Role of folate-homocysteine pathway gene polymorphisms and nutritional cofactors in Down syndrome: A triad study

Study question: Do gene-gene and gene-environment interactions in folate-homocysteine (Hcy) pathway have a predisposing role for Down syndrome (DS)?

Summary answer: The study provides evidence that in addition to advanced age, maternal genotype, micronutrient deficiency and elevated Hcy levels, individually and in combination, are risk factors for Down syndrome.

What is known already: Polymorphisms in certain folate-Hcy-pathway genes (especially the T allele of MTHFR C677T), elevated Hcy and poor folate levels in mothers during pregnancy have been shown to be risk factors for Down syndrome in certain Asian populations (including the eastern region of India), while the same SNPs are not a risk factor in European populations. This conflicting situation alludes to differential gene-environment (nutrition) interactions in different populations which needs to be explored.

Study design, size, duration: Between 2008 and 2012, 151 Down syndrome triads and 200 age-matched controls (Control mothers n = 186) were included in the study. Seven polymorphisms in six genes of folate-Hcy metabolic pathway, along with Hcy, cysteine (Cys), vitamin B12 (vit-B12) and folate levels, were analysed and compared among the case and control groups.

Participants/materials, setting, methods: Genotyping was performed by the PCR-RFLP technique. Levels of homocysteine and cysteine were measured by HPLC while vitamin B12 and folate were estimated by chemiluminescence.

Main results and the role of chance: We demonstrate that polymorphisms in the folate-Hcy pathway genes in mothers collectively constitute a genotypic risk for DS which is effectively modified by interactions among genes and by the environment affecting folate, Hcy and vitamin B12 levels. The study also supports the idea that these maternal risk factors provide an adaptive advantage during pregnancy supporting live birth of the DS child.

Limitations and reasons for caution: Our inability to obtain genotype and nutritional assessments of unaffected siblings of the DS children was an important limitation of the study. Also, its confinement to a specific geographic region (the eastern part) of India, and relatively small sample size is a limitation. A parallel investigation on another population could add greater authenticity to the data.

Wider implications of the findings: For mothers genetically susceptible to deliver a DS child (particularly in South Asia), peri-conceptional nutritional supplementation and antenatal care could potentially reduce the risk of a DS child. Additionally, nutritional strategies could possibly be used for better management of the symptoms of DS children.

Study funding/competing interests: The work is funded through Programme support for Genetic disorders by Department of Biotechnology, Government of India to R.R. The authors declare no conflict of interest.