Chien-Hung Lee

Independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer in Taiwan

A multicenter case‐control study was conducted in northern and southern Taiwan to clarify the independent and combined effects of alcohol intake, tobacco smoking and betel quid chewing on the risk of esophageal cancer. A total of 513 patients with newly diagnosed and histopathologically confirmed squamous cell carcinoma of the esophagus and 818 gender, age and study hospital‐matched controls were included. We found a significant dose‐response relationship between the duration and intensity of consumption of the 3 substances and the development of this neoplasm in this site. Although the amount of alcohol consumed had a stronger effect on the risk of esophageal cancer than the number of years it was consumed, however, the number of years one smoked had a stronger effect on the risk than the amount of cigarettes consumed. The strongest risk factor of esophageal cancer was alcohol intake, with highest risk (OR = 13.9) being for those who consumed more than 900 g/day‐year. Combined exposure to any 2 of 3 substances brought the risks up to 8.8–19.7 fold and, to all 3 substances, to 41.2‐fold. A multiplicative interaction effect for alcohol drinkers who smoked on cancer risk was detected, whereas an additive interaction effect was found among drinkers who chewed. The combined effect of all 3 substances accounted for 83.7% of the attributable fraction of contracting esophageal cancer in this population. In conclusion, these results suggest that the intensity and the length of time alcohol and tobacco are used play different roles in the etiology of esophageal cancer. Alcohol separately interacts with tobacco and betel quid in a differently synergistic way in determining the development of this site of cancer.

Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individuals alcohol‐metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case‐control study was conducted. Here, 406 patients with pathology‐proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low‐to‐moderate (0.1–30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low‐to‐moderate drinkers, a smoking‐dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra‐multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk.

Different impact from betel quid, alcohol and cigarette: risk factors for pharyngeal and laryngeal cancer.

The risks of betel quid chewing with or without tobacco, alcohol drinking and cigarette smoking have been well explored in the oral cavity but not in the pharynx and larynx. We conducted a case‐control study to investigate the association of these three risk factors to cancers of the pharynx and larynx in Taiwan. A total cases of 148 pharyngeal cancer, 128 laryngeal cancer and 255 hospital controls, all men, were recruited. Betel quid chewing was a significant independent risk factor (adjusted odds ratio [aOR] = 7.7; 95% confidence interval [CI] = 4.1–15.0) similar to that of alcohol drinking (aOR = 6.6; 95% CI = 3.5–13.0) for pharyngeal cancer, but not for laryngeal cancer (aOR = 1.3; 95% CI = 0.7–2.5) on which cigarette smoking (aOR = 7.1) exerts a stronger significant independent risk than alcohol drinking (aOR = 3.8). For pharyngeal cancers, chewers who consumed >20 quid/day, chewed with inflorescence in the quid or swallowed the betel quid juice were at higher risks; significant dose‐response effects were found in daily quantity of drinking and chewing, and cumulative quantity of drinking. Synergistic effects from the 3 risk factors existed both on the pharynx (aOR = 96.9) and the larynx (aOR = 40.3), and attributed for 93.1% and 92.9% respectively. Our study is the first evidence to show that betel quid chewing without tobacco has different impact on the pharynx (digestive tract) and the larynx (airway), and supports the concept that exposure quantity and direct mucosal contact with the betel quid juice may contribute to carcinogenesis. Our results show an important insight into the impact of betel quid chewing on other sites of the digestive tract other than the oral cavity.

G-2548A Polymorphism of the Leptin Gene Is Correlated with Extreme Obesity in Taiwanese Aborigines

We examined the genetic associations of the G‐2548A polymorphism in the promoter of the leptin (LEP) gene and the Gln223Arg (Q223R) polymorphism of the leptin receptor (LEPR) gene with obesity. Two hundred twenty‐six obese aboriginal subjects (BMI ≥ 27 kg/m2) and 182 aboriginal subjects with normal weight (BMI < 25 kg/m2) participated in this study. The polymorphisms of LEP G‐2548A and LEPR Q223R were genotyped by polymerase chain reaction/restriction fragment length polymorphism, and their anthropometric characteristics were measured. Levels of leptin, triglycerides, and cholesterol were measured after overnight fasting. We found that the frequencies of the LEP G/G homozygote (22.6%) with Mendelian recessive (χ2 = 7.89, p = 0.005) and codominant (χ2 = 7.93, p = 0.02) models to be higher in the extremely obese subjects (BMI ≥ 35 kg/m2) than in normal weight subjects (6.9%) but not in moderately obese subjects (35 > BMI ≥ 27 kg/m2). There was no difference in genotypic frequency of the LEPR Q223R polymorphism between the extreme obese and control groups. We suggest that the LEP −2548 G/G homozygote plays a genetic recessive role in the development of extreme obesity in Taiwanese aborigines.

