Jeannette T. Bensen

Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study) ☆

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family Tree Study, and 1,442 families in the NHLBI Family Heart Study in Massachusetts, Minnesota, North Carolina, and Utah. Utah families with a positive family history of CHD (FRS > or =0.5) represented only 14% of the general population but accounted for 72% of persons with early CHD (men before age 55 years, women before age 65 years) and 48% of CHD at all ages. For strokes, 11% of families with FRS > or =0.5 accounted for 86% of early strokes (<75 years) and 68% of all strokes. Analyses of >5,000 families sampled each year in Utah for 14 years demonstrated a gradual decrease in the frequency of a strong positive family history of CHD (-26%/decade) and stroke (-15%/decade) that paralleled a decrease in incidence rates (r = 0.86, p <0.001 for CHD; r = 0.66, p <0.01 for stroke). Because of the collaboration of schools, health departments, and medical schools, the Health Family Tree Study proved to be a highly cost-efficient method for identifying 17,064 CHD-prone families and 13,106 stroke-prone families (at a cost of about

Accuracy of proband reported family history: The NHLBI Family Heart Study (FHS)

27 per high-risk family) in whom well-established preventive measures can be encouraged. We conclude that most early cardiovascular events in a population occur in families with a positive family history of cardiovascular disease. Family history collection is a validated and relatively inexpensive tool for family-based preventive medicine and medical research.

Family risk score of coronary heart disease (CHD) as a predictor of CHD: the atherosclerosis risk in communities (ARIC) study and The NHLBI Family Heart Study

Proband‐reported family histories are widely used in research and counseling, yet little is known about the validity of family history reporting. The Family Heart Study (FHS), a population‐based study of familial cardiovascular disease, gathered family history information from 3,020 middle‐aged probands in four U.S. communities. Probands reported on the history of coronary heart disease (CHD), diabetes, hypertension, and asthma among a total of 10,316 living relatives (9,186 siblings, 1,130 parents) and 2,685 spouses. Questionnaires were returned by 6,672 siblings, 901 parents, and 2,347 spouses, yielding response rates of 73, 79, and 87%, respectively. Utilizing the relatives self‐report as the standard, sensitivity of the proband report on their spouse, parent, and sibling was 87, 85, and 81% for CHD, 83, 87, and 72% for diabetes, 77, 76, and 56% for hypertension, and 66, 53, and 39% for asthma, respectively. Most specificity values were above 90%. Analyses using generalized estimating equations (GEE) were performed to evaluate differences in proband accuracy based on the probands age, gender, disease state, center, and ethnicity. In multivariate models, age, gender, and disease status were significantly associated with the accuracy of probands report of sibling disease history, but had little effect on the accuracy of their report on spouses or parents. In general, older probands were significantly less accurate reporters of disease than younger probands. These results demonstrate that CHD family history can be captured effectively based on proband reports, but suggest that additional family contacts may be helpful when working with older probands or with chronic diseases that have few recognized medical events or procedures. Genet. Epidemiol. 17:141–150, 1999.© 1999 Wiley‐Liss, Inc.

Identification of a Novel Human Cytokine Gene in the Interleukin Gene Cluster on Chromosome 2q12-14

Family history of coronary heart disease (CHD) has been found to be a risk factor for CHD in numerous studies. Few studies have addressed whether a quantitative measure of family history of CHD (family risk score, FRS) predicts CHD in African Americans. This study assessed the association between FRS and incident CHD of participants, and the variation of the association by gender and race. Participants in the study were a biracial population‐based cohort with 3,958 African Americans and 10,580 Whites aged 45–64 years old in the ARIC baseline survey (1987–1989). They were randomly selected from four U. S. communities. During follow‐up (1987–1993), 352 participants experienced the onset of CHD. Incidence density of CHD (per 1,000 person‐years) was 7.8 and 3.6 among African‐American men (AAM) and women (AAW), and 7.2 and 2.2 among White men (WM) and women (WW). The hazard rate ratio (HRR) of CHD associated with one standard deviation increase of FRS was 1.52 in AAW, 1.46 in AAM, 1.41 in WW, and 1.68 in WM. The HRRs decreased 4.6% in AAW, 1.4% in WW, 5.7% in AAM, and 3.0% in WM, but increased 2.1% in AAM after adjustment for selected covariates. FRS predicts incident CHD in African Americans and Whites, men and women. The relation of FRS to incident CHD can be only partially explained by the selected risk factors in the biological causal pathways: IMT, T‐G, LDL, HDL, Lp(a), fibrinogen and hypertension. No significant difference by race has been found in this study. Genet. Epidemiol. 18:236–250, 2000.

