Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study

Journal of Thrombosis and Thrombolysis, Nov 2016

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.

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Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study

Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study Kexin Sun 0 1 2 3 Jing Song 0 1 2 3 Kuo Liu 0 1 2 3 Kai Fang 0 1 2 3 Ling Wang 0 1 2 3 Xueyin Wang 0 1 2 3 Jing Li 0 1 2 3 Xun Tang 0 1 2 3 Yiqun Wu 0 1 2 3 Xueying Qin 0 1 2 3 Tao Wu 0 1 2 3 Pei Gao 0 1 2 3 Dafang Chen 0 1 2 3 Yonghua Hu 0 1 2 3 0 Beijing Center for Disease Prevention and Control , No.16 He Pingli Middle Street, Dongcheng District, Beijing 100013 , China 1 Department of Epidemiology and Biostatistics, Capital Medical University , 10 You'anmenwai Xitoutiao, Beijing 100069 , China 2 Department of Epidemiology and Biostatistics, Peking University Health Science Center , 38 Xueyuan Road, Beijing 100191 , China 3 Pingshan New District Center for Disease Control and Prevention , Shenzhen 518118, Guangdong , China 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 (CCAIMT) 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-efects regression model to verify SNP-CIMT associations and to explore the potential genegene 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 signii - cantly associated with CCA-IMT (p = 0.021) and CIMT (p = 0.019). In multi-level mixed-efects regression model, CBS rs2851391 was positively signiicantly associated with CCA-IMT (Coef = 0.032, se = 0.009, raw p < 0.001) after Bonferoni correction (corrected α = 0.0056). Genegene 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 CCAIMT (p = 0.007) and CIMT (p = 0.022). Signiicant asso - ciations 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. Homocysteine; Single nucleotide polymorphism; Carotid intima-media thickness; Atherosclerosis; Sib pair; Gene-gene interaction - * Yonghua Hu 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 stratiication [ 2]. Hyperhomocysteinemia is an independent risk factor for arteriosclerotic vascular diseases [3, 4]. However, 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. Hcy can be inluenced by genetic factors. Altered func tioning of catalytic enzymes in Hcy metabolic pathways caused by gene mutations may lead to inhibition of certain pathways and elevation of plasma Hcy level [6, 7]. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionines synthase reductase (MTRR), betaine-homocysteine methyltransferase (BHMT) are enzymes in Hcy remethylation pathway. Cystathionineβ-synthase (CBS) is the key enzyme in Hcy transsulfuration pathway. Serine hydroxymethyltransferase 1 (SHMT1) sequesters 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation, thus to inhibit Hcy metabolism through methionine synthesis pathway. Genetic association studies between encoding genes of these enzymes and cardiovascular studies are previously studied [8, 9]. Diferent enzymes in Hcy metabolic pathways interact with each other. Complex interactions between variations of corresponding genes, especially interactions between functional polymorphisms, can contribute to Hcy metabolic disorder and subsequent diseases. Interactions between MTHFR 677 C>T (rs1801133) and CBS 844ins68 [10– 12], MTHFR 677 C>T and MTRR 66 A>G (rs1801394) [13] were found with regard to Hcy. Same interactions were shown to elevate neural tube defects risk [14]. However, the interactive efects of Hcy related SNPs on CIMT were not fully explored. To investigate the associations between Hcy metabolism rela (...truncated)


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Kexin Sun, Jing Song, Kuo Liu, Kai Fang, Ling Wang, Xueyin Wang, Jing Li, Xun Tang, Yiqun Wu, Xueying Qin, Tao Wu, Pei Gao, Dafang Chen, Yonghua Hu. Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study, Journal of Thrombosis and Thrombolysis, 2017, pp. 401-410, Volume 43, Issue 3, DOI: 10.1007/s11239-016-1449-x