Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community.

OBJECTIVE: Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. APPROACH AND RESULTS: We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 ± 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. CONCLUSIONS: Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD.

Clinical correlates of change in inflammatory biomarkers: The Framingham Heart Study.

OBJECTIVES: Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community. METHODS: We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time. RESULTS: Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r(2) = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity. CONCLUSION: Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors.

Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies.

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia.

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

Relations of biomarkers of distinct pathophysiological pathways and atrial fibrillation incidence in the community.

BACKGROUND: Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial. METHODS AND RESULTS: In 3120 Framingham cohort participants (mean age 58.4+/-9.7 years, 54% women), we related 10 biomarkers that represented inflammation (C-reactive protein and fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP] and N-terminal proatrial natriuretic peptide), oxidative stress (homocysteine), the renin-angiotensin-aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion; n=2673) to incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05 to 12.8 years). In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise-selection models (P<0.01 for entry and retention), log-transformed BNP (hazard ratio per SD 1.62, 95% confidence interval 1.41 to 1.85, P<0.0001) and C-reactive protein (hazard ratio 1.25, 95% confidence interval 1.07 to 1.45, P=0.004) were chosen. The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95% confidence interval 0.75 to 0.81) to 0.80 (95% confidence interval 0.78 to 0.83) and showed an integrated discrimination improvement of 0.03 (95% confidence interval 0.02 to 0.04, P<0.0001), with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and C-reactive protein did not appreciably improve risk prediction over the model that incorporated BNP in addition to the risk factors. CONCLUSIONS: BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention requires further investigation.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators.

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10(-323)). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10(-13)). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immunoflow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications.

The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.

BACKGROUND: Environmental and genetic correlates of inflammatory marker variability are incompletely understood. In the family-based Framingham Heart Study, we investigated heritability and candidate gene associations of systemic inflammatory biomarkers. METHODS AND RESULTS: In offspring participants (n=3710), we examined 11 inflammatory biomarkers (CD40 ligand, C-reactive protein, intercellular adhesion molecule-1, interleukin-6, urinary isoprostanes, monocyte chemoattractant protein-1, myeloperoxidase, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor II, fibrinogen). Heritability and bivariate genetic and environmental correlations were assessed by Sequential Oligogenic Linkage Analysis routines in 1012 family members. We examined 1943 tagging single-nucleotide polymorphisms in 233 inflammatory pathway genes with >or=5 minor allele carriers using a general genetic linear model. Clinical correlates explained 2.4% (CD40 ligand) to 28.5% (C-reactive protein) of the variability in inflammatory biomarkers. Estimated heritability ranged from 10.9% (isoprostanes) to 44.8% (P-selectin). Most correlations between biomarkers were weak although statistically significant. A total of 45 single-nucleotide polymorphism-biomarker associations met the q-value threshold of 0.25. Novel top single-nucleotide polymorphisms were observed in ICAM1 gene in relation to intercellular adhesion molecule-1 concentrations (rs1799969, P=1.32 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 10(-5)). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 10(-5)). Novel potential candidates (APCS, MPO) need to be replicated. CONCLUSIONS: Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.

Relation of multiple inflammatory biomarkers to incident atrial fibrillation.

Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models, the inflammatory biomarker panel was associated with incident AF (p = 0.03). With stepwise selection (p <0.01 for entry and retention), log-transformed osteoprotegerin was associated with incident AF (hazard ratio per SD 1.30, 95% confidence interval 1.08 to 1.56, p = 0.006). Adjusting for interim myocardial infarction or heart failure attenuated the association between osteoprotegerin and incident AF (hazard ratio 1.18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events.

Meat and heterocyclic amine intake, smoking, NAT1 and NAT2 polymorphisms, and colorectal cancer risk in the multiethnic cohort study.

