Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Association between family history with lung cancer incidence and mortality risk in the Asia Cohort Consortium.

Family history of lung cancer (FHLC) has been widely studied but most prospective cohort studies have primarily been conducted in non-Asian countries. We assessed the association between FHLC with risk of lung cancer (LC) incidence and mortality in a population of East Asian individuals. A total of 478,354 participants from 11 population-based cohorts in the Asia Cohort Consortium were included. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7,785 LC incident cases were identified. FHLC (any LC subtype) was associated with an increased risk of LC incidence (HR = 1.45, 95% CI = 1.30-1.63). The positive association was observed in men and women (HR = 1.44, 95% CI = 1.26-1.66 in men; HR = 1.47, 95% CI = 1.22-1.79 in women), and in both never-smokers and ever-smokers (HR = 1.43, 95% CI = 1.18-1.73 in never-smokers; HR = 1.46, 95% CI =1.27-1.67 in ever-smokers). FHLC was associated with an increased risk of lung adenocarcinoma (HR = 1.63, 95% CI: 1.36-1. 94), squamous cell carcinoma (HR = 1.88, 95% CI: 1.46-2.44), and other non-small cell LC (HR = 1.94, 95% CI: 1.02-3.68). However, we found no evidence of significant effect modification by sex, smoking status, and ethnic groups. In conclusion, FHLC was associated with increased risk of LC incidence and mortality, and the associations remained consistent regardless of sex, smoking status and ethnic groups among the East Asian population.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Relationship between urinary potassium excretion, serum potassium levels and cardiac injury in non-dialysis chronic kidney disease: KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD).

Although the cardiovascular benefits of an increased urinary potassium excretion have been suggested, little is known about the potential cardiac association of urinary potassium excretion in patients with chronic kidney disease. In addition, whether the cardiac association of urinary potassium excretion was mediated by serum potassium levels has not been studied yet. We reviewed the data of 1633 patients from a large-scale multicentre prospective Korean study (2011-2016). Spot urinary potassium to creatinine ratio was used as a surrogate for urinary potassium excretion. Cardiac injury was defined as a high-sensitivity troponin T ≥ 14 ng/l. OR and 95 % (CI for cardiac injury were calculated using logistic regression analyses. Of 1633 patients, the mean spot urinary potassium to creatinine ratio was 49·5 (sd 22·6) mmol/g Cr and the overall prevalence of cardiac injury was 33·9 %. Although serum potassium levels were not associated with cardiac injury, per 10 mmol/g Cr increase in the spot urinary potassium to creatinine ratio was associated with decreased odds of cardiac injury: OR 0·917 (95 % CI 0·841, 0·998), P = 0·047) in multivariate logistic regression analysis. In mediation analysis, approximately 6·4 % of the relationship between spot urinary potassium to creatinine ratio and cardiac injury was mediated by serum potassium levels, which was not statistically significant (P = 0·368). Higher urinary potassium excretion was associated with lower odds of cardiac injury, which was not mediated by serum potassium levels.

Ethnic-specific associations between body mass index and gastric cancer: a Mendelian randomization study in European and Korean populations.

BACKGROUND: Given the uncertainties surrounding the associations in previous epidemiological studies, we conducted linear and nonlinear Mendelian randomization (MR) studies to evaluate whether body mass index (BMI) associated with gastric cancer (GC) risk in European and Korean. METHODS: Genome-wide association study-summary statistics were used from the Pan-UK Biobank, the Genetic Investigation of Anthropometric Traits consortium, the K-CHIP consortium, and BioBank Japan. BMI-associated single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) in MR to identify the association between BMI and GC. Both linear and nonlinear MR analyses were performed. Sensitivity analyses were also conducted for individuals below or above a BMI of 24 kg/m2. RESULTS: The study used 22 and 55 SNPs as IVs for BMI in European and Korean populations, respectively. Genetically predicted BMI was positively associated with GC risk in the European population (Odds ratio per 1 kg/m2 increase; 95% CI = 1.17; 1.01-1.36 using simple median method), but no significant association was observed in the Korean population. However, the nonlinear MR identified a U-shaped association between BMI and GC in the Korean population, with both low and high BMIs associated with increased GC risk. A BMI of 24 kg/m2 presented the lowest risk. Sensitivity analyses did not yield any genome-wide significant SNPs. CONCLUSION: While MR analysis suggests a linear association between BMI and GC in those of European ancestry, nonlinear MR hints at a U-shaped association in Koreans. This suggests the association between BMI and GC risk may vary according to ethnic ancestry.

Family history and gastric cancer incidence and mortality in Asia: a pooled analysis of more than half a million participants.

BACKGROUND: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study. METHODS: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes. RESULTS: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41). CONCLUSIONS: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer.