Biomedical subjects

Eric Boerwinkle

Publications and source records attributed to Eric Boerwinkle.

At least 55 records · Page 3Linked to original sources

PubMed2006

A scan statistic for identifying chromosomal patterns of SNP association.

We have developed a single nucleotide polymorphism (SNP) association scan statistic that takes into account the complex distribution of the human genome variation in the identification of chromosomal regions with significant SNP associations. This scan statistic has wide applicability for genetic analysis, whether to identify important chromosomal regions associated with common diseases based on whole-genome SNP association studies or to identify disease susceptibility genes based on dense SNP positional candidate studies. To illustrate this method, we analyzed patterns of SNP associations on chromosome 19 in a large cohort study. Among 2,944 SNPs, we found seven regions that contained clusters of significantly associated SNPs. The average width of these regions was 35 kb with a range of 10-72 kb. We compared the scan statistic results to Fisher's product method using a sliding window approach, and detected 22 regions with significant clusters of SNP associations. The average width of these regions was 131 kb with a range of 10.1-615 kb. Given that the distances between SNPs are not taken into consideration in the sliding window approach, it is likely that a large fraction of these regions represents false positives. However, all seven regions detected by the scan statistic were also detected by the sliding window approach. The linkage disequilibrium (LD) patterns within the seven regions were highly variable indicating that the clusters of SNP associations were not due to LD alone. The scan statistic developed here can be used to make gene-based or region-based SNP inferences about disease association.

Chromosome Mapping↗

PubMed2006

An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP).

A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.

Adult↗

PubMed2006

A comparison of serum creatinine-based methods for identifying chronic kidney disease in hypertensive individuals and their siblings.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) equation is often used to determine an estimated glomerular filtration rate (eGFR) from serum creatinine. This study compared kidney disease as defined by reduced eGFR, elevated serum creatinine, or elevated urinary albumin-to-creatinine ratio (ACR). METHODS: As part of the Genetic Epidemiology Network of Arteriopathy study, a community-based sample was ascertained through sibships having at least two members with essential hypertension. Kidney disease was defined by reduced eGFR (<60 mL/min/1.73 m(2)), elevated serum creatinine (>97.5(th) percentile for sex-specific normal individuals), or elevated ACR (>95(th) percentile for sex-specific normal individuals). RESULTS: The sample (n = 2653) was 65% female, 61% African American, and 77% hypertensive, with a mean (+/- SD) age of 61 +/- 10 years. There was greater agreement between kidney disease defined by elevated ACR and an elevated serum creatinine level (kappa = 0.19) than between kidney disease defined by elevated ACR and a reduced eGFR (kappa = 0.07). The multivariable-adjusted odds ratio of kidney disease for male versus female sex was 0.92 (95% CI, 0.75 to 1.12) by reduced eGFR, but was 2.08 (95% CI, 1.62 to 2.67) by elevated serum creatinine and 2.11 (95% CI, 1.63 to 2.74) by elevated ACR. The multivariable-adjusted odds ratio of kidney disease for subjects of African American versus white ethnicity was 0.27 (95% CI, 0.22 to 0.33) by reduced eGFR but was 1.17 (95% CI, 0.91 to 1.51) by elevated serum creatinine and 3.87 (95% CI, 2.89 to 5.25) by elevated ACR. CONCLUSION: In a predominantly hypertensive population, kidney disease identified by elevated ACR was more concordant with elevated serum creatinine than with reduced eGFR. The MDRD equation, derived using kidney disease patients, may misrepresent the gender- and ethnicity-specific risk of kidney disease.

Adult↗

PubMed2006

Longitudinal analysis of haplotypes and polymorphisms of the APOA5 and APOC3 genes associated with variation in serum triglyceride levels: the Bogalusa Heart Study.

