Folsom, Aaron R.

Abstract Objective: Controversy remains regarding the association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) risk. To clarify and extend the existing data, we prospectively evaluated the association between self-reported type 2 DM (onset at >30 years of age) and incident CRC, overall and by anatomic subsite, among postmenopausal women in the Iowa Women's Health Study (n = 35,230). Methods: After 14 years of follow-up, a total of 870 incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up. CRC risks were estimated using Cox proportional hazards regression models. Results: After adjusting for age, body mass index and other potential confounding variables, the relative risk (RR) for women with DM versus women without DM was modestly increased at 1.4 [95% confidence interval (95% CI), 1.1-1.8]. By anatomic subsite, the RR for proximal colon cancer was statistically significantly increased (RR, 1.9; 95% CI, 1.3-2.6), whereas the RRs for distal colon (RR, 1.1; 95% CI, 0.6-1.8) and rectal cancer (RR, 0.8; 95% CI, 0.4-1.6) were not statistically different from unity. Analyses that included DM ascertained at baseline and follow-up yielded similar results. Conclusion: In this large, prospective study of postmenopausal women, the association between DM and incident CRC was found to be subsite specific. If confirmed by others, this finding implies that CRC prevention strategies among type 2 DM patients should include examination of the proximal colon.

Abstract Overweight [body mass index (BMI) 25.0-29.9 kg/m2] and obesity (BMI ≥30 kg/m2) are risk factors for several malignancies. The Iowa Women's Health Study was examined to determine whether increased BMI was associated with leukemia development. Over 40,000 Iowa women (ages 55-69 years) completed a self-administered lifestyle and health questionnaire in 1986 that included current height and weight. Two hundred women developed leukemia during the period 1986 to 2001 including 74 acute myelogenous leukemia (AML) and 88 chronic lymphocytic leukemia. The risk of AML was increased among women who reported being overweight or obese (relative risk, 1.9; 95% confidence interval, 1.0-3.4; relative risk, 2.4; 95% confidence interval, 1.3-4.5; Ptrend = 0.006) compared with women of normal weight. There was little evidence of a positive association for chronic lymphocytic leukemia (Ptrend = 0.6). Given the prevalence of overweight and obesity in the United States, the population attributable risk of AML due to obesity could approach 30%.

Abstract In 1997, the American Institute for Cancer Research (AICR) published 14 recommendations related to diet for individuals to reduce cancer incidence on a global basis; smoking was also discouraged. We operationalized these into nine recommendations that are particularly relevant to western populations in a cohort of 29,564 women ages 55 to 69 years at baseline in 1986 who had no history of cancer or heart disease. The cohort was followed through 1998 for cancer incidence (n = 4,379), cancer mortality (n = 1,434), cardiovascular disease (CVD) mortality (n = 1,124), and total mortality (n = 3,398). The median number (range) of recommendations followed was 4 (0-8), and 33% of the cohort had ever smoked. Women who followed no or one recommendation compared with six to nine recommendations were at an increased risk of cancer incidence [relative risk (RR) 1.35, 95% confidence interval (CI) 1.15-1.58] and cancer mortality (RR 1.43, 95% CI 1.11-1.85), but there was no association with CVD mortality (RR 1.06, 95% CI 0.78-1.43). We calculated the population attributable risk (PAR) to estimate the proportion of cancer incidence, cancer mortality, and CVD mortality that theoretically would have been avoidable if the entire cohort had never smoked, had followed six to nine recommendations, or had done both. The PARs for smoking were 11% (95% CI 10-13) for cancer incidence, 21% (95% CI 17-24) for cancer mortality, and 20% (95% CI 16-23) for CVD mortality. The PARs for not following six to nine recommendations were 22% (95% CI 12-30) for cancer incidence, 11% (95% CI −5 to 24) for cancer mortality, and 4% (95% CI −20 to 19) for CVD mortality. When smoking and the operationalized AICR recommendations were combined together, the PARs were 31% (95% CI 19-37) for cancer incidence, 30% (95% CI 15-40) for cancer mortality, and 22% (95% CI 4-36) for CVD mortality. These data suggest that the adherence to the AICR recommendations, independently and in conjunction with not smoking, is likely to have a substantial public health impact on reducing cancer incidence and, to a lesser degree, cancer mortality at the population level.