BACKGROUND: N-acetyltransferases (NAT) 1 and 2 are polymorphic enzymes catalyzing the metabolic activation of heterocyclic amines. We investigated the modifying effects of NAT1 and NAT2 polymorphisms on the association of meat consumption, heterocyclic amine intake, and smoking with colorectal cancer risk. METHOD: In the Multiethnic Cohort study, participants completed a smoking history and a food-frequency questionnaire at recruitment and a cooked meat module 5 years later to estimate heterocyclic amine intake (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline). Blood samples were collected from incident cases and age-, sex-, ethnicity-, frequency-matched controls to determine genotypes. For analysis of meat intake and smoking, data were available for 1,009 cases and 1,522 controls; for heterocyclic amine intake analyses, 398 cases and 1,444 controls were available. Multivariate logistic regression models were used to estimate odds ratios. RESULTS: Smoking was associated with an increased colorectal cancer risk (odds ratio, 1.51; 95% confidence interval, 1.17-1.95) for > or =30 pack-years compared with never smokers (P trend = 0.0004). The association was stronger with presence of the "rapid" compared with the "slow/intermediate" NAT2 genotype (P interaction = 0.003). No significant associations were observed for intakes of red meat, processed meat, and heterocyclic amine, or meat doneness preference, but a dietary pattern high in meat showed a weak positive interaction with the NAT2 genotype (P interaction = 0.05). CONCLUSION: The enhanced association between smoking and colorectal cancer risk in subjects with the NAT2 rapid genotype supports a role for NAT2 and tobacco smoke heterocyclic amines in the etiology of colorectal cancer. This study only provides weak support for a similar association with meat heterocyclic amines.

Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.

BACKGROUND: Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers. METHODS: We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45-95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. FINDINGS: 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0.05, except body-mass index p=0.08), clinical model C statistic 0.78 (95% CI 0.76-0.80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0.78 (95% CI 0.75-0.80) to 0.79 (0.77-0.82), p=0.005. Echocardiographic measurements did not improve risk reclassification (p=0.18). INTERPRETATION: From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community, assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures.

Association of genetic variation in the transforming growth factor beta-1 gene with serum levels and risk of colorectal neoplasia.

In the normal intestinal epithelium transforming growth factor beta-1 (TGFbeta-1) acts as a growth inhibitor, but in malignant cells it may act as a tumor promoter. However, only limited information is available on genetic variation in the TGFB1 gene and its relationship to circulating levels and risk of colorectal cancer. To characterize associations of genetic variation [tagging single-nucleotide polymorphisms (tagSNP) and haplotypes with frequency >0.05] at the TGFB1 locus with circulating TGFbeta-1 and risk of colorectal neoplasia, we conducted two case-control studies (including 271 colorectal adenoma cases and 544 controls, and 535 colorectal adenocarcinoma cases and 656 controls) among Japanese Americans, Caucasians, and Native Hawaiians in Hawaii. Serum TGFbeta-1 was measured by sandwich ELISA among the subjects of the first study. The variant A allele for tagSNP rs6957 was associated with higher serum TGFbeta-1 [means (in ng/mL) and 95% confidence interval (95% CI) for AA or AG, 32.6 (30.6-34.7); GG, 29.0 (25.1-32.9); P(difference) = 0.05] after adjusting for age and other factors. Homozygous carriers of the variant G allele for tagSNP rs11466345 had a statistically significantly lower risk of adenocarcinoma [AG versus AA: odds ratio (OR), 0.9 (95% CI, 0.7-1.2); GG versus AA: OR, 0.4 (95% CI, 0.2-0.7); P(trend) = 0.01]. The haplotype carrying both variants was also statistically significantly associated with a reduced risk of adenocarcinoma (OR, 0.3; 95% CI, 0.1-0.8). Although not statistically significant, the direction and magnitude of the corresponding ORs were similar for adenoma. These results suggest that a haplotype containing SNP rs11466345 at the 3' end of TGFB1 is associated with genetic susceptibility to colorectal neoplasia.

Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002.