Intercountry prevalences and practices of betel-quid use in south, southeast and eastern asia regions and associated oral preneoplastic disorders: An international collaborative study by asian betel-quid consortium of south and east Asia

Health risks stemming from betel‐quid (BQ) chewing are frequently overlooked by people. Updated epidemiological data on the increased BQ use among Asian populations using comparable data collection methods have not been widely available. To investigate the prevalence, patterns of practice and associated types of oral preneoplastic disorders, an intercountry Asian Betel‐quid Consortium study (the ABC study) was conducted for Taiwan, Mainland China, Malaysia, Indonesia, Nepal and Sri Lanka. A random sample of 8,922 subjects was recruited, and the data were analyzed using survey‐data modules adjusted for the complex survey design. Chewing rates among men (10.7–43.6%) were significantly higher than women (1.8–34.9%) in Taiwan, Mainland China, Nepal and Sri Lanka, while womens rates (29.5–46.8%) were higher than that for men (9.8–12.0%) in Malaysia and Indonesia. An emerging, higher proportion of new‐users were identified for Hunan in Mainland China (11.1–24.7%), where Hunan chewers have the unique practice of using the dried husk of areca fruit rather than the solid nut universally used by others. Men in the Eastern and South Asian study communities were deemed likely to combine chewing with smoking and drinking (5.6–13.6%). Indonesian women who chewed BQ exhibited the highest prevalence of oral lichen planus, oral submucous fibrosis and oral leukoplakia (9.1–17.3%). Lower schooling, alcohol drinking and tobacco smoking were identified as being associated with BQ chewing. In conclusion, the ABC study reveals the significant cultural and demographic differences contributing to practice patterns of BQ usage and the great health risks that such practices pose in the Asian region.

The Heterogeneity in Risk Factors of Lung Cancer and the Difference of Histologic Distribution between Genders in Taiwan

Objective: The difference in histologic patterns of lung cancer between men and women in Taiwan may be associated with the heterogeneity in causal factors of lung cancer between the sexes. Methods: Cases consisted of 236 male and 291 female incident cases with newly diagnosed and histologically confirmed primary carcinoma of the lung, and were compared to one or two individually matched controls. Results: Cigarette smoking, occupations, and previous tuberculosis history were found to independently correlate with an elevated risk of squamous/small cell carcinoma and adenocarcinoma for male patients. However, there was little difference in the effect of these risk factors except smoking. The use of fume extractors in the kitchen, and the habit of waiting to fry after the fumes were emitted, separately explained the majority of the attributable fraction of female squamous/small cell carcinoma (28.2%) and adenocarcinoma (47.7%). With the exception of a kitchen with fume extractors and a clinical history of tuberculosis, the environmental causal factors of lung cancer were heterogeneous between these two histologic cell groups. Conclusions: Our results suggested that the causal factors of lung cancer might be specific for the type of tumor concerned. The gender-specific risk factors of lung cancer could partly explain the difference in cell-type distribution between men and women.

Up-regulation of Inflammatory Signalings by Areca Nut Extract and Role of Cyclooxygenase-2 −1195G>A Polymorphism Reveal Risk of Oral Cancer

Because the mRNA expression of cyclooxygenase-2 (COX-2) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of COX-2 and its upstream effectors in three oral epithelial carcinoma cell lines (KB, SAS, and Ca9-22) by using areca nut extract (ANE) and saliva-reacted ANE (sANE). A case-control study of 377 oral squamous cell carcinoma (OSCC) patients and 442 controls was conducted to evaluate the gene-environment interaction between COX-2 promoter polymorphisms and substance use of alcohol, betel quid, and cigarettes (ABC) in risk of OSCC. The heterogeneous characteristics of the oral site and the COX-2 -1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB>>Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the COX-2 up-regulation might be mostly elicited from alternative nuclear factor-kappaB activation. In the case-control study, betel chewing [adjusted odds ratios (aOR), 42.2] posed a much higher risk of OSCC than alcohol drinking and cigarette smoking (aORs, 2.4 and 1.8, respectively), whereas the COX-2 -1195A/A homozygote presented a potential genetic risk (OR, 1.55). The strongest joint effect for OSCC was seen in betel chewers with -1195A/A homozygote (aOR, 79.44). In the non-betel chewing group, the -1195A/G and A/A genotypes together with the combined use of alcohol and cigarettes increased risk to 15.1-fold and 32.1-fold, respectively, compared with the G/G genotype without substance use. Taken together, these findings illustrate a valuable insight into the potential role of the COX-2 promoter region in contributing to the development of betel-related OSCC, including ANE/sANE-induced transcriptional effects and enhanced joint effects of COX-2 -1195A allele with substance use of ABC.

Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders

Objective To study the associations of gout, tophi and uric acid levels with the gout-related SLC2A9 (solute carrier family 2, member 9) single nucleotide polymorphisms (SNPs) between two different racial groups. Methods Eight SLC2A9 SNPs were genotyped in 109 subjects with gout and 191 control subjects from Han Chinese men in Taiwan and 69 subjects with gout and 168 control subjects from the Solomon Islands. Results Non-synonymous SLC2A9 rs3733591 Arg265His was associated with risk for gout and tophaceous gout in Han Chinese subjects (p=0.0012 and p=0.0044). The genetic effect of this SNP on tophaceous gout was replicated in Solomon Islanders (p=0.0184). Patients with SLC2A9 Arg265His risk C-allele consistently had a higher risk for tophi (OR 2.05–2.15) than non-tophi (OR 0.91–1.62). SNP rs3733591 described 3.68% and 5.98% of the total variability in uric acid levels for Chinese and Solomon Island subjects, respectively. Conclusion Non-synonymous SNP rs3733591 variant within the SLC2A9 gene from two geographically diverse populations served as an important genetic checkpoint for tophaceous gout and increased uric acid levels.

The effect of maternal betel quid exposure during pregnancy on adverse birth outcomes among aborigines in Taiwan

In considering documented developmental toxicity and teratogenicity found in earlier research, maternal betel quid chewing may very well be linked to a higher risk of adverse birth outcomes. The aim of this study was to investigate the significance of betel quid chewing, together with the use of cigarettes or alcohol, either independently or combined, on birth-related outcomes. A total of 1264 aboriginal women who had just given birth in 10 hospitals in Southern and Eastern Taiwan were recruited. Information on their maternal and newborn characteristics was obtained from medical charts and by performing personal interviews using a validated questionnaire. Maternal areca nut chewing during pregnancy was found to be significantly associated with both birth weight loss (-89.54 g) and birth length reduction (-0.43 cm). A significantly lower male newborn rate (aOR=0.62) was observed among aboriginal women with a habit of betel quid chewing during pregnancy. The use of this substance conveyed a 2.40- and 3.67-fold independent risk of low birth weight and full-term low birth weight, respectively. An enhanced risk (aOR=3.26-5.99) of low birth weight was observed among women concomitantly using betel quid, cigarette and alcohol during gestation. Our findings suggest that betel quid chewing during pregnancy has a substantial effect on a number of birth outcomes, including sex ratio at birth, lower birth weight and reduced birth length.

Consumption of Sugar-Sweetened Beverages Is Associated with Components of the Metabolic Syndrome in Adolescents

Sugar-sweetened beverages (SSBs) are the principle source of added sugar in diets. Cardiometabolic disturbances can occur from early childhood to adulthood. The aim of this cross-sectional study was to examine the gender-specific association of SSB intake with metabolic syndrome (MetS) and its components among adolescents in Taiwan. A total of 2727 adolescents aged 12 to 16 years randomly selected from three diverse economic areas in Southern Taiwan by using a multistage-sampling strategy participated in this study. Demographic, dietary, physical and anthropometric parameters were measured, and serum lipid profiles and glucose levels were determined. The International Diabetes Federation (IDF) specifies that MetS requires abdominal obesity and ≥2 abnormal components, and Cook criteria for MetS require ≥3 abnormal components. We applied survey-data modules to data analyses, and used multiple regression and logistic models to adjust for covariates. An increased SSB intake was linked to a greater waist circumference in both sexes and to systolic blood pressure in boys (P for trend: ≤0.043). Male moderate and high consuming SSB drinkers exhibited triglyceride levels that were 8.0 and 8.2 mg/dL significantly higher, respectively, than those of nondrinkers. Compared with nondrinkers, boys who consumed >500 mL/day (high quantity) of SSBs exhibited 10.3-fold (95% confidence intervals (CIs): 1.2-90.2) and 5.1-fold (95% CIs: 1.01-25.5) risks of contracting MetS, as defined by the IDF and Cook criteria for MetS, respectively. In girls, the risk estimates for the same comparison were not significant by the IDF criteria (6.5-fold risk, 95% CIs: 0.9-∞) or Cook criteria (5.9-fold risk, 95% CIs: 0.8-43.8) for MetS. High SSB consumption was also linked to 1.9-fold (95% CIs: 1.1-3.1) and 2.7-fold (95% CIs: 1.3-5.7) higher risks of being at a greater overall metabolic risk in girls and boys, respectively. In conclusion, a high SSB intake is associated with adolescent MetS among boys but not girls in Taiwan.