Obesity-Related Genetic Determinants of Heart Failure Prognosis.

PURPOSE: Recent advances in genomics offer a smart option for predicting future risk of disease and prognosis. The objective of this study was to examine the prognostic value in heart failure (HF) patients, of a series of single nucleotide polymorphisms (SNPs). METHODS: A selection of 192 SNPs found to be related with obesity, body mass index, circulating lipids or cardiovascular diseases were genotyped in 191 patients with HF. Anthropometrical and clinical variables were collected for each patient, and death and readmission by HF were registered as the primary endpoint. RESULTS: A total of 53 events were registered during a follow-up period of 438 (263-1077) days (median (IQR)). Eight SNPs strongly related to obesity and HF prognosis were selected as possible prognostic variables. From these, rs10189761 and rs737337 variants were independently associated with HF prognosis (HR 2.295 (1.287-4.089, 95% CI); p = 0.005), whereas rs10423928, rs1800437, rs737337 and rs9351814 were related with bad prognosis only in obese patients (HR 2.142 (1.438-3.192, 95% CI); p = 0.00018). Combined scores of the genomic variants were highly predictive of poor prognosis. CONCLUSIONS: SNPs rs10189761 and rs737337 were identified, for the first time, as independent predictors of major clinical outcomes in patients with HF. The data suggests an additive predictive value of these SNPs for a HF prognosis. In particular for obese patients, SNPs rs10423928, rs1800437, rs737337 and rs9351814 were related with a bad prognosis. Combined scores weighting the risk of each genomic variant could effect interesting new tools to stratify the prognostic risk of HF patients.

Alcohol consumption and survival after a breast cancer diagnosis: a literature-based meta-analysis and collaborative analysis of data for 29,239 cases.

BACKGROUND: Evidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts. METHODS: A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts. RESULTS: We identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre- or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease. CONCLUSION: There was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease. IMPACT: Considering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.

Urinary tract infections and reduced risk of bladder cancer in Los Angeles.

We investigated the association between urinary tract infections (UTIs) and transitional cell carcinoma of the bladder in a population-based case-control study in Los Angeles covering 1586 cases and age-, gender-, and race-matched neighbourhood controls. A history of bladder infection was associated with a reduced risk of bladder cancer among women (odds ratio (OR), 0.66; 95% confidence interval (CI), 0.46-0.96). No effect was found in men, perhaps due to power limitations. A greater reduction in bladder cancer risk was observed among women with multiple infections (OR, 0.37; 95% CI, 0.18-0.78). Exclusion of subjects with a history of diabetes, kidney or bladder stones did not change the inverse association. A history of kidney infections was not associated with bladder cancer risk, but there was a weak association between a history of other UTIs and slightly increased risk among men. Our results suggest that a history of bladder infection is associated with a reduced risk of bladder cancer among women. Cytotoxicity from antibiotics commonly used to treat bladder infections is proposed as one possible explanation.

Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study.

We investigated the effects of individual fatty acids on breast cancer in a prospective study of 35,298 Singapore Chinese women aged 45-74 years, who were enrolled during April 1993 to December 1998 (The Singapore Chinese Health Study). At recruitment, each study subject was administered, in-person, a validated, semiquantitative food frequency questionnaire consisting of 165 food and beverage items. As of December 31, 2000, 314 incident cases of breast cancer had occurred. We used the Cox regression methods to examine individual fatty acids in relation to breast cancer risk, with adjustment for age at baseline interview, year of interview, dialect group, level of education, daily alcohol drinking, number of live births, age when menstrual periods became regular, and family history of breast cancer. Consumption of saturated, monounsaturated or polyunsaturated fat overall was unrelated to risk. On the other hand, high levels of dietary n-3 fatty acids from fish/shellfish (marine n-3 fatty acids) were significantly associated with reduced risk. Relative to the lowest quartile of intake, individuals in the higher three quartiles exhibited a 26% reduction in risk (relative risk (RR)=0.74, 95% confidence interval (CI)=0.58, 0.94)); RRs were similar across the top three quartiles of intake (0.75, 0.75, 0.72, respectively). Overall, there was no association between n-6 fatty acids and breast cancer risk. However, among subjects who consumed low levels of marine n-3 fatty acids (lowest quartile of intake), a statistically significant increase in risk was observed in individuals belonging to the highest vs the lowest quartile of n-6 fatty acid consumption (RR=1.87, 95% CI=1.06-3.27); the corresponding RR for advanced breast cancer was 2.45 (95% CI=1.20-4.97, P for trend=0.01). To our knowledge, these are the first prospective findings linking the intake of marine n-3 fatty acids to breast cancer protection.

