD=3.0 at 182 cM) and 12 (LOD=3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD >or= 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.

Adult↗

PubMed2006

An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study.

BACKGROUND: There has been interest in recent years in whether additional, and in particular novel, risk factors or blood markers, such as C-reactive protein, can enhance existing coronary heart disease (CHD) prediction models. METHODS: Using a series of case-cohort studies, the prospective Atherosclerosis Risk in Communities (ARIC) Study assessed the association of 19 novel risk markers with incident CHD in 15,792 adults followed up since 1987-1989. Novel markers included measures of inflammation, endothelial function, fibrin formation, fibrinolysis, B vitamins, and antibodies to infectious agents. Change in the area under the receiver operating characteristic curve (AUC) was used to assess the additional contribution of novel risk markers to CHD prediction beyond that of traditional risk factors. RESULTS: The basic risk factor model, which included traditional risk factors (age, race, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes), predicted CHD well, as evidenced by an AUC of approximately 0.8. The C-reactive protein level did not add significantly to the AUC (increase in AUC of 0.003), and neither did most other novel risk factors. Of the 19 markers studied, lipoprotein-associated phospholipase A(2), vitamin B(6), interleukin 6, and soluble thrombomodulin added the most to the AUC (range, 0.006-0.011). CONCLUSIONS: Our findings suggest that routine measurement of these novel markers is not warranted for risk assessment. On the other hand, our findings reinforce the utility of major, modifiable risk factor assessment to identify individuals at risk for CHD for preventive action.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2006

Influence of genomic loci on measures of chronic kidney disease in hypertensive sibships.

Genomewide linkage analyses were conducted of serum creatinine, estimated GFR (eGFR), and urine albumin-creatinine ratio (UACR) in search of genetic susceptibility loci for chronic kidney disease in 1351 black (median age 63 yr, 70% women, 79% hypertensive) and 1022 white individuals (median age 61 yr, 56% women, 75% hypertensive) from sibships in which two or more members had essential hypertension diagnosed before age 60 yr. After adjustment for gender, age, diabetes, and use of angiotensin inhibitors, the logarithm-transformed measure of serum creatinine was heritable in both ethnic groups (0.45 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]), as was eGFR (0.52 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]). Log UACR was heritable in black individuals (0.30, P < 0.001) but not in white individuals (0.12; P = 0.059). In black individuals, the univariate maximum multipoint logarithm of odds scores (MLS) were observed on chromosome 7 for log serum creatinine (MLS = 3.65, at 43 cM from pter; P = 0.00002) and eGFR (MLS = 2.52, at 45 cM from pter; P = 0.00033) and for log UACR (MLS = 2.91, at 112 cM from pter; P = 0.00012). In white individuals, only one MLS for log serum creatinine and one for eGFR achieved the logarithm of odds score criterion for "suggestive" evidence of linkage (2 < or = MLS < 3), both on chromosome 3 (at 211 and 209 cM, respectively); however, none did so for log UACR. In black individuals, bivariate linkage analyses of log serum creatinine and pulse pressure (i.e., systolic-diastolic BP) provided "suggestive" evidence of a region on chromosome 5 with pleiotropic effects on both traits (MLS = 3.62, at 85 cM from pter; P = 0.00023). These findings support the utility of genetic linkage analyses for identification of novel risk factors that influence measures of chronic kidney disease, particularly among black individuals.

Black or African American↗

PubMed2006

Consistent effects of genes involved in reverse cholesterol transport on plasma lipid and apolipoprotein levels in CARDIA participants.

OBJECTIVE: To identify common variations in genes in the reverse cholesterol transport pathway with nongender-specific influence on plasma lipid and apolipoprotein levels. METHODS AND RESULTS: An average of 5 single nucleotide polymorphisms (SNPs) were genotyped within each of 45 genomic regions (54 genes) in blacks (1131 females and 812 males) and whites (1102 females and 954 males) from the Coronary Artery Risk Development in Young Adults (CARDIA) study. SNPs and gene-based 3-SNP haplotypes were evaluated for their ability to predict variation in plasma apolipoproteins (apo) A-I and apoB, total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides (TG). We identified 14 SNPs in 6 candidate gene regions that explained statistically significant variation in the same trait in both genders of at least one race and with evidence of consistent genotype mean trend across gender within race. Haplotype analyses identified 9 candidate gene regions that explained statistically significant variation in one or both races. CONCLUSIONS: Four gene regions, ABCA1, APOA1/C3/A4/A5, APOE/C1/C4/C2, and CETP, explained plasma lipoprotein variation most consistently across strata. Other gene regions that influence plasma lipid and apolipoprotein levels within race include CYP7A1, LPL, PPARA, SOAT1, and SREBF2.

