Linda E. Kelemen

Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE)

BACKGROUND Cardiovascular disease rates vary greatly between ethnic groups in Canada. To establish whether this variation can be explained by differences in disease risk factors and subclinical atherosclerosis, we undertook a population-based study of three ethnic groups in Canada: South Asians, Chinese, and Europeans. METHODS 985 participants were recruited from three cities (Hamilton, Toronto, and Edmonton) by stratified random sampling. Clinical cardiovascular disease was defined by history or electrocardiographic findings. Carotid atherosclerosis was measured with B-mode ultrasonography. Conventional (smoking, hypertension, diabetes, raised cholesterol) and novel risk factors (markers of a prothrombotic state) were measured. FINDINGS Within each ethnic group and overall, the degree of carotid atherosclerosis was associated with a higher prevalence of cardiovascular disease. South Asians had the highest prevalence of this condition compared with Europeans and Chinese (11%, 5%, and 2%, respectively, p=0.0004). Despite this finding, Europeans had more atherosclerosis (mean of the maximum intimal medial thickness 0.75 [0.16] mm) than South Asians (0.72 [0.15] mm), and Chinese (0.69 [0.16] mm). South Asians had an increased prevalence of glucose intolerance, higher total and LDL cholesterol, higher triglycerides, and lower HDL cholesterol, and much greater abnormalities in novel risk factors including higher concentrations of fibrinogen, homocysteine, lipoprotein (a), and plasminogen activator inhibitor-1. INTERPRETATION Although there are differences in conventional and novel risk factors between ethnic groups, this variation and the degree of atherosclerosis only partly explains the higher rates of cardiovascular disease among South Asians compared with Europeans and Chinese. The increased risk of cardiovascular events could be due to factors affecting plaque rupture, the interaction between prothrombotic factors and atherosclerosis, or as yet undiscovered risk factors.

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Folate receptor α (FRα) is a membrane‐bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRα levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRα might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRα gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRα in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumors machinery sustains FRα levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRα‐positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions.

Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the Iowa women's health study.

Obesity and adult weight gain are well-established risk factors for postmenopausal breast cancer. Although there are a few studies demonstrating the contribution of adult weight gain to breast cancer risk, whether weight gain during a critical time period is specifically associated with risk, or whether subsequent weight loss among women who have gained weight will reduce the excess risk, is not firmly established. We investigated the association of changes in weight (loss or gain in excess of 5% of body weight) using two risk factor models: (a) age 18 to 30 years and age 30 years to menopause and (b) age 30 years to menopause and after the menopause to the baseline study in 1986 on risk of postmenopausal breast cancer in a prospective cohort of 33,660 postmenopausal women in Iowa. Over 15 years of follow-up, 1,987 cases of breast cancer occurred. Data were analyzed using proportional hazards regression models adjusted for established breast cancer risk factors. The most frequently observed pattern of body weight over time was a consistent increase; these women were observed to have the highest rates of breast cancer and served as the reference category for all comparisons. The lowest-risk groups were (a) women who maintained or lost weight from age 18 to 30 years and then lost weight from age 30 years to menopause [risk ratio (RR), 0.36; 95% confidence interval (95% CI), 0.22-0.60] and (b) women who maintained or lost weight from age 30 years to menopause and then lost weight after the menopause (RR, 0.48; 95% CI, 0.22-0.65). Women who gained weight from age 30 years to menopause but then lost weight after the menopause experienced risk reductions (RR, 0.77; 95% CI, 0.64-0.92) although perhaps slightly smaller in magnitude than women who maintained their weight in both time intervals (RR, 0.63; 95% CI, 0.55-0.73). Women who gained weight from age 18 to 30 years and then lost weight from age 30 years to menopause had comparable risk reductions (RR, 0.61; 95% CI, 0.46-0.8) with women who maintained their weight in both time intervals (RR, 0.73; 95% CI, 0.64-0.84). Women who gained weight during the period from age 30 years to menopause but who had stable weight after menopause had rates similar to the reference group. These data suggest prevention of weight gain between age 18 years and menopause or weight loss and maintenance during these years reduces risk of postmenopausal breast cancer.