Phenobarbital use and bladder cancer risk.

BACKGROUND: Two epidemiologic studies have reported an inverse association between use of phenobarbital (PB) and bladder cancer development. It was proposed that PB use protects against bladder cancer by inducing enzymes that participate in the detoxification of human bladder carcinogens, such as the aminobiphenyls and naphthylamines, which are found in cigarette smoke. METHODS: A population-based case-control study was conducted in Los Angeles, California, involving 815 incident bladder cancer cases and an equal number of controls who were matched to the index cases by neighborhood, sex, date of birth (within 5 years), and race. Detailed information on lifetime use of PB was collected through in-person interviews. RESULTS: Ever use (20 or more times over lifetime) of PB was not associated with risk of bladder cancer (OR: 0.86; 95% CI: 0.54, 1.39). Regular use of PB also was not associated with risk of bladder cancer in either men or women, in either smokers or non-smokers, although the number of regular users in cases and controls were relatively small (21 cases vs. 15 controls, OR: 1.20; 95% CI: 0.59, 2.45). In fact, compared with non-users, subjects in the highest category of lifetime PB consumption were at a non-significant 2.46-fold increased risk of bladder cancer (95% CI: 0.90, 6.78). CONCLUSIONS: The present study did not observe a protective role of PB use in bladder cancer development in the general population.

Family history and risk of renal cell carcinoma.

Few analytical epidemiological studies have investigated family history (FH) of urinary tract cancers as a potential risk factor for renal cell carcinoma (RCC). A population-based case-control study involving 550 non-Asian RCC patients 25 to 74 years of age and an equal number of sex-, age-, and race-matched neighborhood controls was conducted in Los Angeles, California. Detailed information on FH of cancer, medical and medication histories, and other life-style factors was obtained through in-person interviews. Having a first-degree relative with kidney cancer was associated with a significantly increased risk of RCC [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.04-5.9] after adjustment for potential confounding factors. Having a first and/or second-degree relative with kidney cancer was similarly associated with an increased risk of RCC (OR, 2.9; 95% CI, 1.4-6.3). Risk factors for RCC identified in the Los Angeles study include cigarette smoking, chronic obesity, history of hypertension, regular use of analgesics and amphetamines, intake of cruciferous vegetables (protective), and history of hysterectomy. None of the above risk factor-RCC associations differed significantly between RCC cases with and without a FH of kidney cancer. A FH of urinary tract cancers other than kidney cancer was not associated with RCC risk (OR, 0.7; 95% CI, 0.3-1.7). A FH of nonurinary tract cancers also was unrelated to RCC risk (OR, 1.1; 95% CI, 0.9-1.5).

Gender- and smoking-related bladder cancer risk.

BACKGROUND: There is growing evidence that, when smoking habits are comparable, women incur a higher risk of lung cancer than men. Because smokers are also at risk for bladder cancer, we investigated possible sex differences in the susceptibility to bladder cancer among smokers. METHODS: A population-based, case--control study was conducted in Los Angeles, CA, involving 1514 case patients with bladder cancer and 1514 individually matched population control subjects. Information on tobacco use was collected through in-person interviews. Peripheral blood was collected from study participants to measure 3- and 4-aminobiphenyl (ABP)-hemoglobin adducts, a marker of arylamine exposure. Data were analyzed to determine whether the risk of bladder cancer differs between male and female smokers and whether female smokers exhibit higher levels of ABP-hemoglobin adducts than male smokers with comparable smoking habits. All statistical tests were two-sided. RESULTS: Cigarette smokers had a statistically significant 2.5-fold higher risk (95% confidence interval = 2.1 to 3.0) of bladder cancer than never smokers. Use of filtered versus nonfiltered cigarettes, low-tar versus higher tar cigarettes, or the pattern of inhalation did not modify the risk. The risk of bladder cancer in women who smoked was statistically significantly higher than that in men who smoked comparable numbers of cigarettes (P =.016 for sex-lifetime smoking interaction). Consistent with the sex difference in smoking-related bladder cancer risk, the slopes of the linear regression lines of the 3- and 4-ABP--hemoglobin adducts by cigarettes per day were statistically significantly steeper in women than in men (P values for sex differences <.001 and.006, respectively). CONCLUSION: The risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes.