Family history of coronary heart disease and pre-clinical carotid artery atherosclerosis in African Americans and whites: The ARIC study

Genes in the interleukin-1 (IL-1) gene cluster on human chromosome 2 play an important role in mediating inflammatory responses and are associated with numerous diseases. We have identified a novel IL-1-like gene, IL-1F10, on human chromosome 2q13-14.1 near the IL-1 receptor antagonist gene (IL-1RN). The IL1F10 gene is encoded by 5 exons spanning over 7.8 kb of genomic DNA. The 1008-bp IL-1F10 cDNA encodes a 152-amino acid protein that shares between 41% and 43% amino acid identity with human IL-1 receptor antagonist (IL-1Ra) and FIL-1delta, respectively. IL-1F10 shares characteristics of the IL-1Ra family, including key amino acid consensus sequences and a similar genomic structure. By multitissue first-strand cDNA PCR analysis, IL-1F10 mRNA is expressed in heart, placenta, fetal liver, spleen, thymus, and tonsil. The expression in a variety of immune tissues and similarity to IL-1Ra suggest a role of IL-1F10 in the inflammatory response.

MnSOD Val-9Ala genotype, pro- and anti-oxidant environmental modifiers, and breast cancer among women on Long Island, New York

The association between family history of coronary heart disease (CHD) and morbidity and mortality due to atherosclerotic sequelae, although well documented in population‐based samples of whites, has been little studied in African Americans. Less is known about the relationship between a family history of CHD and pre‐clinical atherosclerosis. We report the relation between family history of CHD, summarized in a family risk score (FRS), and asymptomatic atherosclerosis at the extracranial carotid arteries, measured by B‐mode ultrasound. The FRS was assessed in relatives of 3,034 African Americans and 9,048 white probands aged 45 to 64 years, in the four community‐based cohorts of the ARIC Study. The analyses were restricted to individuals free of clinically manifest CHD. The distribution of CHD FRS by ethnic‐gender groups was right skewed, with slightly higher mean values for white than African‐American males, and for African‐American than white females. In a series of multivariate linear regression models with mean carotid artery intima‐media wall thickness (IMT) as the dependent variable, FRS was associated positively with IMT in white and African‐American women and white men. In a multiple regression model, approximately one‐half of the quantitative statistical relationship of the CHD FRS with IMT in whites was statistically explained by the major risk factors considered as intervening, explanatory variables in this analysis. This association in African‐American women was fully explained by the major risk factors. The FRS was not, however, associated with atherosclerosis or major risk factors in African‐American males, in the ARIC Study. Genet. Epidemiol. 16:165–178, 1999.

Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster

Excessive oxidative stress may induce and promote breast carcinogenesis. Manganese superoxide dismutase (MnSOD) is critical to management of oxidative stress by catalyzing the formation of hydrogen peroxide from two superoxide anions. To examine the relationship between MnSOD Val-9Ala polymorphism, breast cancer and potential modifiers, we analyzed data from a large population-based case-control study. Study participants completed an in-home interviewer-administered questionnaire, and self-completed a Block food frequency questionnaire. Age-adjusted unconditional logistic models included 1034 cases and 1084 controls. As compared with Val/Val genotype, we found no association between MnSOD Ala/Val (ORxa0=xa00.98, 95% CI: 0.79–1.21) and Ala/Ala (ORxa0=xa01.00, 95% CI: 0.79–1.28) genotypes and breast cancer. Results did not differ by menopausal status, stage of tumor, or estrogen and progesterone receptor status. No discernable patterns of interaction were found between this MnSOD variant and anti-oxidative exposures, including fruit and vegetable intake or NSAID use, or pro-oxidant exposures, including smoking and alcohol. This study provides little evidence that variation in Val-9Ala polymorphism of MnSOD alone or through substantial interaction with key exposures believed to be pro- or anti-oxidant properties influences breast cancer risk.