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (>/= 35) kg/m(2)) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

Development and evaluation of cultural food frequency questionnaires for South Asians, Chinese, and Europeans in North America

We developed three ethnic food frequency questionnaires (FFQs) to characterize the diets of South Asian, Chinese, and European immigrants. FFQs were developed from foods reported in the diet records and recalls of 29 South Asians, 25 Chinese, and 20 Europeans participating in a pilot study from 1995-1996 in Hamilton, Ontario, Canada. The FFQ and a seven-day diet record were then administered to 342 South Asians, 317 Chinese, and 346 Europeans participating in the Study of Health Assessment and Risk in Ethnic groups (SHARE) in three Canadian centers from 1996-1998. For FFQ validation, a subset of these participants completed a second seven-day diet record and second FFQ 8 to 10 months later. The FFQ generally underestimated macronutrient and overestimated micronutrient intake compared with the records. Consumption of most macronutrients was lower among South Asians. Energy-adjusted deattenuated correlation coefficients between the records and second FFQ ranged from 0.32 to 0.73 (South Asians), 0.17 to 0.84 (Chinese), and 0.30 to 0.83 (Europeans). The FFQs generally performed well and will be used to investigate diet-disease relations in SHARE. Lower correlations for dietary fats among Chinese persons (0.17 to 0.31) may be improved with more direct questions on the FFQ regarding brand, type, and amount of oil consumed in stirfry servings.

Age-specific Trends in Mammographic Density The Minnesota Breast Cancer Family Study

Mammographic density is a strong risk factor for breast cancer, yet few studies have evaluated density trends, and associated factors, over time. The authors retrieved and digitized mammograms (> or =1 per woman) imaged in 1990-2003 to evaluate percent density (PD) in the Minnesota Breast Cancer Family cohort. Multivariable-adjusted, mixed-effects, repeated-measures models incorporating a natural cubic spline provided estimates of nonlinear trends in PD with age and were used to examine association with covariates. Overall, 5,698 mammograms from 1,689 women with covariate information were digitized. In descriptive analyses, the highest median PD was 33.1% (interquartile range, 21.8%; n = 230) among premenopausal women, 31.0% (interquartile range, 23.2%; n = 175) among women who transitioned from pre- to postmenopause, and 18.7% (interquartile range, 22.2%; n = 1,284) among postmenopausal women. On average, premenopausal compared with postmenopausal women had 1.9% (p = 0.001) higher PD. In repeated-measures analyses, greater declines in PD occurred with menopause and among women with higher baseline PD; current postmenopausal hormone use and higher body mass index modified these declines (p interaction < 0.001). No significant modification of the density change with age was seen with parity/age at first birth, age at menarche, oral contraceptive use, family history of breast or ovarian cancer in a first- or second-degree relative, educational level, smoking status, or alcohol intake were observed. These data suggest that menopause, baseline PD, postmenopausal hormone use, and body mass index predict changes in mammographic density trends during adult life.

Strong Evidence of a Genetic Determinant for Mammographic Density, a Major Risk Factor for Breast Cancer