Use of permanent hair dyes and bladder-cancer risk.

A population-based case-control study was conducted in Los Angeles, California, which involved 1,514 incident cases of bladder cancer and an equal number of age-, sex- and ethnicity-matched controls. Information on personal use of hair dyes was obtained from 897 cases and their matched controls. After adjustment for cigarette smoking, a major risk factor for bladder cancer, women who used permanent hair dyes at least once a month experienced a 2.1-fold risk of bladder cancer relative to non-users (p for trend = 0.04). Risk increased to 3.3 (95% CI = 1.3-8.4) among regular (at least monthly) users of 15 or more years. Occupational exposure to hair dyes was associated with an increased risk of bladder cancer in this study. Subjects who worked for 10 or more years as hairdressers or barbers experienced a 5-fold (95% CI = 1.3-19.2) increase in risk compared to individuals not exposed.

Non-steroidal anti-inflammatory drugs and bladder cancer prevention.

Inclusion of phenacetin among 'proven' human carcinogens by the IARC in 1987, raised concerns about the carcinogenic potential of acetaminophen, its major metabolite. Acetaminophen has been implicated as a possible causal agent in the development of cancer of the renal pelvis. The bladder and renal pelvis, which derive from the same embryological structure, share the same transitional type of epithelium. Past studies have been inconclusive on the possible relationship among these analgesics and bladder cancer but no large, highly detailed study of this association has been conducted. A population-based case-control study conducted in Los Angeles, California, involved 1514 incident bladder cancer cases and an equal number of controls who were matched to the index cases by sex, date of birth (within 5 years) and race. Detailed information on medication use and prior medical conditions was collected through in-person interviews. Regular use of analgesics was not associated with an increased risk of bladder cancer in either men or women. In fact, compared with non- or irregular users, regular analgesic users were at a decreased risk of bladder cancer overall (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.68-0.96). However, there were clear differences in both the direction and strength of the associations between the different formulation classes of analgesics and bladder cancer risk. Intake of phenacetin was positively related to bladder cancer risk in a dose-dependent manner while intake of its major metabolite in humans, acetaminophen, was unrelated to risk. Intake of all classes of NSAIDs, except pyrazolon derivatives, were negatively associated with bladder cancer risk, with suggestive evidence that the protective effect varies in strength by subcategories of formulation. Acetic acids seemed to exhibit the strongest protective effect, whereas aspirin/other salicylic acids and oxicam showed the weakest protection.

Increased risk of renal cell carcinoma subsequent to hysterectomy.

In etiological studies of renal cell carcinoma, the associations between exogenous hormones, reproductive factors, or gynecological operations have not been well examined. Our aim was to evaluate gender-specific risk factors for renal cell carcinoma using data from a population-based case-control study conducted in Los Angeles, California and to elucidate possible underlying mechanisms. A population-based case-control study involving 422 female renal cell carcinoma patients, ages 25-74 years, and an equal number of sex-, age-, and race-matched neighborhood controls was conducted in Los Angeles, California. Detailed information regarding reproductive history, hysterectomy, use of exogenous estrogens, and other medical and lifestyle factors was collected through in-person interviews. Compared to women with an intact uterus, those who had undergone hysterectomy were at an increased risk for renal cell carcinoma (odds ratio, 1.8; 95% confidence interval, 1.3-2.5). Parity and use of estrogen replacement therapy were no longer risk factors for renal cell carcinoma when hysterectomy was adjusted for in the analysis. No association between renal cell carcinoma and use of oral contraceptives was found. Limited epidemiological data do not support an endocrine explanation for the observed hysterectomy-renal cell cancer association. We conjecture that unintentional injury to the ureter during the surgical procedure, which results in renal cell damage and consequent renal cell proliferation, may be a cause of the increased cancer risk in hysterectomized women.

Regular use of analgesics is a risk factor for renal cell carcinoma.

Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case-control study involving 1204 non-Asian RCC patients aged 25-74 and an equal number of sex-, age- and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non- or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6-1.4).

Cruciferous vegetables in relation to renal cell carcinoma.

