Studies of Association of Environmental Risk Factors in Down Syndrome

Down syndrome (DS) is the most common live-born birth defect in humans. The genetic cause of DS is trisomy of chromosome 21. 94% of cases of DS trisomy are due to maternal chromosomal non-disjunction. Advanced maternal age has been identified as a key risk factor for DS. However, it is not clearly understood yet how maternal age effect increases chromosome non-disjunction. Recently, it has been suggested that factors involved in meiotic chromosome segregation may be altered in aged oocytes and such molecular abnormality could be caused or accelerated by maternal environmental factors. Epidemiologic studies have tried to investigate effect of maternal environmental factors on DS. The most commonly-studied factors are maternal peri-conceptional smoking and oral contraceptive use. However, the evidence of association of those factors with DS has not been consistent. In this thesis, a DS cohort in Kolkata, India was investigated for studying association of maternal peri-conceptional behavioral factors on DS. The characteristics of exposure to two factors, smokeless chewing tobacco use (SCT) and oral contraceptive use (OC), are unique in this cohort as compared to previous study populations. In this population both exposures tend to be started early in life and in high dose. By using logistic and linear regression methods, I found significant association of maternal SCT and OC use with DS. SCT interacts with maternal age, having a stronger effect in younger mothers compared to older mothers, while the effect of OC use on risk is the same at all ages. SCT use is also associated with meiotic type (I vs. II) of chromosome non-disjunction and with lack of recombination in meiosis I type non-disjunction. Furthermore, maternal SCT use is strongly associated with maternal telomere length, which has been shown to be a molecular marker of aging. SCT use decreases maternal telomere length, especially among women bearing DS child with meiosis I type non-disjunction. In conclusion, with Indian DS cohort, this thesis was able to find evidence of interactions among three major risk factors in DS: tobacco use, oral contraceptive use, and maternal age. This study has great public health significance because better understanding of the risk factors for DS can lead to improved prevention and screening strategies