rs234706
mixedMag 2.8This is a synonymous variant in the CBS gene — it does not change the protein's amino acid sequence.
Key Literature Trait Associations
Aneurysmal subarachnoid hemorrhage
A candidate-gene study examined CBS rs234706 in 149 patients with aneurysmal subarachnoid hemorrhage (aSAH) and 50 controls. The GG genotype (homozygous reference) was independently associated with unfavorable functional outcome (modified Rankin Scale score 3–6) both at hospital discharge and at last follow-up, though it was not associated with clinical vasospasm or delayed cerebral ischemia. The finding is biologically plausible given that CBS produces hydrogen sulfide (H2S), which has neuroprotective and vasodilatory properties, and that reduced CBS activity (tagged by the GG genotype) may impair post-hemorrhage recovery. However, the small control group (n=50) and single-site design limit confidence in this association.
Preeclampsia
Several studies in Norwegian and Dutch populations have examined CBS rs234706 in preeclampsia. In a study of 198 participants, the minor allele (A/T), which is paradoxically associated with lower homocysteine levels, was found to confer approximately 2.1-fold increased odds of mild late-onset preeclampsia (OR 2.10; 95% CI 1.15–3.85; p=0.016). A follow-up study focusing on early-onset preeclampsia did not identify rs234706 as a significant independent risk variant; associations were primarily driven by a different CBS tag-SNP (rs11203172). These findings suggest the role of rs234706 in preeclampsia is modest and may reflect complex CBS haplotype effects on hydrogen sulfide signaling rather than homocysteine elevation alone.
Transsulfuration Pathway
The CBS C699T variant (rs234706) is a synonymous polymorphism in cystathionine beta-synthase, which catalyzes the first step of the transsulfuration pathway converting homocysteine to cystathionine. The A allele (699T) has been associated with CBS upregulation, potentially lowering homocysteine levels. Homozygous carriers showed reduced risk of cleft lip/palate (OR 0.50). In normal populations, CBS upregulation appears protective against hyperhomocysteinemia.
Oral cleft
A family-based study in Norway examined maternal one-carbon metabolism variants and offspring cleft risk in 362 CL/P families and 191 CPO families. Mothers carrying two copies of the CBS C699T T allele (A allele at rs234706) had a relative risk of 0.50 (95% CI 0.26–0.96; p=0.008) for having a child with cleft lip with or without cleft palate, suggesting a maternal protective effect. No interaction with folate supplementation status was detected. The study did not find significant effects for cleft palate only. This is a single moderately sized study and the biological mechanism linking CBS transsulfuration to craniofacial development remains incompletely characterized.
Preterm birth
A Chinese case-control study of 503 DNA samples (315 preterm births, 188 controls) examined CBS C699T among 12 folate metabolism SNPs. The CBS C699T variant alone showed no significant individual association with preterm birth risk. However, seven preterm infants but no term infants carried a compound mutation combining CBS C699T with MTHFD G1958A and MTR A2756G, suggesting a possible epistatic interaction. Evidence remains insufficient to draw firm conclusions about rs234706 as an independent preterm birth risk factor, and replication in larger or non-Asian populations is needed.
▶ClinVar annotation
Classic homocystinuria; Connective tissue disorder; Familial thoracic aortic aneurysm and aortic dissection (TAAD); HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED; not specified
View on ClinVar →▶Research that mentions this SNP (6)
▶Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study populationAssociationN=2,079Tonia C. Carter et al.(2011)· American Journal of Medical Genetics Part A
This case-control and family-based study evaluated 64 SNPs in 34 genes for associations with spina bifida in 558 Irish case-families and 994 controls. Spina bifida was significantly associated with LEPR rs1805134 (GRR: 1.5, P = 0.0264) and COMT rs737865 (GRR: 1.4, P = 0.0206), with additional confirmations of previous findings in MTHFR 677C>T and other genes, suggesting roles for leptin signaling and methylation pathways in neural tube defect pathogenesis.