ATP Binding Cassette Transporter 1↗

PubMed2006

Apolipoprotein E polymorphisms predict low density lipoprotein cholesterol levels and carotid artery wall thickness but not incident coronary heart disease in 12,491 ARIC study participants.

Elevated levels of low density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease, and recent advancements have provided evidence that carotid artery intima-media thickness (IMT) is associated with increased occurrence of cardiovascular events. Apolipoprotein E (ApoE) has been widely studied in regard to its role in lipid transport and metabolism, but the role that ApoE genetic variation plays in relation to carotid artery IMT and risk of incident coronary heart disease remains a subject of debate. In 1987-2001, the authors examined the effect of each ApoE allele (epsilon2, epsilon3, epsilon4) on LDL cholesterol and carotid IMT, as well as the association with coronary heart disease risk, in 12,491 participants of the US Atherosclerosis Risk in Communities Study. ApoE epsilon2, epsilon3, and epsilon4 allele frequencies were determined, respectively, in Whites (0.08, 0.77, 0.15) and African Americans (0.11, 0.67, 0.22). These alleles did not predict incident coronary heart disease in either racial group. The ApoE epsilon2 allele was associated with lower LDL cholesterol and the epsilon4 allele with higher LDL cholesterol in both Whites and African Americans. The ApoE epsilon2 and epsilon4 alleles were associated with carotid IMT measures in both racial groups, but, after adjusting for lipid parameters, only the epsilon4 allele was associated with carotid IMT measures in African Americans.

Apolipoproteins E↗

PubMed2006

Novel genomic loci influencing plasma homocysteine levels.

BACKGROUND AND PURPOSE: Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. METHODS: Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63+/-10 years, 70% women) and 964 non-Hispanic whites (61+/-7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. RESULTS: Mean (+/-SD) homocysteine levels were 10.4+/-5.27 mumol/L in blacks and 10.0+/-2.84 micromol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h2=0.70) and in non-Hispanic whites (h2=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds> or =3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). CONCLUSIONS: Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2006

Evidence for consistent intragenic and intergenic interactions between SNP effects in the APOA1/C3/A4/A5 gene cluster.

OBJECTIVE: Evaluate the consistency of the contribution of interactions between single nucleotide polymorphism (SNP) genotype effects to variation in measures of lipid metabolism across ethnic strata within gender. METHODS AND RESULTS: We considered 80 SNPs within the apolipoprotein (APO) A1/C3/A4/A5 gene cluster using an over-parameterized general linear model to identify SNPs whose genotype effects combine non-additively to influence plasma levels of high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG) in a consistent manner across ethnic strata. We analyzed population-based samples of unrelated 18 to 30 year old African-Americans (n = 1,858) and European-Americans (n = 1,973) ascertained without regard to health at four field centers (Birmingham, Ala.; Chicago, Ill.; Minneapolis, Minn. and Oakland, Calif., USA) by the Coronary Artery Risk Development in Young Adults (CARDIA) study. To identify which SNP genotype effects combine non-additively we used a two-tier analysis strategy. We first required that pairs of SNPs show statistically significant non-additivity in both ethnic strata within a gender, where experiment-wise significance was evaluated using a permutation test to determine the probability of observing the number of tests significant in both ethnic strata by chance alone. Second, we required no significant evidence of heterogeneity of the relationship between the phenotype and the two SNP genotypes across ethnic strata and across field centers within each ethnic group. From this strategy we identified ten pairs of SNPs, involving thirteen SNPs, that displayed statistically significant non-additivity of SNP genotype effects on TC. Only one of these thirteen SNPs had statistically significant genotype effects that were consistent across samples. CONCLUSION: Our analyses suggest that ignoring the contribution of interactions between SNP genotype effects when modeling multi-SNP genotype-phenotype relationships may result in an underestimate of the contribution of genetic variation to variation in quantitative cardiovascular disease (CVD) risk factor traits.

Adolescent↗

PubMed2006

A genome scan for loci influencing levels and trends of lipoprotein lipid-related traits since childhood: The Bogalusa Heart Study.

