A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

Abstract

Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant −4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10 −7 ) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS −4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.

A genetic association study detects haplotypes associated with obstructive heart defects

“…Studies have found that the expression of fetal CBS is concentrated in the neural and cardiac tissues, supporting a hypothesis of its involvement in embryo cardiac development (Quere et al 1999; Robert et al 2003). In particular, a recent study in Han Chinese population identified a functional variant (rs2850144) in CBS that is significantly associated with the genetic susceptibility to CHDs (Zhao et al 2012). This SNP (rs2850144, BP: 43370045) was not genotyped in our study, but it is located approximately 5.5 kb from the identified haplotype block (BP 43354960–43364494).…”

Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population

“…Numerous studies showed that one-carbon metabolism gene polymorphisms were associated with the balance of one-carbon metabolism and the genome-wide DNA methylation levels in breast cancer and colorectal cancer14151617. Moreover, our previous study identified several noncoding variants within one-carbon metabolism genes were able to impair the one-carbon metabolism balance and were associated with increased risk of birth defect181920. However, whether those noncoding variants contributed to the occurrence of cancer remains unknown.…”

“…Furthermore, to the best of our knowledge, there are few studies of the possible correlation between genetic variations in the noncoding region of one-carbon metabolism genes and PCa risk have been published. The aim of the present study was to investigate the contribution of functional non-coding variants to the risk of PCa in a large-scale hospital-based case-control study, including MTR rs28372871, MTR rs1131450, MTRR rs326119 and CBS rs2850144181920. Moreover, we assessed the effects of other extensively reported polymorphisms of genes in the one-carbon metabolism pathway, including MTR rs1805087 and MTRR rs18013944631, on the risk of PCa in our cohort.…”

Recent advances in understanding the genetics of congenital heart defects

“…Two new studies examined possible roles of common polymorphisms in the methionine synthase reductase ( MTRR ) and cystationine β–synthase ( CBS) genes in more than 2300 CHD cases and a like number of controls, both groups being Han Chinese [18,19]. For MTRR , the minor c.56+781 A>C intronic allele engendered a 1.36-fold per allele increase in CHD risk such that individuals with the CC genotype had a 1.8-fold risk [18].…”

“…For CBS , a-4673C>G allele in the promoter reduced the risk of CHD such that child with the CG genotype had a 15% and those with the GG genotype had a 40% reduction in CHD risk compared to children with the reference CC genotype [19]. No epistatic relationship to the MTRR c.56+781 C allele was detected.…”