▶Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndromeAssociationN=243Adam E. Locke et al.(2010)· Genetic Epidemiology
This case-control study examined folate pathway gene variants in 121 DS-AVSD cases and 122 DS controls (no CHD). Tag SNPs in MTHFR, MTR, MTRR, CBS, and SLC19A1 were genotyped. SLC19A1 showed significant gene-level association with atrioventricular septal defect (P=0.01), with multiple tag SNPs nominally associated (OR 1.08-1.72). All significant SLC19A1 SNPs showed strong LD (r²≥0.80) with the nonsynonymous variant rs1051266 (c.80A>G, p.H27R). MTHFR c.1298A was over-transmitted to cases (P=0.05) and under-transmitted to controls (P=0.02), showing association in FBAT analysis (P=0.03 dominant, P=0.01 additive). These results suggest folate pathway disruption contributes to AVSD risk in Down syndrome individuals.
▶Variability in Ethanol Biodisposition in Whites Is Modulated by Polymorphisms in the Adh1b and Adh1c GenesReviewCarmen Martínez et al.(2010)· Hepatology
A comprehensive review of nutrigenetics and nutrigenomics examining how genetic variants influence individual responses to nutrients and dietary interventions. The paper discusses associations between numerous SNPs (rs9939609 in FTO, rs2287019 in GIPR, rs7903146 in TCF7L2, rs5219 in KCNJ11, and many others) and metabolic traits including obesity, type 2 diabetes, and other chronic diseases, along with epigenetic mechanisms by which phytochemicals (curcumin, resveratrol, lycopene) modulate gene expression. The review synthesizes current evidence for precision nutrition approaches tailored to individual genetic profiles.
▶Oral facial clefts and gene polymorphisms in metabolism of folate/one‐carbon and vitamin A: a pathway‐wide association studyAssociationN=425Abee L. Boyles et al.(2009)· Genetic Epidemiology
A pathway-wide association study in 425 case-parent triads examined 109 SNPs in 29 folate/one-carbon metabolism genes and 68 SNPs in 16 vitamin A metabolism genes for associations with cleft lip/palate (CL/P) and cleft palate only (CPO). Despite strong epidemiologic evidence that folic acid and vitamin A reduce cleft risk, no convincing genetic associations were found; the strongest association was FOLH1 with CPO (p=0.0008), but findings were fewer than expected by chance and inconsistent with protective effects of vitamin supplementation, suggesting vitamin metabolism gene polymorphisms do not play an etiologic role in oral facial clefts.
▶Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial cleftsAssociationN=553Abee L. Boyles et al.(2008)· American Journal of Medical Genetics Part A
This family-based association study examined 12 polymorphisms in one-carbon metabolism genes (BHMT, CBS, MTHFD1, MTHFR, MTR, MTRR, SLC19A1, TCN2) and their associations with oral facial clefts in 553 Norwegian families. CBS rs234706 showed a significant maternal protective effect on cleft lip/palate risk (LRT p=0.008), with homozygous carriers of the T allele showing reduced risk (RR=0.50, 95% CI 0.26-0.96). MTHFR rs1801133 demonstrated a protective effect in the low-folate supplementation subset (RR=0.60-0.44), and maternal folic acid supplementation ≥400 μg/day was associated with 39% reduction in cleft lip/palate risk.
▶Folate metabolism genes, vegetable intake and renal cancer risk in central EuropeAssociationN=2,652Moore LE et al.(2008)· International Journal of Cancer
A case-control study of 1,097 renal cell carcinoma (RCC) cases and 1,555 controls in Central and Eastern Europe examined common genetic variation in 5 folate metabolism genes. Variants in MTHFR (A222V rs1801133) and TYMS (IVS2-405C rs502396) were significantly associated with RCC risk, with the MTHFR variant increasing risk (OR=1.44) particularly in groups with low vegetable intake, while TYMS variant reduced risk (OR=0.73). The associations demonstrated significant gene-nutrient interactions with vegetable consumption.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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