Meat, smoking, alcohol, and colorectal tumors: the role of genetic susceptibility

Colorectal cancer is the second most common cancer in the Western world and is thought to arise mainly from colorectal adenomas. Red meat and alcohol intake and (long-term) cigarette smoking probably increase colorectal tumor risk. Although risk increase was found to be weak, certain subgroups might be more susceptible to these carcinogens because of inherited polymorphisms resulting in increased activation of potential carcinogens. In this thesis, we investigated whether meat consumption, cigarette smoking, and alcohol intake, in combination with such genetic polymorphisms, increase the risk of colorectal adenomas and colorectal cancer.For this purpose, we used two different study populations. One was an adenoma case-control study with 440 adenoma cases and 447 polyp-free controls recruited among those undergoing endoscopy at eight Dutch outpatient clinics between June 1997 and June 2000. The other was a Dutch prospective cohort enrolled between January 1987 and December 1991. Follow-up for 8.5 years resulted in 102 colorectal cancer cases. We compared these cases with a random sample of 537 controls frequency-matched on age, sex and town. Information on dietary and lifestyle habits was collected through self-administered questionnaires. DNA was isolated from whole blood and genetic polymorphisms were subsequently determined by use of standardized methods.We found that colorectal adenoma risk was not increased with high meat consumption (OR 1.2, 95% CI 0.8-1.9) or unfavorable meat preparation methods. These null-associations were not modified by genetic polymorphisms affecting metabolism of heterocyclic amines that may be formed during preparation of meat at high temperatures ( N -acetyltransferases ( NAT ) 1 and 2, sulfotransferase ( SULT ) 1A1 , and glutathione S- transferases ( GST ) M1 and T1 ). Long-term cigarette smoking increased adenoma risk (OR 2.4, 95% CI 1.4-4.1 for smoking for more than 25 years compared to never smokers). Although most pronounced in those with fast SULT1A1 (OR 4.3, 95% CI 1.6-11.8) and slow NAT2 variants (OR 3.5, 95% CI 1.9-6.4), there was no statistically significant effect modification by genetic polymorphisms involved in metabolism of arylamines and polycyclic aromatic hydrocarbons from cigarette smoke ( NAT1 , NAT2 , SULT1A1 , GSTM1 , GSTT1 , and epoxide hydrolase). Alcohol consumption increased colorectal adenoma risk especially among women (OR 1.8, 95% CI 1.0-3.2 for 10 or more drinks weekly versus less than one drink per week). Among men, adenoma risk increased only with consumption of more than 21 drinks per week (OR 1.8, 95% CI 0.9-3.8). Alcohol is metabolized to carcinogenic acetaldehyde by alcohol dehydrogenase (ADH3). The association between alcohol and adenomas was weakly - but not statistically significantly - stronger among those with the fast ADH3 variant compared to those with imputed slow phenotypes.Colorectal cancer risk increased slightly with frequent red meat consumption (OR 1.6, 95% CI 0.9-2.9, highest vs. lowest intake). Genetic polymorphisms in NAT1 , NAT2 , and GSTM1 did not importantly modify this association. Risk of colorectal cancer was increased with smoking duration, but only among former smokers having smoked for more than 15 years (OR 2.7, 95% CI 1.0-7.4) compared to former smokers having smoked for shorter time. NAT1 , NAT2 , and GSTM1 polymorphisms did not influence this association.In summary, the results of our studies do not point toward strong modifying effects of genetic polymorphisms of enzymes involved in carcinogen metabolism, which is in accordance with results of similar studies on colorectal tumors. Such effects may however be present, but possibly, we were not able to demonstrate them. To elucidate the potential role of genetic susceptibility in colorectal carcinogenesis, alternative epidemiologic study designs and statistical methods should be considered. These observational studies should be conducted simoultaneously with experimental studies aiming to generate more biological knowledge on the diverse processes leading to colorectal tumorigenesis in humans

Estimating the contribution of subclinical tuberculosis disease to transmission: an individual patient data analysis from prevalence surveys