Increased mammographic density (MD), the proportion of dense tissue visible on a mammogram, is a strong risk factor for breast cancer, common in the population and clusters in families. We conducted the first genome-wide linkage scan to identify genes influencing MD. DNA was obtained from 889 relatives (756 women, 133 men) from 89 families. Percent MD was estimated on 618 (82%) female family members using a validated computer-assisted thresholding method. The genome-wide scan included 403 microsatellite DNA markers with an average spacing of 9 cM. Fine mapping of a region of chromosome 5p (5p13.1-5p15.1) was done using 21 additional closely spaced DNA markers. Linkage analyses were conducted to quantify the evidence for a gene responsible for MD across the genome. The maximum log odds for linkage (LOD) score from the genome-wide scan was on chromosome 5p (LOD = 2.9, supporting linkage by a factor of 10(2.9) or 794 to 1) with a 1-LOD interval spanning 28.6 cM. Two suggestive regions for linkage were also identified on chromosome 12 (LOD = 2.6, 1-LOD interval of 14.8 cM; and LOD = 2.5, 1-LOD interval of 17.2 cM). Finer mapping of the region surrounding the maximum LOD on chromosome 5p resulted in stronger and statistically significant evidence for linkage (LOD = 4.2) and a narrowed 1-LOD interval (13.4 cM). The putative locus on chromosome 5p is likely to account for up to 22% of variation in MD. Hence, 1 or more of the 45 candidate genes in this region could explain a large proportion of MD and, potentially, breast cancer.

Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Studies suggest that underglycosylation of the cell membrane mucin MUC1 may be associated with epithelial ovarian cancer. We identified 26 genes involved in glycosylation and examined 93 single nucleotide polymorphisms (SNP) with a minor allele frequency of ≥0.05 in relation to incident ovarian cancer. Cases were ascertained at the Mayo Clinic, Rochester, MN (n = 396) or a 48-county region in North Carolina (Duke University; n = 534). Ovarian cancer–free controls (n = 1,037) were frequency matched to the cases on age, race, and residence. Subjects were interviewed to obtain data on risk factors and a sample of blood for DNA and genotyped using the Illumina GoldenGate assay. We excluded subjects and individual SNPs with genotype call rates of <90%. Data were analyzed using logistic regression, with adjustment for age and residence. We fitted dominant, log additive, and recessive genetic models. Among Caucasians, nine SNPs in eight genes were associated with risk at P < 0.05 under at least one genetic model before adjusting for multiple testing. A SNP in GALNT1 (rs17647532) was the only one that remained statistically significant after Bonferroni adjustment for multiple testing but was not statistically significant in Hardy-Weinberg equilibrium among controls. Haplotype analyses revealed a global association of GALNT1 with risk (P = 0.038, under a recessive genetic model), which largely reflected a decreased risk of one haplotype (0.10 frequency; odds ratio, 0.07; P = 0.01) compared with the most common haplotype (0.39 frequency). These results suggest that genetic polymorphisms in the glycoslyation process may be novel risk factors for ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(2):397–404)

Multivitamin and Alcohol Intake and Folate Receptor α Expression in Ovarian Cancer

Folate receptor α (FRα) expression in epithelial ovarian cancer may be related to folate intake. We examined this association using multivitamin intake, a proxy for folic acid, and assessed whether the relation was modified by alcohol intake, a folate agonist. Cases (n = 148) with suspected epithelial ovarian cancer, of ages ≥20 years, were seen at Mayo Clinic, Minnesota, between 2000 and 2004; those with tumor specimens (n = 108) were included in analyses. Outpatient controls (n = 148) without cancer and with at least one ovary intact were matched to cases by age (within 5 years) and state of residence. Multivitamin (≥4 pills/wk) and weekly alcohol (≥5 drinks) intakes were assessed. Tumor specimens were analyzed immunohistochemically for FRα. Multivariable rate ratios (RR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. In case-control analysis, the RRs of multivitamin intake with absent/weak/moderate and strong-expressing FRα tumors were 0.30 (95% CI, 0.12-0.70) and 0.47 (95% CI, 0.24-0.91), respectively. For alcohol, the associations were 0.84 (95% CI, 0.24-2.86) and 1.65 (95% CI, 0.69-3.93), respectively. In case-case analysis, the RR associated with developing strong-expressing versus other FRα tumors was 3.13 (95% CI, 1.14-8.65) for multivitamins and 1.58 (95% CI, 0.45-5.60) for alcohol. The data did not support evidence for an interaction between multivitamin and alcohol intake with risk of developing a strong-expressing FRα tumor. The association of multivitamin intake with ovarian cancer may depend on FRα expression level.