Polymorphisms in the APOC3 and APOA5 genes, from the APOA1/APOC3/APOA4/APOA5 gene cluster on chromosome 11q23, have been associated with interindividual variation in plasma triglycerides. APOA5 polymorphisms implicated include 2 in the promoter region (-1131 T/C and -3 A/G) and 1 in exon 2 (+56 C/G). APOC3 polymorphisms implicated include 1 (SstI) in the 3' untranslated region and 1 (-2854 G/T) in the APOC3-APOA4 intergenic region. We analyzed the associations of haplotypes and multilocus genotypes of these polymorphisms on longitudinal serum triglyceride profiles in 360 African American and 823 white subjects from the Bogalusa Heart Study. Subjects were examined from 2 to 8 times (mean +/- SD, 5.4 +/- 1.3) between 1973 and 1996, at ages ranging from 4 to 38 years, with 1978 observations in African Americans and 4465 in whites. Serum triglycerides were significantly higher among whites across all ages. Allele frequencies differed significantly between African Americans and whites at all but the APOA5 +56 C/G locus. Linkage disequilibrium among the loci was higher in whites and haplotype diversity lower: 6 haplotypes had estimated frequencies of more than 1% in African Americans, 5 in whites. Individually, all polymorphisms except APOC3 -2854 G/T showed significant associations with triglyceride levels in the full sample. However, genotype models including all 5 loci showed significant triglyceride associations for only 3 (APOC3 SstI, APOA5 -1131 T/C, and APOA5 +56 C/G); significant interactions among them indicated their effects were not independent. Neither APOC3 -2854 G/T nor APOA5 -3 A/G had significant effects when the other 3 loci were in the models. The EM algorithm was used to estimate haplotype frequencies and assign haplotype probabilities to individuals, which is conditional on their genotypes; individuals' haplotype probability vectors were then used as predictors in multilevel mixed models of longitudinal triglyceride profiles. Of haplotypes comprising, in order, APOC3 SstI and -2854 G/T and APOA5 -1131 T/C, -3 A/G, and +56 C/G, 3 were significantly associated with higher triglycerides, even after adjusting for multiple tests: GGTAG (P = .002), GTTAG (P < .0001), and CGCGC (P = .0002). Each GGTAG haplotype carried would be expected to raise triglyceride levels (relative to those of GTTAC homozygotes) by approximately 19 mg/dL, each GTTAG haplotype by approximately 15 mg/dL, and each CGCGC haplotype by approximately 7 mg/dL. Haplotypes comprising the 3 loci implicated by genotype analyses (SstI, -1131 T/C, and +56 C/G) were also tested: haplotypes C_C_C and G_T_G significantly raised triglycerides, even after adjustment for multiple comparisons (P < .002 for both), with each copy of C_C_C expected to raise triglycerides by approximately 7 mg/dL and each copy of G_T_G by approximately 15 mg/dL. Overall, our findings support those of others in associating specific polymorphisms and haplotypes in the APOA1/C3/A4/A5 gene cluster with higher serum triglyceride levels. However, the degree to which polymorphisms in the APOC3 and APOA5 genes may be independently associated with triglyceride levels remains to be determined.

Adolescent↗

PubMed2006

NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: the Atherosclerosis Risk in Communities study.

OBJECTIVE: Endothelial nitric oxide synthase (NOS3) activity and cigarette smoking significantly influence endothelial function. We sought to determine whether cigarette smoking modified the association between NOS3 polymorphisms and risk of coronary heart disease or stroke. METHODS: All 1085 incident coronary heart disease cases, all 300 incident ischemic stroke cases, and 1065 reference individuals from the Atherosclerosis Risk in Communities study were genotyped for the T-786C and E298D polymorphisms in NOS3. Using a case-cohort design, associations between genotype/haplotype and disease risk were evaluated by multivariable proportional hazards regression. Multiplicative scale interaction testing evaluated the influence of cigarette smoking history at baseline on these associations. RESULTS: In Caucasians, association between E298D genotype and risk of coronary heart disease was significantly modified by current smoking status (interaction P=0.013), with the highest risk observed in smokers carrying the variant D298 allele relative to nonsmokers carrying two E298 alleles (adjusted hazard rate ratio 2.07, 95% confidence interval 1.39-3.07). In African-Americans, association between T-786C genotype and risk of ischemic stroke was significantly modified by pack-year smoking history (interaction P=0.037), with the highest risk observed in >or=20 pack-year smokers carrying the variant C-786 allele relative to <20 pack-year smokers carrying two T-786 alleles (adjusted hazard rate ratio 4.03, 95% confidence interval 1.54-10.6). CONCLUSIONS: An interaction between the E298D and T-786C polymorphisms in NOS3, cigarette smoking, and risk of incident coronary heart disease and ischemic stroke events appears to exist, suggesting a potential complex interplay between genetic and environmental factors and cardiovascular disease risk.

Black or African American↗

PubMed2005

Contribution of regulatory and structural variations in APOE to predicting dyslipidemia.

The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the 2, 3, and 4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.