Coronary heart disease is the result of life-long processes. Previous genetic linkage analyses of lipid and lipoprotein variables that can be measured throughout life have focused on a single measure at one point in time. Genome-wide linkage analyses were performed in the present study to identify loci influencing the long-term levels and trends of high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDLC) and triglycerides in a longitudinal cohort. Microsatellite markers (n=357) were typed on 779 white and 444 black siblings, ages 14-43 years. Subjects had been examined serially 2-13 times with 6963 serial observations over an average of 22 years from childhood to adulthood. Total and incremental area under the growth curves of lipid traits was calculated and used as measures for long-term levels and trends. After adjusting for age, sex and body mass index, heritability estimates of total area values for all lipid variables were higher than those of a single measurement in either childhood or adulthood. In blacks, significant linkage to LDLC incremental area (peak LOD=3.6 at 50 cM) was observed on chromosome 1; and suggestive linkage for total area of LDLC (LOD=2.9 at 21 cM) on chromosome 19. Only one suggestive linkage (LOD=2.2 at 161 cM) on chromosome 2 was identified in whites for LDLC incremental area. Other suggestive linkage (LOD> or =2.0) was noted for LDLC and HDLC in terms of either total or incremental area on chromosomes 2, 5, 7 and 15 for blacks and whites. Several lipid-related candidate genes such as low-density lipoprotein receptor (LDLR), LDL receptor-related proteins 3 and 8, ApoE, ApoAII and ApoCII are located in these regions. Linkage evidence found in this community-based study indicates that regions on these chromosomes harbor genetic loci that affect the propensity to develop dyslipidemia from childhood.

Adolescent↗

PubMed2006

Quantitative trait loci influencing low density lipoprotein particle size in African Americans.

Genomic regions that influence LDL particle size in African Americans are not known. We performed family-based linkage analyses to identify genomic regions that influence LDL particle size and also exert pleiotropic effects on two closely related lipid traits, high density lipoprotein cholesterol (HDL-C) and triglycerides, in African Americans. Subjects (n = 1,318, 63.0 +/- 9.5 years, 70% women, 79% hypertensive) were ascertained through sibships with two or more individuals diagnosed with essential hypertension before age 60. LDL particle size was measured by polyacrylamide gel electrophoresis, and triglyceride levels were log-transformed to reduce skewness. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Univariate and bivariate linkage analyses were performed using a variance components approach. LDL particle size was highly heritable (h(2) = 0.78) and significantly (P < 0.0001) genetically correlated with HDL-C (rho(G) = 0.32) and log triglycerides (rho(G) = -0.43). Significant evidence of linkage for LDL particle size was present on chromosome 19 [85.3 centimorgan (cM), log of the odds (LOD) = 3.07, P = 0.0001], and suggestive evidence of linkage was present on chromosome 12 (90.8 cM, LOD = 2.02, P = 0.0011). Bivariate linkage analyses revealed tentative evidence for a region with pleiotropic effects on LDL particle size and HDL-C on chromosome 4 (52.9 cM, LOD = 2.06, P = 0.0069). These genomic regions may contain genes that influence interindividual variation in LDL particle size and potentially coronary heart disease susceptibility in African Americans.

Adult↗

PubMed2006

Epistatic effects between two genes in the renin-angiotensin system and systolic blood pressure and coronary artery calcification.

BACKGROUND: Coronary artery calcification (CAC) is an important indicator of future coronary artery disease events. Since elevated blood pressure (BP) is an important predictor of CAC, genetic polymorphisms in the renin-angiotensin system and their interaction may play a role in explaining CAC quantity variation. MATERIAL/METHODS: As part of the Epidemiology of Coronary Artery Calcification Study, 166 asymptomatic women and 166 asymptomatic men were genotyped for the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and the -6 promoter polymorphism of the angiotensinogen (AGT) gene. We used a novel method to detect gene-gene interaction and compared it to the standard two-way analysis of variance (ANOVA) method. RESULTS: Based on a two-way ANOVA model, there was no evidence for epistasis for either systolic BP or CAC in either men or women. However, using a novel method, we found evidence of significant gene-gene interaction in systolic BP in men and gene-gene interaction in both systolic BP levels and CAC quantity in women. CONCLUSIONS: Our study demonstrates that new methods of assessing epistasis maybe important in understanding the complex genetics of systolic blood pressure as well as subclinical coronary atherosclerosis.

Adult↗

PubMed2006

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.

BACKGROUND: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. METHODS: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. RESULTS: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). CONCLUSIONS: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.

Black People↗

PubMed2006

Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: interaction with cigarette smoking.

