Aaron R. Folsom

Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the TERT gene are associated with risk of incident coronary heart disease, incident ischemic stroke, and mortality in participants in the biracial population-based Atherosclerosis Risk in Communities (ARIC) study, including rs2736100 that was found to influence mean telomere length in a genome-wide analysis. ARIC is a prospective study of the etiology and natural history of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline in 1987–1989. Haplotype tagging SNPs in TERT were genotyped using a custom array containing nearly 49,000 SNPs in 2,100 genes associated with cardiovascular and metabolic phenotypes. Cox proportional hazards models were used to assess the association between the TERT polymorphisms and incident cardiovascular disease and mortality over a 20-year follow-up period in 8,907 whites and 3,022 African-Americans with no history of disease at the baseline examination, while individuals with prevalent cardiovascular disease were not excluded from the analyses of mortality. After adjustment for age and gender, and assuming an additive genetic model, rs2736122 and rs2853668 were nominally associated with incident coronary heart disease (hazards rate ratio = 1.20, p = 0.02, 95 % confidence interval = 1.03– 1.40) and stroke (hazards rate ratio = 1.17, p = 0.05, 95 % confidence interval = 1.00 - 1.38), respectively, in African-Americans. None of the variants was significantly associated with cardiovascular disease in white study participants or with mortality in either racial group. Replication in additional population-based samples combined with genotyping of polymorphisms in other genes involved in maintenance of telomere length may help to determine whether genetic variants associated with telomere homeostasis influence the risk of cardiovascular disease in middle-aged adults.

OBJECTIVE: Our objective was to explore the geographic effects on the postoperative survivability of primary malignant central nervous system (CNS) tumors reported in the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Using the SEER*Stat software available at www.seer.cancer.gov/seerstat version 6.6.1 and the Incidence - SEER 17 Regs Limited-Use + Hurricane Katrina Impacted Louisiana Cases, Nov 2008 Sub (1973–2006 varying) database, survival rates of 22,380 patients diagnosed with a malignant primary CNS tumor and who underwent surgical treatment were analyzed. The survival rates of 6 cities, including Seattle, San Francisco, San Jose-Monterey, Los Angeles, Detroit, and Atlanta were compared to one another, as were 9 states, including New Jersey, Hawaii, California, Louisiana, Iowa, Kentucky, Utah, and New Mexico. Finally, all 15 of these cities and states were compared. RESULTS: All statistical differences in this study refer to direct comparisons using a 99% confidence interval (P = 0.01). Statistical differences existed between survival rates in various cities through the first 6 months of follow-up. The cities with the highest mean survival rates were Seattle, San Francisco, and San Jose-Monterey. Atlanta and Detroit had the lowest mean survival rates at 1 month and 2 months, respectively. At years 1 and 2, those statistical differences were no longer present. Conversely there was no statistical difference between the 9 states compared until the 1 and 2 year follow-up. The states with the highest mean survival rates were New Jersey, Hawaii, Utah, and New Mexico. While patients in Hawaii consistently had a very high mean survival rate, patients in Utah at 2 years had by far the highest survival rate with a statistical difference from all states except Hawaii and New Mexico. The lowest mean survival rates were found in Louisiana, Iowa, Connecticut, and Kentucky. CONCLUSIONS: There is a significant correlation between geographic location and outcome for those patients surgically treated for primary malignant CNS tumors.

Objectives. We assessed whether markers of acculturation (birthplace and number of US generations) and socioeconomic status (SES) are associated with markers of subclinical cardiovascular disease—carotid artery plaque, internal carotid intima-media thickness, and albuminuria—in 4 racial/ethnic groups. Methods. With data from the Multi-Ethnic Study of Atherosclerosis (n = 6716 participants aged 45–84 years) and race-specific binomial regression models, we computed prevalence ratios adjusted for demographics and traditional cardiovascular risk factors. Results. The adjusted US- to foreign-born prevalence ratio for carotid plaque was 1.20 (99% confidence interval [CI] = 0.97, 1.39) among Whites, 1.91 (99% CI = 0.94, 2.94) among Chinese, 1.62 (99% CI = 1.28, 2.06) among Blacks, and 1.23 (99% CI = 1.15, 1.31) among Hispanics. Greater carotid plaque prevalence was found among Whites, Blacks, and Hispanics with a greater number of generations with US residence (P < .001) and among Whites with less education and among Blacks with lower incomes. Similar associations were observed with intima-media thickness. There was also evidence of an inverse association between albuminuria and SES among Whites and Hispanics. Conclusions. Greater US acculturation and lower SES were associated with a higher prevalence of carotid plaque and greater intima-media thickness but not with albuminuria. Maintenance of healthful habits among recent immigrants should be encouraged.

OBJECTIVE—The purpose of this study was to determine whether a variation in the transcription factor 7-like 2 (TCF7L2) gene, which influences diabetes risk, is associated with incidence of cancers. RESEARCH DESIGN AND METHODS—We related diabetes and TCF7L2 variation with occurrence of several common cancers in a prospective cohort study of 13,117 middle-aged adults initially free of cancer in 1987–1989. We assessed five single nucleotide polymorphisms (SNPs) in TCF7L2 including the putative SNP (rs7903146) for diabetes. We identified incident cancers through 2000 via cancer registries, supplemented by hospital records. RESULTS—Diabetes was associated marginally inversely with incidence of prostate cancer but not with incidence of colorectal, colon, lung, or breast cancer. The T allele of rs7903146 (frequency 30%) was associated with increased risk of colorectal cancer and, more specifically, colon cancer, with adjusted hazard ratios (95% CI) of 1.0 for CC, 1.25 (0.85–1.83) for CT, and 2.15 (1.27–3.64) for TT genotypes (P_trend = 0.009). TCF7L2 variation also was associated with lung cancer incidence in whites but not blacks, but residual confounding by smoking may be present. CONCLUSIONS—Subjects who were initially cancer-free and carrying certain genetic variants of TCF7L2, most notably the T allele of rs7903146, have an increased risk of colon cancer. This association appears to be an independent gene effect not explained by diabetes. Because the T allele of rs7903146 is common, if a causal link is established, this variant could account for a sizable proportion (∼17% here) of cases of colon cancer in the general population.

Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non–dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population.