Black or African American↗

PubMed2005

Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Measurement of inflammatory markers has been reported to identify individuals at increased risk for ischemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a proinflammatory enzyme secreted by macrophages. We assessed Lp-PLA2 and C-reactive protein (CRP) levels along with traditional risk factors to examine their relation to ischemic stroke. METHODS: A proportional hazards model was used in a prospective case-cohort study of 12,762 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study who were observed for about 6 years. RESULTS: Mean Lp-PLA2 and CRP levels adjusted for sex, race, and age were higher in the 194 stroke cases than the 766 noncases, whereas low-density lipoprotein cholesterol (LDL-C) level was not significantly different. Both Lp-PLA2 and CRP levels were associated with ischemic stroke after adjustment for age, sex, and race: hazard ratios were 2.23 for the highest vs the lowest tertile of Lp-PLA2 and 2.70 for CRP level higher than 3 vs lower than 1 mg/L. In a model that included smoking, systolic hypertension, lipid levels, and diabetes, Lp-PLA2 and CRP levels in the highest category were associated with hazard ratios of 1.91 (95% confidence interval, 1.15-3.18; P = .01) and 1.87 (95% confidence interval, 1.13-3.10; P = .02), respectively. Individuals with high levels of both CRP and Lp-PLA2 were at the highest risk after adjusting for traditional risk factors compared with individuals with low levels of both, whereas others were at intermediate risk. CONCLUSION: Levels of Lp-PLA2 and CRP may be complementary beyond traditional risk factors in identifying middle-aged individuals at increased risk for ischemic stroke.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2005

A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA study.

Little is known about the genetics of peripheral arterial disease (PAD). We performed linkage analyses to identify genomic regions that influence ankle-brachial index (ABI), a measure of PAD, in 1310 African Americans (AA) (mean age 62+/-9 years) and 796 non-Hispanic whites (NHW) (mean age 58+/-9 years) belonging to hypertensive sibships. ABI was determined at two sites in each lower extremity and the lower of the two average ABIs was used in the analyses after adjustment for age, age(2), sex, weight, total cholesterol, HDL cholesterol, and ever-smoking. Genotypes were measured at microsatellite marker loci spaced approximately 10cM apart across the 22 autosomes. Heritability was assessed by SOLAR and linkage analyses performed using a variance components approach. Modest heritability (h(2)) was noted for the fully adjusted ABI in each ethnic group (h(2)=0.195, P=0.002 in AA; h(2)=0.212, P=0.006 in NHW). Univariate linkage analyses demonstrated tentative evidence of linkage (multipoint LOD=1.3-2.0) for ABI on chromosomes 1p, 6q, 7q, 10p, and 16p in AA and on chromosome 3p and 3q in NHW. In conclusion, ABI is a modestly heritable trait in AA and NHW hypertensive sibships. Quantitative trait linkage analyses identified several chromosomal regions that may harbor genes influencing ABI.

Black or African American↗

PubMed2005

Apolipoprotein E genotype and incident ischemic stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: A relationship between the apolipoprotein E (apoE) genotype and ischemic stroke has been inconsistently reported. We explored this relation in the Atherosclerosis Risk in Communities Study (ARIC). METHODS: The ARIC cohort involves 15 792 men and women, aged 45 to 64 years at baseline and sampled from 4 U.S. communities. Between 1987 and 2001, 498 incident ischemic strokes occurred. RESULTS: After stratifying by race and sex and adjusting for other nonlipid risk factors, there was no significant relation between the apoE genotype and incident stroke, except in black women (hazard ratio for epsilon2 genotype relative to epsilon3/epsilon3=0.53; 95% CI, 0.28 to 0.99). CONCLUSIONS: For the most part, in this middle-aged sample, apoE was not a risk factor for incident ischemic stroke.

Apolipoproteins E↗

PubMed2005

WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic.

Single nucleotide polymorphisms (SNPs) in genes encoding or influencing renal sodium transport systems were investigated as potential predictors of blood pressure (BP) response to a thiazide diuretic. A sample of 585 adults with essential hypertension (30 to 59.9 years of age; 50% blacks; 47% women) were treated with hydrochlorothiazide for 4 weeks (25 mg daily, orally) to determine office BP responses. Ambulatory BP responses were measured in a subset of 228 subjects. After adjustment for ethnicity, sex, age, and waist-to-hip ratio, 3 SNPs in WNK1 (rs2107614, rs2277869, and rs1159744), encoding a lysine-deficient protein kinase that regulates thiazide-sensitive sodium-potassium cotransport, made statistically significant contributions to predicting ambulatory BP responses, accounting for 2% to 4% of variation in systolic and diastolic responses (P<0.05). SNPs in the beta2-adrenoceptor (rs2400707) and the epithelial sodium channel gamma-subunit (rs5723 and rs5729) were associated with similar magnitude of variation in ambulatory systolic BP response (P=0.028) or office diastolic BP response (P<0.05), respectively. However, SNPs evaluated in the furosemide-sensitive sodium-potassium chloride cotransporter, potassium inwardly rectifying channel, chloride channel, thiazide-sensitive sodium chloride cotransporter, epithelial sodium channel beta-subunit, and the mineralocorticoid receptor were not associated with significant variation in ambulatory or office BP responses. Polymorphisms in genes regulating renal sodium transport, in particular WNK1, predict interindividual differences in antihypertensive responses to hydrochlorothiazide.

