Jae Woong Sull

Body mass index and cancer risk in Korean men and women

Obesity is associated with diverse health risks, but the role of body weight (BMI) as a risk factor for all and site‐specific cancers remains controversial and risks for cancer associated with obesity have not been well‐characterized in Asians. Body weight and risk for cancer were examined in a 14‐year prospective cohort study of 1,213,829 Koreans aged 30–95 years insured by the National Health Insurance Corporation who had a biennial medical evaluation in 1992–1995. Incidence rates for all cancers and site‐specific cancers were examined in relation to BMI. Age‐ and smoking‐status adjusted hazard ratios (HR) with 95% confidence intervals (CI) were examined using the Cox proportional hazards model. For both sexes, the average baseline BMI was 23.2 kg/m2, and the association of risk for all‐cancers with BMI was positive. Obese men (BMI ≥ 30 kg/m2) were at increased risk for developing the following cancers: stomach (1.31, 1.05–1.64), colon (1.42, 1.02–1.98), liver (1.63, 1.27–2.10) and gallbladder (1.65, 1.11–2.44). Obese women (BMI ≥ 30 kg/m2) were at increased risk for developing liver cancer (1.39, 1.00–1.94), pancreatic cancer (1.80, 1.14–2.86) and breast cancer among women aged ≥50 years old (1.38, 1.00–1.90). The HRs were comparable in never and ever smokers for all cancers and all specific sites except for lung cancer. For all cancers common to both sexes, the association was significantly weaker (p < 0.01) in females. Our study provides further confirmation of the excess cancer risk associated with obesity. Rising obesity in Asian populations raises concern that increasing numbers of avoidable cancer cases will occur among Asians.

Adiponectin concentrations: a genome-wide association study.

Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10(-15) in the initial sample, p = 6.58 × 10(-39) in the second genome-wide sample, and p = 2.12 × 10(-32) in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10(-83). The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10(-58)) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults.

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2–5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright’s fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6–WNT10A and COL4A3–COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

Body Mass Index and Stroke Mortality by Smoking and Age at Menopause Among Korean Postmenopausal Women

Background and Purpose— The association between body mass index and mortality caused by subtypes of stroke among postmenopausal women in terms of smoking status and age at menopause remains controversial. Methods— The data were derived from a cohort study of 3321 with 17.8 years of follow-up (1985 to 2002). Hazard ratios (HRs) and 95% CIs for strokes as related to body mass index were estimated by Cox proportional hazard models adjusted for age, hypertension, smoking, drinking, occupation, education, self-reported health, and age at menopause. A stratified analysis was conducted by age at menopause and smoking status. Results— The obese group (body mass index ≥27.5 kg/m2) had higher risks of total stroke mortality (HR, 1.59; 95% CI, 1.05 to 2.42) and hemorrhagic stroke mortality (HR, 2.91; 95% CI, 1.37 to 6.19) than the normal weight group (18.5≤ body mass index <23.0). Among ever smokers, the obese group showed significantly increased risks of total stroke mortality (HR, 2.33; 95% CI, 1.00 to 5.43) and ischemic stroke mortality (HR, 7.21; 95% CI, 1.18 to 44.3). Obesity had more effect on stroke mortality among women who experienced menopause at age <50 than women with age ≥50. For the obese group of the former, the HR of total stroke was 2.04 (95% CI, 1.25 to 3.34) and that of hemorrhagic stroke 6.46 (95% CI, 2.42 to 17.25). Conclusions— In this prospective study, obesity raised the risks of total stroke mortality and hemorrhagic stroke mortality among Korean menopausal women. It was more evident with women who experienced menopause at age <50. The obese group of ever smokers was at an increased risk of ischemic stroke mortality.

Reproductive risk factors for cardiovascular disease mortality among postmenopausal women in Korea: the Kangwha Cohort Study, 1985-2005.

Objective:The relationship between reproductive factors and the risk of mortality from cardiovascular disease in postmenopausal women is unclear. In this study, we aimed to investigate this relationship in Korean postmenopausal women. Methods:Subcohort analysis was carried out using the data of 3,257 postmenopausal women (age, ≥55 y at study entry) from the Kangwha Cohort Study who were followed up from 1985 until 2005. Cox proportional hazards models were used to evaluate the associations between reproductive factors and cardiovascular disease mortality. Results:The risk of cardiovascular mortality in women who were 20 to 22 years old at first childbirth was 26% lower (95% CI, 0.60-0.92) than that in women younger than 20 years at first childbirth, after adjustment for age at entry, body mass index, hypertension, drinking, smoking, education, and occupation. Early first childbirth was associated with increased cardiovascular disease mortality (P trend = 0.036). The risk of coronary heart disease mortality was 51% lower in women who were 17 to 18 years old at menarche (95% CI, 0.25-0.95) than that in women who were younger than 17 years at menarche. Conclusions:An inverse relationship between age at first childbirth and the risk of cardiovascular disease mortality exists. In addition, early menarche may be a reproductive risk factor for coronary heart disease mortality.