Little is known about the possible role of diet in the development of renal cell carcinoma (RCC). A population-based case-control study was conducted in non-Asians of Los Angeles; it included 1,204 RCC patients and an equal number of neighborhood controls matched to the index cases by sex, date of birth (within 5 years) and ethnicity. Information on intake frequencies of food groups rich in vitamins A and C, various carotenoids and nitrosamines or their precursors was collected through in-person, structured interviews. After adjustment for non-dietary risk factors including level of education, obesity, history of hypertension, cigarette smoking and regular use of analgesics and amphetamines, there were strong inverse associations between cruciferous and dark green vegetable intakes and RCC risk (both p values for linear trend < 0.001). In terms of nutrients, there were significant inverse associations of RCC risk with consumption of a variety of carotenoids including alpha-carotene (p < 0.001), beta-carotene (p = 0.004), beta-cryptoxanthin (p = 0.01) and lutein (p = 0.005). However, after adjustment for these nutrients, we still observed a significant residual effect of cruciferous vegetables, suggesting that other substances present in these vegetables may be responsible, at least partially, for the observed reduction in risk of RCC. Dietary nitrosamines and their precursors were not related to RCC risk.

Hypertension, obesity and their medications in relation to renal cell carcinoma.

A population-based, case-control study was conducted in Los Angeles County, California, to investigate the inter-relationships of obesity, hypertension and medications in relation to renal cell carcinoma (RCC) risk. A total of 1204 RCC patients and an equal number of neighbourhood controls were included. Obesity was a strong risk factor for RCC. A fourfold increase in risk was observed for those with usual body mass index (kg m(-2)) of > or = 30 vs < 22. A history of hypertension was another strong, independent risk factor for RCC [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.8, 2.6]. There was little evidence that use of diuretics was directly related to RCC development. Use of diuretics for reasons other than hypertension (primarily for weight control) was unrelated to risk among self-reported normotensive subjects (OR = 1.2; 95% CI = 0.7, 2.2). Among hypertensive subjects, heavy users of diuretics experienced similar risk as light users (OR = 0.9 among subjects with lifetime dose of > or = 137 g compared with those with lifetime dose of < 43 g). Similarly, normotensive subjects who took non-diuretic antihypertensives regularly showed no increased risk for RCC (OR = 1.1; 95% CI = 0.6-1.8), and intake among hypertensive subjects did not further increase their risk. Regular use of amphetamine-containing diet pills was associated with a twofold increase in RCC risk (95% CI = 1.4-2.8) and the risk increased with increasing dose of amphetamines. However, the fraction of cases possibly related to this exposure is small (population-attributable risk = 5%).

Tobacco use in relation to renal cell carcinoma.

The modest effect of cigarette smoking on renal cell carcinoma (RCC) requires a study with a large number of subjects to definitively answer the question of whether smoking is causally related to RCC. A population-based case-control study was conducted in Los Angeles, California that involved 1204 RCC patients and an equal number of neighborhood controls who were matched to the index cases by sex, date of birth (within 5 years), and race. Detailed information on tobacco use was collected through in-person interviews. Cigarette smoking was associated with a statistically significant 35% increase in the risk of RCC [odds ratio (OR), 1.35; 95% confidence interval (CI), 1.14-1.60]. The risk increased with increasing number of cigarettes smoked per day (two-sided P < 0.001, linear trend test). Former smokers (OR, 1.24; 95% CI, 1.02-1.50) had a lower risk of RCC than current smokers (OR, 1.53; 95% CI, 1.23-1.90). Compared with current smokers, those who quit smoking 10 or more years ago experienced a statistically significant 30% reduction in the risk of RCC. Current smokers who smoked 40 or more cigarettes/day experienced a nearly 2-fold increase in the risk of RCC compared with lifelong nonsmokers. The association between cigarette smoking and RCC was similar in men and women. There were no measurable differences in the risk of RCC between filtered and nonfiltered cigarette smokers or between those who inhaled cigarette smoke deeply and those who inhaled lightly after adjustment for the number of cigarettes smoked per day and current smoking status. After the effect of cigarette smoking was accounted for, heavy cigar smokers (14 or more cigars/week) exhibited a statistically significant 70% increase in the risk of RCC, but no increased risk of RCC was observed for the use of pipes or smokeless tobacco. Seventeen percent of RCC (21% in men and 11% in women) in Los Angeles, California can be attributed to cigarette smoking.