Adult↗

PubMed2005

P-selectin Thr715Pro polymorphism predicts P-selectin levels but not risk of incident coronary heart disease or ischemic stroke in a cohort of 14595 participants: the Atherosclerosis Risk in Communities Study.

OBJECTIVE: Inflammation, characterized by the recruitment/adhesion of circulating leukocytes by cellular adhesion molecules, plays an important role in the pathogenesis of atherosclerosis. Genetic analyses of P-selectin, a key adhesion molecule in the progression of atherosclerosis, have provided conflicting results regarding the role of variation within the P-selectin gene and risk for heart disease. No studies have examined the association of this polymorphism with stroke. Therefore, we examined the association of the P-selectin Thr715Pro polymorphism with incident coronary heart disease (CHD) and ischemic stroke among 14595 participants in the prospective cohort of the Atherosclerosis Risk in Communities (ARIC) Study. METHODS AND RESULTS: Incidences of ischemic stroke and CHD were determined through annual telephone calls and hospital and death certificate surveillance. Four hundred fifty-six validated ischemic stroke and 1533 CHD events were identified. P-selectin Pro715 allele frequency was determined in whites and African-Americans, respectively, for CHD cases (0.11, 0.02), CHD non-cases (0.11, 0.02), ischemic stroke cases (0.11, 0.02) and stroke non-cases (0.11, 0.02). The P-selectin Pro715 allele was not associated with risk of CHD or stroke in whites or African-Americans. P-selectin levels, however, were associated with the P-selectin Thr715Pro variant in whites, but not in African-Americans. CONCLUSIONS: Genotypes carrying the P-selectin Pro715 variant allele are associated with decreased P-selectin levels compared to the homozygous wild-type genotype in whites. The P-selectin Thr715Pro polymorphism is not associated with incident CHD or ischemic stroke in either whites or African-Americans.

Alleles↗

PubMed2005

The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke.

Stroke is the leading cause of severe disability and the third leading cause of death, accounting for one of every 15 deaths in the USA. We investigated the association of polymorphisms in the soluble epoxide hydrolase gene (EPHX2) with incident ischemic stroke in African-Americans and Whites. Twelve single nucleotide polymorphisms (SNPs) spanning EPHX2 were genotyped in a case-cohort sample of 1336 participants from the Atherosclerosis Risk in Communities (ARIC) study. In each racial group, Cox proportional hazard models were constructed to assess the relationship between incident ischemic stroke and EPHX2 polymorphisms. A score test method was used to investigate the association of common haplotypes of the gene with risk of ischemic stroke. In African-Americans, two common EPHX2 haplotypes with significant and opposing relationships to ischemic stroke risk were identified. In Whites, two common haplotypes showed suggestive indication of an association with ischemic stroke risk but, as in African-Americans, these relationships were in opposite direction. These findings suggest that multiple variants exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence; some associated with a higher incidence and others with a lower incidence.

Black or African American↗

PubMed2005

Genomic loci with pleiotropic effects on coronary artery calcification.

We measured 381 genomewide markers and performed genetic linkage analyses in search of loci influencing coronary artery calcification (CAC), a measure of atherosclerosis determined by electron beam computed tomography, in 948 non-Hispanic white siblings (mean age [+/-standard deviation] = 59.6 +/- 9.9 years; 73.7% hypertensive). Measured risk factors for atherosclerosis included body mass index, pulse pressure, and high-density lipoprotein (HDL)-cholesterol. After adjustment for sex and age, the logarithm transformed measure of CAC was heritable (0.40 +/- 0.08, P < 0.0001) and genetically correlated with body mass index (0.28, P < 0.001), pulse pressure (0.36, P < 0.001), and HDL-cholesterol (-0.19, P < 0.001). Univariate linkage analysis demonstrated evidence of linkage for CAC, defined by maximum LOD scores (MLS) >or= 1.30, on chromosomes 1p, 4p, 5q, 7p, 13q, and 14q. Bivariate linkage analyses of CAC with each risk factor provided evidence of two regions with pleiotropic effects on CAC and HDL-cholesterol on chromosomes 4p16 (MLS=3.03, P = 0.00084) and 9q12 (MLS = 3.21, P = 0.00056), and of a region with pleiotropic effects on CAC and body mass index on chromosome 17p11 (MLS = 3.04, P = 0.00082). Inasmuch as the chromosome 9 and 17 regions were not detected in the univariate linkage analysis for CAC, multivariate linkage analyses of CAC and genetically correlated risk factors may help localize genes for coronary atherosclerosis.