Background: The new 2013 ACC/AHA cholesterol guidelines recommend statin therapy to reduce atherosclerotic cardiovascular disease. Statins inhibit cholesterol biosynthesis which may impair gonadal steroidogenesis. Higher levels of estradiol (E2) and lower levels of sex hormone binding globulin (SHBG) are associated with greater central obesity, metabolic syndrome and diabetes in both men and postmenopausal women. There is however limited information regarding the impact of statins on endogenous sex hormones in large population studies. Methods: We included 3163 men and 1977 women from the baseline examination of the MESA study who had measurement of serum sex hormones: total and bioavailable testosterone (T), E2, dehydroepiandrosterone (DHEA) and SHBG, and excluded those on hormone replacement therapy and non-statin lipid medications. Results: Of the 5140 individuals examined, statin users (n=812) were 67 + 9 years old, 57% males, 41% Whites, 29% Blacks, 11% Chinese and 19% Hispanics. After adjustment for age, gender and race, total cholesterol, HDL-c and BMI, compared to non-users of statins, statin users had significantly lower SHBG by 4.5 nmol/L (95% CI; -6.1, -2.9) and DHEAS by 0.9 nmol/L (95% CI; -1.4, -0.4). No significant gender interaction with statin was seen. No association was noted between statin use and E2, total and bioavailable T. Conclusion: Statin use is associated inversely with serum SHBG and DHEA levels. This is particularly interesting in light of the association of statin use and diabetes, raising the possibility of mediation by endogenous hormones.

Abstract Recent studies have reported an increased risk of breast, endometrial, ovarian, and gall bladder cancer associated with ERT. One proposed mechanism by which ERT increases risk is through the binding of estrogen to receptors at the tissue site. Estrogen receptors are also present on certain hematopoietic cells as well as on myeloid leukemia cells. Further, downregulation of the estrogen receptor through DNA methylation has been associated with increased acute myeloid leukemia (AML) survival. We evaluated whether ERT is associated with an increased risk of leukemia, particularly AML, in the Iowa Women’s Health Study. A cohort of 37,172 post-menopausal Iowa women ages 55 to 69 years with no history of prior cancer was linked annually to the population-based state cancer registry through 2001. In addition to other self-reported cancer risk factors, participants were asked about current and former use of ERT in 1986 and on four subsequent follow-up questionnaires. A total of 201 cases of leukemia were identified over 16 years of follow-up including 64 AMLs and 87 chronic lymphocytic leukemias (CLLs). Compared to never users of ERT at study baseline, current [multivariate relative risk (RR), 1.09; 95% Confidence Interval (CI) 0.70–1.72) and former users (RR=0.81, 95% CI=0.58–1.14) were at no increased risk of developing leukemia. For AML, current users also had no increased risk (RR=0.86, 95% CI=0.39–1.92) and there was a suggestion that former users had a slight decreased risk (RR=0.68, 95% CI=0.38–1.22). For CLL, all results were around unity. Duration of ERT or time-dependent use had no appreciable effect on the RRs. We conclude that ERT use is unlikely to be a risk factor for leukemia, including AML. Supported by NCI R01 CA39741.

Abstract Introduction We tested the hypotheses that higher levels of and persistence of midlife leisure‐time physical activity (LTPA) are associated long‐term with lower cognitive decline and less incident dementia. Methods A total of 10,705 participants (mean age: 60 years) had LTPA (no, low, middle, or high) measured in 1987‐1989 and 1993‐1995. LTPA was assessed in relation to incident dementia and 14‐year change in general cognitive performance. Results Over a median follow‐up of 17.4 years, 1063 dementia cases were observed. Compared with no LTPA, high LTPA in midlife was associated with lower incidence of dementia (hazard ratio [95% confidence interval], 0.71 [0.61, 0.86]) and lower declines in general cognitive performance (−0.07 standard deviation difference [−0.12 to −0.04]). These associations were stronger when measured against persistence of midlife LTPA over 6 years. Discussion LTPA is a readily modifiable factor associated inversely with long‐term dementia incidence and cognitive decline.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.