Lifestyle and genetic determinants of mammographic density in Malaysian women / Shivaani Mariapun

• Main Author: Mariapun, Shivaani
• Format: Thesis
• Published: 2014
• Subjects: R Medicine (General)
• Online Access: http://studentsrepo.um.edu.my/7375/4/Full_thesis_Electronic_copy_270814_FINALVERSION_Redacted.pdf; http://studentsrepo.um.edu.my/7375/

Mammographic density is a strong risk factor for breast cancer. This trait is quantitative and modifiable, making it a useful biomarker for breast cancer risk. Studies investigating determinants of density in Asia have been conducted almost exclusively in developed Asian countries where breast cancer incidence is higher compared to most other Asian nations. This study aims to determine the lifestyle factors, including risk factors for breast cancer, which modulate density in a Malaysian cohort, and if ethnic differences in density reflect the variation in breast cancer incidence rates among Malay, Chinese and Indian women in the general population. Given the high heritability of density, this study also seeks to investigate whether genetic determinants of density, breast cancer risk and breast size in other populations are associated with density in this multiethnic cohort As part of an opportunistic mammogram screening programme, women aged 40 to 74 years, were screened between October 2011 and November 2013. Mammographic density was estimated using a fully-automated thresholding method. The relationship of lifestyle factors and ethnicity to density, expressed as percent density, dense and nondense areas, were examined in 989 subjects using linear regression. A systematic literature search was performed to identify SNPs of interest and the independent effect of each of these SNPs with density was analysed in 1334 subjects using linear regression. Percent density was positively associated with age and height, and negatively with weight, BMI, menopause, parity and oral contraceptives use. Dense area was associated with weight, BMI and menopause in the same direction as percent density. Dense area was also inversely associated with number of full term pregnancies and daily soy intake. Nondense area was associated with all the variables associated with percent density, except parity and oral contraceptives use, in the opposite direction. Chinese ethnicity was associated with higher percent density and smaller nondense area compared to Malay and Indian ethnicities, while Indian ethnicity was associated with larger dense area compared to Malay and Chinese ethnicities. Of the 33 SNPs analysed, 12 SNPs (rs10034692, rs2046210, rs10484919, rs7816345, rs703556, rs7289126 and rs17001868, rs4849887, rs10941679, rs17817449, rs62314947 and rs12173579) were associated with density after adjustment for age, BMI, menopausal status and parity. Three of these (rs2046210, rs10484919 and rs12173579 near ESR1) are in complete linkage disequilibrium in Asians (LD 1000 Genomes CHB+JPT, D’ = 1.00). This study found associations of mammographic density with lifestyle factors, including breast cancer risk factors, which are consistent with causality and with associations seen in Western and other Asian populations. Percent density and nondense area in this study reflect some but not all ethnic variations in the breast cancer incidence rates in the general population. Notably, dense area explained some of the variations in risk that could not be explained by percent density and nondense area. Several genetic variants associated with density, breast cancer risk and breast size in other populations appear to also modify density in this cohort.