Polymorphisms in adiposity-related genes are associated with age at menarche and menopause in breast cancer patients and healthy women.

STUDY QUESTION: Is there any effect of genetic polymorphisms in adiposity-related genes on the timing of menarche and menopause and the total duration of menstruation among Korean women? SUMMARY ANSWER: Our results suggest that the adiposity-related genes LEP, LEPR and PPARγ may play a role in the onset and cessation of menstruation, and the total duration of menstruation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Previous candidate-gene approaches have mainly presented the results for genes related to the estrogen metabolism pathway. Most genes of interest that participate in steroid-hormone metabolism, such as estrogen receptor α and estrogen receptor ß, have been associated with age at menarche and menopause. This study shows the possibility that adiposity-related genes also influence the duration of menstruation. PARTICIPANTS AND SETTING: We recruited 400 breast cancer patients and 452 healthy participants from a case-control study at the Center for Breast Cancer, National Cancer Center in Korea. Ten single nucleotide polymorphisms (SNPs) in the leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma (PPARγ) genes were investigated to evaluate their possible effects on menstruation. Associations between SNPs and age at menarche, age at menopause and duration of menstruation were evaluated. MAIN RESULTS: Four SNPs (rs2167270 of LEP, rs7602 of LEPR and rs4684846 and rs3856806 of PPARγ) were associated with late menarche (≥ 17-year-old). Four SNPs (rs2167270 of LEP and rs1801282, rs2120825, and rs3856806 of PPARγ) were associated with early menopause (<40-year-old) among post-menopausal women. In logistic regression models with covariate adjustment, women with the GG genotype of rs7602 (LEPR) had a higher risk for late menarche [odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.01-3.31] compared with their counterparts carrying the GA or AA genotypes. In addition, the GG genotype of rs2167270 (LEP) was inversely associated with a duration of menstruation of <30 years (OR = 0.59, 95% CI = 0.31-1.00) compared with the GA or AA genotypes. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: We obtained information on the age at menarche and menopause from self-administered questionnaires, and some participants might have had difficulty in remembering their age at menarche and menopause. However, this is a non-differential misclassification and should not appreciably affect the interpretation of the results of this study.

The beneficial effect of leisure-time physical activity on bone mineral density in pre- and postmenopausal women.

Regular exercise and physical activity (PA) are known to be protective factors for maintaining bone mineral density (BMD) and preventing osteoporotic fracture. We investigated the associations between leisure-time PA and BMD in 2,903 premenopausal and 2,267 postmenopausal women in Korea. BMDs of the lumbar spine and femur were measured using dual-energy X-ray absorptiometry. Leisure-time PA levels were assessed by a self-administrated questionnaire, and a total metabolic equivalent (MET) score was obtained. Regardless of menopausal status, performing more than moderate levels of leisure-time PA or total MET score had a significant positive association with BMD at both the lumbar spine and femur. In the premenopausal group, women whose total MET score was 1,050-1,500 (MET-min/week) appeared to have the highest lumbar spine and femoral BMD (p < 0.001). The associations between PA level and lumbar spine and femoral BMD were also shown in the postmenopausal group (p < 0.001). In addition, we found dose-response relationships between increasing exercise level and femoral BMD in both the premenopausal and postmenopausal groups. Our results indicate that a more than moderate level of leisure-time PA plays a role in maintaining BMD.

Lack of effects of peroxisome proliferator-activated receptor gamma genetic polymorphisms on breast cancer risk: a case-control study and pooled analysis.

A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PPARγ) gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphisms in the PPARγ gene are associated with the susceptibility of breast cancer. We performed a candidate gene association study between PPARγ polymorphisms and breast cancer and a meta-analysis on the association of breast cancer with selected PPARγ variants. Six single nucleotide polymorphisms (SNPs) in the PPARγ gene were analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea. Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage test for trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previously analyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility. Our findings from the candidate gene association study showed no association between the PPARγ gene polymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study also refuted an association of the PPARγ gene with breast cancer. Our findings suggest that the PPARγ gene may not harbor variants that alter breast cancer susceptibility, although a moderate sample size might have precluded a decisive conclusion.

Association between CASR polymorphisms, calcium intake, and colorectal cancer risk.

AIM: The current study aimed to assess the effect of dietary calcium intake and possible interactions with calcium-sensing receptor (CASR) gene polymorphisms on colorectal cancer risk. METHODS: A total of 420 colorectal cancer cases and 815 controls were included in the analysis. Calcium intake was investigated using a 103 item semi-quantitative food frequency questionnaire, and four single nucleotide polymorphisms (SNPs) within the CASR, rs10934578, rs12485716, rs2270916, and rs4678174, were evaluated. RESULTS: No SNPs were associated with colorectal cancer risk after adjusting for covariates. Overall, no significant effect modification by CASR polymorphisms on the association between calcium intake and colorectal cancer risk were detected. However, all 4 of the polymorphisms within the CASR showed significantly higher odds ratios for association with colorectal cancer risk in the low-calcium-intake group compared to the high-calcium-intake group. In the case of rs2270916, individuals with the CC genotype and low calcium intake showed an increased colorectal cancer risk compared to their counterparts with the TT genotype and high calcium intake (OR = 2.11, 95% CI = 1.27-3.51). CONCLUSIONS: Subjects with lower calcium intake exhibited a higher colorectal cancer risk compared with subjects with the same genotype who had higher calcium intake. Our results suggest that individuals who have low dietary calcium intake should be aware of their increased colorectal cancer risk and prevention strategies.

Unbalanced sample size effect on genome-wide population differentiation studies.

The fixation index (F(ST)) is one of the most widely used measurements of genetic distance between populations. The data set from the international HapMap project has been served as a reference data set for population differentiation studies. F(ST) is commonly used in order to compare the sample data with HapMap data. In this study, however, we show that the use of F(ST) without consideration of sample sizes may mislead the result. In particular, we first demonstrate that F(ST) suffers from imbalance of sample sizes through simulation studies and through the analysis of a large scale Korean genome-wide association data. Then, we propose a modified version of F(ST) which is shown to be more robust to imbalance of sample size. In addition, the chi-square test commonly used for homogeneity test is shown to perform similarly to the modified version of F(ST).

Increasing trend of colorectal cancer incidence in Korea, 1999-2009.

PURPOSE: This study was conducted in order to demonstrate changing trends in colorectal cancer incidence according to sex, age group, and anatomical location in the Korean population. MATERIALS AND METHODS: Data from the Korea Central Cancer Registry between 1999 and 2009 were analyzed. Annual percent changes (APCs) of sex- and age-specific incidence rates for cancer of the proximal colon (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10] code C18.0-18.5), distal colon (C18.6-18.7), and rectum (C19-20), and male-to-female incidence rate ratios (IRR) were calculated. RESULTS: The age-standardized incidence rate (ASR) of colorectal cancer was 27 (per 100,000) in 1999 and increased to 50.2 in 2009 among men (APC, 6.6%). The ASR for women was 17.2 in 1999 and 26.9 in 2009 (APC, 5.1%). The rectum was the most common site of cancer among both men and women during 1999 and 2009. However, the distal colon had the highest APC (10.8% among men and 8.4% among women), followed by the proximal colon (7.9% among men and 6.6% among women), and rectum (5.2% among men and 2.4% among women). The proportion of rectal cancer decreased from 51.5% in 1999 to 47.1% in 2009 among men, and from 50.5% to 42.8% among women. An increase in the male-to-female IRR was observed for distal colon cancer and rectal cancer, whereas the IRR for proximal colon cancer was stable. CONCLUSION: The rapid increase in colorectal cancer incidence is mainly attributed to the increase in colon cancer, especially distal colon cancer, and may be explained by a transition of risk factors for subsites or by the effect of colorectal cancer screening.