Abstract
Carotid intima-media thickness (CIMT) is a good surrogate for atherosclerosis. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. We aim to investigate the relationships between homocysteine (Hcy) related biochemical indexes and CIMT, the associations between Hcy related SNPs and CIMT, as well as the potential gene–gene interactions. The present study recruited full siblings (186 eligible families with 424 individuals) with no history of cardiovascular events from a rural area of Beijing. We examined CIMT, intima-media thickness for common carotid artery (CCA-IMT) and carotid bifurcation, tested plasma levels for Hcy, vitamin B6 (VB6), vitamin B12 (VB12) and folic acid (FA), and genotyped 9 SNPs on MTHFR, MTR, MTRR, BHMT, SHMT1, CBS genes. Associations between SNPs and biochemical indexes and CIMT indexes were analyzed using family-based association test analysis. We used multi-level mixed-effects regression model to verify SNP-CIMT associations and to explore the potential gene–gene interactions. VB6, VB12 and FA were negatively correlated with CIMT indexes (p < 0.05). rs2851391 T allele was associated with decreased plasma VB12 levels (p = 0.036). In FABT, CBS rs2851391 was significantly associated with CCA-IMT (p = 0.021) and CIMT (p = 0.019). In multi-level mixed-effects regression model, CBS rs2851391 was positively significantly associated with CCA-IMT (Coef = 0.032, se = 0.009, raw p < 0.001) after Bonferoni correction (corrected α = 0.0056). Gene–gene interactions were found between CBS rs2851391 and BHMT rs10037045 for CCA-IMT (p = 0.011), as well as between CBS rs2851391 and MTR rs1805087 for CCA-IMT (p = 0.007) and CIMT (p = 0.022). Significant associations are found between Hcy metabolism related genetic polymorphisms, biochemical indexes and CIMT indexes. There are complex interactions between genetic polymorphisms for CCA-IMT and CIMT.
Highlights
Carotid intima-media thickness (CIMT), a technique to monitor carotid artery wall alterations using ultrasonography, is a noninvasive measurement of preclinical atherosclerosis [1]
We investigated 9 single nucleotide polymorphisms (SNPs) in 6 well-studied candidate genes (MTHFR, MTR, MTRR, betaine-homocysteine methyltransferase (BHMT), Serine hydroxymethyltransferase 1 (SHMT1), CBS) involved in homocysteine metabolism
TG, Hcy, vitamin B6 (VB6), vitamin B12 (VB12), folic acid (FA), PAI-1 were analyzed on natural logarithmic scale
Summary
Carotid intima-media thickness (CIMT), a technique to monitor carotid artery wall alterations using ultrasonography, is a noninvasive measurement of preclinical atherosclerosis [1]. It has often been considered as a surrogate of early atherosclerosis and is widely used for cardiovascular risk stratification [2]. The association between elevated plasma homocysteine (Hcy) and CIMT remains controversial [5]. This prompts the need for genetic association studies to investigate the involvement of Hcy in early stage of atherogenesis. Genetic association studies between encoding genes of these enzymes and cardiovascular studies are previously studied [8, 9]
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