Genetic variation of TP53, polycyclic aromatic hydrocarbon-related exposures, and breast cancer risk among women on Long Island, New York

A dense gene-based SNP map was constructed across a 360-kb region containing the interleukin-1 gene cluster (IL1A, IL1B, and IL1RN), focusing on IL1RN. In total, 95 polymorphisms were confirmed or identified primarily by direct sequencing. Polymorphisms were precisely mapped to completed BAC and genomic sequences spanning this region. The polymorphisms were typed in 443 case-control subjects from Caucasian and African American groups. Consecutive pair-wise marker linkage disequilibrium was not strictly correlated with distance and ranged from D=0.0079 to 1.000 and D=0.0521 to 1.0000 in Caucasians and African Americans, respectively. Single markers and haplotypes in IL1 cluster genes were evaluated for association with end-stage renal disease (ESRD). Eleven SNPs show some evidence of association with ESRD, with the strongest associations in two IL1A variants, one SNP, rs1516792-3, in intron 5 (p=0.0015) and a 4-bp insertion/deletion within the 3UTR, rs16347-2 (p=0.0024), among African Americans with non-T2DM-associated ESRD.

Catechol-O-methyltransferase haplotypes and breast cancer among women on Long Island, New York

Backgroundp53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function.ObjectivesWe evaluated whether three well-characterized TP53 variants—Ex4xa0+xa0119 Cxa0>xa0G (rs#1042522, Arg72Pro), IVS6xa0+xa062 Axa0>xa0G (rs#1625895), and an IVS3 16xa0bp insertion/ deletion (INDEL; rs#17878362)—were associated with breast cancer risk in a population-based case-control study.MethodsGenotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls.ResultsFor the Ex4xa0+xa019 Cxa0>xa0G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH–DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6xa0+xa062 Axa0>xa0G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (ORxa0=xa00.49, 95% CI 0.27–0.90; ORxa0=xa00.42, 95% CI 0.22–0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk.ConclusionsThese results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.

Association Analysis of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism in Hispanics and African Americans: The IRAS Family Study

The gene encoding catechol-O-methyltransferase (COMT), critical to the inactivation of reactive catechol estrogens, has several single nucleotide polymorphisms (SNPs) that influence enzyme activity. A 3-SNP haplotype (IVS1+255 C>T; Ex4-12 G>A; 3′UTR-521 A>G), which has been shown to reduce COMT expression in the human brain, has been identified. To evaluate the influence of genetic variation of COMT on breast cancer risk, these 3-SNPs were genotyped in 1052 cases and 1098 controls. We estimated the associations between breast cancer and individual SNPs, as well as, multilocus haplotypes. We also examined surrogates of hormone exposure as potential modifiers of the putatively functional Ex4-12 SNP-breast cancer association. Odds ratios (OR) and 95% confidence intervals (CI) were based on age-adjusted unconditional logistic regression models. We found no association between the individual SNPs alone and breast cancer. When examining the association between breast cancer and the 3-SNP haplotypes, we observed a 19% increase in risk associated with each copy of the TGG haplotype (OR=1.19, 95% CI 0.96–1.49), relative to the common TAA haplotype, which was statistically significant when assuming a dominant model (OR=1.32, 95% CI 1.05–1.67, p-value=0.02). In this report of COMT haplotypes and breast cancer, we found some evidence that additional genetic variability beyond the Ex4-12 G>A SNP contributes to risk of breast cancer among a small subgroup of women; however, these results need to be replicated in additional studies.