Influence of MTHFR Polymorphisms and Folate Pathway Metabolites on Comorbidities in Down Syndrome
Biochemical/Metabolic and Therapeutics
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Introduction:
Down syndrome (DS), a common aneuploidy involving chromosome 21, is associated with disruptions in the folate pathway, including dysregulation of the rate limiting MTHFR enzyme. Polymorphisms C677T and A1298C in the MTHFR gene reduce its activity, thus elevating homocysteine levels resulting higher risk for vascular conditions like stroke and deep vein thrombosis. DS comorbidities, including congenital heart defects (CHD) and thyroid disorders, could be influenced by folate pathway metabolites and MTHFR polymorphisms. This study investigates these genetic and biochemical parameters in children with DS to clarify their potential role in DS-related comorbidities.
Methods:
This study enrolled 75 pediatric patients with DS and 30 age- and sex-matched healthy controls. DS patients were stratified by comorbidities into four subgroups: DS without CHD or hypothyroidism (n=15), DS with CHD only (n=27), DS with hypothyroidism only (n=16), and DS with both CHD and hypothyroidism (n=17). Homocysteine and cysteine levels were measured using LC-MS, and MTHFR gene polymorphisms were sequenced via Sanger method. Statistical analyses were conducted using SPSS (Statistical products Service Solution) to assess associations between these parameters and comorbidities at significance level p <0.05, and ROC (Receiver Operator Curve) analysis was used to evaluate the predictive potential of these factors for DS-related comorbidities.
Results:
MTHFR 677T (29.3%) and 1298C (78.6%) was overrepresented in DS children (p<0.05) as compared to healthy controls. C677T dimorphism was present only in heterozygous state. Further, for A1298C, a significant over-representation (p<0.05) of both homozygous (20%) and heterozygous (58.6%) was observed in DS individuals compared to controls. Conversely, no homozygosity of A1298C was observed in healthy controls.
On stratified analysis between different subgroups, significantly (p<0.05) higher prevalence of C677T was observed in DS individuals with hypothyroidism compared to controls and patients without both CHD and hypothyroidism. None of the DS children with neither CHD nor hypothyroidism were homozygous for A 1298C, though significantly higher representation was observed in subgroup having both these comorbidities compared to all other subgroups.
Significantly higher (p<0.05) levels of homocysteine were observed in DS patients with both CHD and hypothyroidism than in those without these comorbidities. Cysteine levels were also significantly elevated (p<0.05) in DS patients compared to controls, particularly in those with both CHD and hypothyroidism and CHD alone.
ROC analysis indicated that homocysteine, cysteine, and MTHFR polymorphisms could plausibly serve as predictive marker for hypothyroidism with or without CHD in DS patients, with accuracies of 72% and 79%, respectively.
Conclusion:
This study identifies a significant association of MTHFR polymorphisms (C677T and A1298C), homocysteine and cysteine levels, in DS patients with or without comorbidities (hypothyroidism and/or CHD). Our findings suggest relevance of these genetic and biochemical markers with predictive potential for comorbidity risk assessment, supporting the potential for early, targeted interventions.
Down syndrome (DS), a common aneuploidy involving chromosome 21, is associated with disruptions in the folate pathway, including dysregulation of the rate limiting MTHFR enzyme. Polymorphisms C677T and A1298C in the MTHFR gene reduce its activity, thus elevating homocysteine levels resulting higher risk for vascular conditions like stroke and deep vein thrombosis. DS comorbidities, including congenital heart defects (CHD) and thyroid disorders, could be influenced by folate pathway metabolites and MTHFR polymorphisms. This study investigates these genetic and biochemical parameters in children with DS to clarify their potential role in DS-related comorbidities.
Methods:
This study enrolled 75 pediatric patients with DS and 30 age- and sex-matched healthy controls. DS patients were stratified by comorbidities into four subgroups: DS without CHD or hypothyroidism (n=15), DS with CHD only (n=27), DS with hypothyroidism only (n=16), and DS with both CHD and hypothyroidism (n=17). Homocysteine and cysteine levels were measured using LC-MS, and MTHFR gene polymorphisms were sequenced via Sanger method. Statistical analyses were conducted using SPSS (Statistical products Service Solution) to assess associations between these parameters and comorbidities at significance level p <0.05, and ROC (Receiver Operator Curve) analysis was used to evaluate the predictive potential of these factors for DS-related comorbidities.
Results:
MTHFR 677T (29.3%) and 1298C (78.6%) was overrepresented in DS children (p<0.05) as compared to healthy controls. C677T dimorphism was present only in heterozygous state. Further, for A1298C, a significant over-representation (p<0.05) of both homozygous (20%) and heterozygous (58.6%) was observed in DS individuals compared to controls. Conversely, no homozygosity of A1298C was observed in healthy controls.
On stratified analysis between different subgroups, significantly (p<0.05) higher prevalence of C677T was observed in DS individuals with hypothyroidism compared to controls and patients without both CHD and hypothyroidism. None of the DS children with neither CHD nor hypothyroidism were homozygous for A 1298C, though significantly higher representation was observed in subgroup having both these comorbidities compared to all other subgroups.
Significantly higher (p<0.05) levels of homocysteine were observed in DS patients with both CHD and hypothyroidism than in those without these comorbidities. Cysteine levels were also significantly elevated (p<0.05) in DS patients compared to controls, particularly in those with both CHD and hypothyroidism and CHD alone.
ROC analysis indicated that homocysteine, cysteine, and MTHFR polymorphisms could plausibly serve as predictive marker for hypothyroidism with or without CHD in DS patients, with accuracies of 72% and 79%, respectively.
Conclusion:
This study identifies a significant association of MTHFR polymorphisms (C677T and A1298C), homocysteine and cysteine levels, in DS patients with or without comorbidities (hypothyroidism and/or CHD). Our findings suggest relevance of these genetic and biochemical markers with predictive potential for comorbidity risk assessment, supporting the potential for early, targeted interventions.
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