Blood Pressure↗

PubMed2005

Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study.

BACKGROUND: Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. METHODS AND RESULTS: We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives > or =55 years of age with > or =1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata. CONCLUSIONS: ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response.

Aged↗

PubMed2005

Apolipoprotein E and progression of chronic kidney disease.

CONTEXT: Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the epsilon2 allele increasing and the epsilon4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. OBJECTIVE: To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. DESIGN, SETTING, AND PARTICIPANTS: Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10,661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. MAIN OUTCOME MEASURES: Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 micromol/L) or more above baseline, examined by APOE genotypes and alleles. RESULTS: During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, epsilon2 moderately increased and epsilon4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (epsilon2: 1.08 [95% CI, 0.93-1.25] and epsilon4: 0.85 [95% CI, 0.75-0.95] compared with epsilon3; likelihood ratio test, P = .008). Epsilon4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). Epsilon2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. CONCLUSIONS: APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.

Apolipoproteins E↗

PubMed2005

Mining genetic epidemiology data with Bayesian networks I: Bayesian networks and example application (plasma apoE levels).

MOTIVATION: The wealth of single nucleotide polymorphism (SNP) data within candidate genes and anticipated across the genome poses enormous analytical problems for studies of genotype-to-phenotype relationships, and modern data mining methods may be particularly well suited to meet the swelling challenges. In this paper, we introduce the method of Belief (Bayesian) networks to the domain of genotype-to-phenotype analyses and provide an example application. RESULTS: A Belief network is a graphical model of a probabilistic nature that represents a joint multivariate probability distribution and reflects conditional independences between variables. Given the data, optimal network topology can be estimated with the assistance of heuristic search algorithms and scoring criteria. Statistical significance of edge strengths can be evaluated using Bayesian methods and bootstrapping. As an example application, the method of Belief networks was applied to 20 SNPs in the apolipoprotein (apo) E gene and plasma apoE levels in a sample of 702 individuals from Jackson, MS. Plasma apoE level was the primary target variable. These analyses indicate that the edge between SNP 4075, coding for the well-known epsilon2 allele, and plasma apoE level was strong. Belief networks can effectively describe complex uncertain processes and can both learn from data and incorporate prior knowledge. AVAILABILITY: Various alternative and supplemental networks (not given in the text) as well as source code extensions, are available from the authors. SUPPLEMENTARY INFORMATION: http://bioinformatics.oxfordjournals.org.

Apolipoproteins E↗

PubMed2005

Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels.

Elevated plasma levels of C-reactive protein (CRP), an inflammation-sensitive marker, have emerged as an important predictor of future cardiovascular disease and metabolic abnormalities in apparently healthy men and women. Here, we performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus. Of the common single-nucleotide polymorphisms (SNPs) identified, several in the CRP promoter region are strongly associated with CRP levels in a large cohort study of cardiovascular risk in European American and African American young adults. We also demonstrate the functional importance of these SNPs in vitro.

Adolescent↗

PubMed2005

An entropy-based statistic for genomewide association studies.

Efficient genotyping methods and the availability of a large collection of single-nucleotide polymorphisms provide valuable tools for genetic studies of human disease. The standard chi2 statistic for case-control studies, which uses a linear function of allele frequencies, has limited power when the number of marker loci is large. We introduce a novel test statistic for genetic association studies that uses Shannon entropy and a nonlinear function of allele frequencies to amplify the differences in allele and haplotype frequencies to maintain statistical power with large numbers of marker loci. We investigate the relationship between the entropy-based test statistic and the standard chi2 statistic and show that, in most cases, the power of the entropy-based statistic is greater than that of the standard chi2 statistic. The distribution of the entropy-based statistic and the type I error rates are validated using simulation studies. Finally, we apply the new entropy-based test statistic to two real data sets, one for the COMT gene and schizophrenia and one for the MMP-2 gene and esophageal carcinoma, to evaluate the performance of the new method for genetic association studies. The results show that the entropy-based statistic obtained smaller P values than did the standard chi2 statistic.

Entropy↗