Binge Drinking and Hypertension on Cardiovascular Disease Mortality in Korean Men and Women: A Kangwha Cohort Study

Background and Purpose— The purpose of this study was to examine combined effects of hypertension and binge drinking on the risk of mortality from cardiovascular disease in Koreans. Methods— This study followed a cohort of 6100 residents in Kangwha County, aged ≥55 years as of March 1985, for cardiovascular mortality for 20.8 years up to December 31, 2005. We calculated hazard ratios (HRs) for cardiovascular mortality by blood pressure and binge drinking habits using the Cox proportional hazard model. Binge drinkers and heavy binge drinkers were defined as having ≥6 drinks on 1 occasion and ≥12 drinks on 1 occasion. Results— After adjusting for total alcohol consumption, male heavy binge drinkers with Grade 3 hypertension had a 12-fold increased risk of cardiovascular mortality (HR, 12.7; 95% CI, 3.47 to 46.5), whereas male binge drinkers with Grade 3 hypertension had a 4-fold increased risk of cardiovascular mortality (HR, 4.41; 95% CI, 1.38 to 14.1) when compared with nondrinkers with normal blood pressure. However, in considering separate effects of heavy binge drinking and hypertension on the risk of cardiovascular mortality, HRs were rather low (HR of heavy binge drinkers, 1.88, 1.10 to 3.20; HR of hypertensives, 2.00, 1.70 to 2.35) compared with nondrinkers with normal blood pressure. Conclusions— Binge drinkers and heavy binge drinkers with Grade 3 hypertension showed a marked increase in cardiovascular mortality risk. Even after adjusting for total alcohol consumption, the former revealed 4.41 and the latter indicated 12.7 of HR for the risk of cardiovascular mortality.

Alcohol Consumption and Digestive Cancer Mortality in Koreans: The Kangwha Cohort Study

Background Alcohol consumption is a known risk factor for cancers of the mouth, esophagus, liver, colon, and breast. In this study, we examined the association between alcohol consumption and digestive cancer mortality in Korean men and women. Methods A cohort of 6291 residents of Kangwha County who were aged 55 years or older in March 1985 were followed to 31 December 2005—a period of 20.8 years. We calculated the relative risks of cancer mortality with respect to the amount of alcohol consumed. Cox proportional hazard model was used to adjust for age at entry, smoking, ginseng intake, education status, and pesticide use. Results In men, the risks of mortality from esophageal cancer (relative risk [RR], 5.62; 95% confidence interval [CI], 1.45–21.77) and colon cancer (RR, 4.59; 95% CI, 1.10–19.2) were higher among heavy drinkers, as compared with abstainers. The risks of mortality from colon cancer and bile duct cancer rose with increasing alcohol consumption; these trends were positive and statistically significant (P = 0.04 and P = 0.02, respectively). When participants were stratified by type of alcoholic beverage, soju drinkers had higher risks of mortality from esophageal cancer and colon cancer than makkoli drinkers. In women, the risk of digestive cancer mortality was higher among alcohol drinkers than abstainers, but this difference was not statistically significant. Conclusions Alcohol consumption increases mortality from esophageal cancer and colon cancer in men.

Binge Drinking and Mortality From All Causes and Cerebrovascular Diseases in Korean Men and Women: A Kangwha Cohort Study

Background and Purpose— The purpose of this study was to examine the association between binge drinking and risks of mortality due to all causes of death with a focus on cerebrovascular disease in Korean men and women. Methods— This study followed a cohort of 6291 residents in Kangwha County, aged ≥55 years in March 1985, for their cause-specific mortality for 20.8 years up to December 31, 2005. We calculated hazard ratio of mortality by experience or frequency of binge drinking using the Cox proportional hazard model. Binge drinking was defined as having ≥6 drinks on one occasion. Results— In men, binge drinkers who drink daily had an increased risk of mortality from all causes (hazard ratio, 1.33; 95% CI, 1.11 to 1.60) as compared with nondrinkers. They showed much increased risks of mortality from total stroke (hazard ratio, 1.86; 95% CI, 1.16 to 2.99) and hemorrhagic stroke (hazard ratio, 3.39; 95% CI, 1.38 to 8.35). Female binge drinkers also showed an increased risk of mortality from cardiovascular disease as compared with female nondrinkers, but the outcome was not statistically significant. Conclusions— The results of this study suggest that frequent binge drinking has a harmful effect on hemorrhagic stroke in Korean men. These findings need to be confirmed in further studies.

Serum adiponectin as a useful marker for metabolic syndrome in type 2 diabetic patients

Although adiponectin is generally known as a predictor of metabolic syndrome, potential of adiponectin as a predictor for metabolic syndrome in type 2 diabetes is debated. The purpose of this study is to determine the association between adiponectin and metabolic syndrome in patients with type 2 diabetes.

Differential parental transmission of markers in RUNX2 among cleft case-parent trios from four populations

Isolated cleft lip with or without cleft palate (CL/P) is among the most common human birth defects, with a prevalence around 1 in 700 live births. The Runt‐related transcription factor 2 (RUNX2) gene has been suggested as a candidate gene for CL/P based largely on mouse models; however, no human studies have focused on RUNX2 as a risk factor for CL/P. This study examines the association between markers in RUNX2 and isolated, nonsyndromic CL/P using a case‐parent trio design, while considering parent‐of‐origin effects. Case‐parent trios from four populations (77 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 24 single nucleotide polymorphisms (SNPs) in the RUNX2 gene. We performed the transmission disequilibrium test on individual SNPs. Parent‐of‐origin effects were assessed using the transmission asymmetry test and the parent‐of‐origin likelihood ratio test (PO‐LRT). When all trios were combined, the transmission asymmetry test revealed a block of 11 SNPs showing excess maternal transmission significant at the P<0.01 level, plus one SNP (rs1934328) showing excess paternal transmission (P=0.002). For the 11 SNPs showing excess maternal transmission, odds ratios of being transmitted to the case from the mother ranged between 3.00 and 4.00. The parent‐of‐origin likelihood ratio tests for equality of maternal and paternal transmission were significant for three individual SNPs (rs910586, rs2819861, and rs1934328). Thus, RUNX2 appears to influence risk of CL/P through a parent‐of‐origin effect with excess maternal transmission. Genet. Epidemiol. 2008.