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6–2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62–6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27–92%, 95% PrI) of global transmission is from subclinical TB. Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination

Meat, smoking, alcohol, and colorectal tumors: the role of genetic susceptibility

Colorectal cancer is the second most common cancer in the Western world and is thought to arise mainly from colorectal adenomas. Red meat and alcohol intake and (long-term) cigarette smoking probably increase colorectal tumor risk. Although risk increase was found to be weak, certain subgroups might be more susceptible to these carcinogens because of inherited polymorphisms resulting in increased activation of potential carcinogens. In this thesis, we investigated whether meat consumption, cigarette smoking, and alcohol intake, in combination with such genetic polymorphisms, increase the risk of colorectal adenomas and colorectal cancer.For this purpose, we used two different study populations. One was an adenoma case-control study with 440 adenoma cases and 447 polyp-free controls recruited among those undergoing endoscopy at eight Dutch outpatient clinics between June 1997 and June 2000. The other was a Dutch prospective cohort enrolled between January 1987 and December 1991. Follow-up for 8.5 years resulted in 102 colorectal cancer cases. We compared these cases with a random sample of 537 controls frequency-matched on age, sex and town. Information on dietary and lifestyle habits was collected through self-administered questionnaires. DNA was isolated from whole blood and genetic polymorphisms were subsequently determined by use of standardized methods.We found that colorectal adenoma risk was not increased with high meat consumption (OR 1.2, 95% CI 0.8-1.9) or unfavorable meat preparation methods. These null-associations were not modified by genetic polymorphisms affecting metabolism of heterocyclic amines that may be formed during preparation of meat at high temperatures ( N -acetyltransferases ( NAT ) 1 and 2, sulfotransferase ( SULT ) 1A1 , and glutathione S- transferases ( GST ) M1 and T1 ). Long-term cigarette smoking increased adenoma risk (OR 2.4, 95% CI 1.4-4.1 for smoking for more than 25 years compared to never smokers). Although most pronounced in those with fast SULT1A1 (OR 4.3, 95% CI 1.6-11.8) and slow NAT2 variants (OR 3.5, 95% CI 1.9-6.4), there was no statistically significant effect modification by genetic polymorphisms involved in metabolism of arylamines and polycyclic aromatic hydrocarbons from cigarette smoke ( NAT1 , NAT2 , SULT1A1 , GSTM1 , GSTT1 , and epoxide hydrolase). Alcohol consumption increased colorectal adenoma risk especially among women (OR 1.8, 95% CI 1.0-3.2 for 10 or more drinks weekly versus less than one drink per week). Among men, adenoma risk increased only with consumption of more than 21 drinks per week (OR 1.8, 95% CI 0.9-3.8). Alcohol is metabolized to carcinogenic acetaldehyde by alcohol dehydrogenase (ADH3). The association between alcohol and adenomas was weakly - but not statistically significantly - stronger among those with the fast ADH3 variant compared to those with imputed slow phenotypes.Colorectal cancer risk increased slightly with frequent red meat consumption (OR 1.6, 95% CI 0.9-2.9, highest vs. lowest intake). Genetic polymorphisms in NAT1 , NAT2 , and GSTM1 did not importantly modify this association. Risk of colorectal cancer was increased with smoking duration, but only among former smokers having smoked for more than 15 years (OR 2.7, 95% CI 1.0-7.4) compared to former smokers having smoked for shorter time. NAT1 , NAT2 , and GSTM1 polymorphisms did not influence this association.In summary, the results of our studies do not point toward strong modifying effects of genetic polymorphisms of enzymes involved in carcinogen metabolism, which is in accordance with results of similar studies on colorectal tumors. Such effects may however be present, but possibly, we were not able to demonstrate them. To elucidate the potential role of genetic susceptibility in colorectal carcinogenesis, alternative epidemiologic study designs and statistical methods should be considered. These observational studies should be conducted simoultaneously with experimental studies aiming to generate more biological knowledge on the diverse processes leading to colorectal tumorigenesis in humans