Soluble epoxide hydrolase (EPHX2) catalyses the degradation of the vasoactive and anti-inflammatory epoxyeicosatrienoic acids and may play a role in the pathophysiology of atherosclerosis. 1337 African-Americans and 1645 Whites from the CARDIA study were genotyped for 22 and 15 EPHX2 single nucleotide polymorphisms (SNPs), respectively, to examine the associations of common EPHX2 haplotypes and genotypes with presence of coronary artery calcified plaque (CAC). The potential influence of cigarette smoking, which increases EPHX2 gene expression, on these associations was also assessed. In African-Americans, a common haplotype uniquely tagged by the R287Q polymorphism was associated with significantly greater risk for CAC (OR=1.7; 95% CI=1.04-3.0). In Whites, a common haplotype uniquely tagged by a polymorphism in Intron 11 of the gene was associated with significantly greater risk for CAC (OR=1.3; 95% CI=1.02-1.6). These haplotype-tagging polymorphisms also showed significant associations with CAC in individual SNP analyses, and these relationships were significantly modified by smoking. This detailed investigation of the association of EPHX2 genetic variation with CAC supports EPHX2's emerging role as a risk factor for atherosclerosis, whose effects are influenced by smoking.

Adolescent↗

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

Genetic variation of the renin-angiotensin system and chronic kidney disease progression in black individuals in the atherosclerosis risk in communities study.

The renin-angiotensin system (RAS) regulates BP and may affect chronic kidney disease (CKD) through induction of tissue growth and fibrosis. The angiotensinogen (AGT) promoter G(-6) allele lowers transcription and is inversely associated with hypertension. In white individuals, the A1166C 3'-UTR variant of angiotensin II type 1 receptor (AT1R) has been associated with CKD. CKD associations with these RAS genes are uncertain in high-risk black populations. A prospective population-based study of CKD risk was conducted among 3706 black individuals without severe renal dysfunction at baseline (serum creatinine > or =177 micromol/L [2.0 mg/dl] for men, > or =159 micromol/L [1.8 mg/dl] for women) to examine associations with AGT and AT1R. Incident CKD progression was defined as kidney disease hospitalization or increase in serum creatinine level > or =35 micromol/L (0.4 mg/dl) above baseline. During mean follow-up of 10.2 yr, CKD progression incidence rate (per 1000 person-years) was 8.2 (n = 312 cases). Risk was lower for AGT G(-6) carriers compared with A(-6) (incidence 6.9 versus 9.0; log-rank P = 0.03) and nonsignificantly higher among AT1R C1166 carriers. Adjusting for hypertension and major CKD risk factors, AGT G(-6)decreased risk (relative risk 0.75; 95% confidence interval 0.57 to 0.98). AT1R C1166 increased risk only among those with hypertension (relative risk 1.65; 95% confidence interval 1.14 to 2.39). The AGT G(-6)A polymorphism may play a role in CKD progression in black individuals, consistent with in vitro effects on AGT levels and renal remodeling but independent of BP. The AT1R C1166 allele may increase susceptibility but only in the presence of hypertension.

Black or African American↗

PubMed2006

Contrasting multi-site genotypic distributions among discordant quantitative phenotypes: the APOA1/C3/A4/A5 gene cluster and cardiovascular disease risk factors.

Most tests of association between DNA sequence variation and quantitative phenotypes in samples of randomly chosen individuals rely on specification of genotypic strata followed by comparison of phenotypes across these strata. This strategy often succeeds when phenotypic differences are caused by one or two single nucleotide polymorphisms (SNPs) among the surveyed markers. However, when multiple-SNP haplotypes account for observed phenotypic variation, identification of the best partitioning requires examination of an inordinate number of SNP combinations. An alternative approach is to rank individuals by their phenotypic measures and ask whether attributes of the genotypic variation show a non-random distribution along this phenotypic ranking. One simple version of this strategy selects the top and bottom tails of the distribution, and then tests whether genotypes from these two samples are drawn from a single population. This framework does not require the recovery of phased haplotypes and allows contrasts between large numbers of sites at once. We use a method based on this approach to identify associations between plasma triglyceride level, a risk factor for cardiovascular disease, and multi-site genotypes located in the APOA1/C3/A4/A5 cluster of apolipoprotein genes in unrelated individuals (1,071 African-American females, 780 African-American males, 1,036 European-American females, and 930 European-American males) sampled from four US cities as part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Method performance is investigated using simulations that model genealogical variation and different genetic architectures. Results indicate that this multi-site test can identify genotype-phenotype associations with reasonable power, including those generated by some simple epistatic models.

Adult↗