OBJECTIVE: Efforts to prevent leukemia have been hampered by an inability to identify significant risk factors. Exploring incidence patterns of leukemia subtypes by sex and race/ethnic group may generate new etiologic hypotheses and identify high-risk groups for further study. METHODS: Data from the North American Association of Central Cancer Registries for 1997-2002 were used to assess patterns of leukemia incidence by subtype, sex, age, race and ethnicity. RESULTS: A total of 144,559 leukemia cases were identified, including 66,067 (46%) acute and 71,860 (50%) chronic leukemias. The highest rates of acute myeloid leukemia with and without maturation were observed in Asian-Pacific Islanders (API). Hispanics had a higher incidence of acute lymphocytic leukemia, particularly in childhood, and promyelocytic leukemia than did non-Hispanics. African-Americans had the highest rates of HTLV-1 positive adult T-cell leukemia/lymphoma. A sharp increase in the incidence of chronic myeloid leukemia was observed for both APIs and Hispanics, 85 years and older. CONCLUSION: Known risk factors are unlikely to explain the observed disparities in leukemia incidence. Further studies of differences in environmental and genetic risk factors in these populations by specific leukemia subtype may provide clues to the etiologies of these malignancies.

Allowing for variations in multivitamin supplement composition improves nutrient intake estimates for epidemiologic studies.

Collecting detailed data on dietary supplement use is time-consuming for study participants and investigators, and this is particularly difficult for multivitamin use because of the many different formulations available. Therefore, many studies simply ask about the frequency of multivitamin use and assign default nutrient composition values to obtain nutrient intakes. Multivitamin supplements are important contributors to total nutrient intakes, but it is not known how default values affect the accuracy of intake estimation. In this study, nutrient intakes were calculated from multivitamins consumed by 26,735 multivitamin users who provided detailed information like product name(s) and frequency of use on a mailed questionnaire. We then recalculated the intakes, using 2 different assumptions about the composition of the multivitamin supplements: 1) a single default composition for all products; and 2) four default compositions, 1 for each subtype of multivitamin, i.e., one-a-day with minerals, one-a-day without minerals, B-complex or stress multivitamins, and antioxidant combinations. A total of 1246 different brands of multivitamins were reported and nutrient composition varied widely. Spearman correlation coefficient analyses, using the 4 default nutrient profiles compared with actual nutrient intakes, were >0.5 (P < 0.001) for 12 of 15 nutrients examined. However, correlations using the single default were lower, with only 5 correlations >0.5. Our findings suggest that a questionnaire designed to assess the composition profiles for 4 types of multivitamin products substantially improves the accuracy of nutrient-intake estimates over one that uses a single default nutrient profile for all multivitamin products.

Dietary patterns using the Food Guide Pyramid groups are associated with sociodemographic and lifestyle factors: the multiethnic cohort study.

Dietary patterns have been used to identify typical combinations of foods that may be associated with disease risks. We defined dietary patterns among 195,298 participants of the Multiethnic Cohort Study in Hawaii and Los Angeles in 1993-1996. Intakes of Food Guide Pyramid groups were calculated from a quantitative FFQ for subjects of 5 ethnic groups (African Americans, Hawaiians, Japanese Americans, Latinos, and whites). Three distinct dietary patterns, "Fat and Meat," "Vegetables," and "Fruit and Milk," were identified by exploratory factor analysis with a varimax rotation and validated by confirmatory factor analysis. Similar factor loadings were found for each of 10 ethnic-gender groups in stratified analyses. The odds ratios (OR) for being above the median scores for each factor were calculated. Age, gender, and ethnicity had relatively strong associations with dietary patterns whereas education showed only weak associations. BMI > or = 30 was strongly positively associated with the Fat and Meat pattern (OR = 2.14, 95% CI: 2.08-2.20, vs. BMI < 25). Current smokers showed a positive association with the Fat and Meat pattern (OR = 1.67, CI: 1.62-1.72, vs. nonsmokers) and inverse associations with the Vegetables (OR = 0.66, CI: 0.64-0.68) and Fruit and Milk patterns (OR = 0.53, CI: 0.52-0.55). Physical activity was positively associated with the Vegetables and Fruit and Milk patterns but not with the Fat and Meat pattern. These findings support the hypothesis that dietary patterns are influenced by interrelated sociocultural, demographic, and other lifestyle factors and may be useful in investigations of diet-disease relations.