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Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

ABSTRACT: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD).In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ? 0.049), but not with TCF15 SNPs (P ? 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %).Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

SUBMITTER: Yang WY

PROVIDER: S-EPMC4591634 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

Yang Wen-Yi WY Petit Thibault T Thijs Lutgarde L Zhang Zhen-Yu ZY Jacobs Lotte L Hara Azusa A Wei Fang-Fei FF Salvi Erika E Citterio Lorena L Delli Carpini Simona S Gu Yu-Mei YM Knez Judita J Cauwenberghs Nicholas N Barcella Matteo M Barlassina Cristina C Manunta Paolo P Coppiello Giulia G Aranguren Xabier L XL Kuznetsova Tatiana T Cusi Daniele D Verhamme Peter P Luttun Aernout A Staessen Jan A JA

BMC genetics 20151001

<h4>Background</h4>In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD).<h4>Results</h4>In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardi ...[more]

PMID: 26428460

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Project description:Background Vascular calcification is strongly related to the risk of mortality and cardiovascular (CV) diseases. In vascular calcification, matrix Gla protein (MGP), a small vitamin K-dependent protein, is an important mineralization inhibitor. Recent studies showed that circulating MGP is associated with mortality risk. However, the longitudinal association between urinary excretion of MGP and all-cause mortality was not established. Materials and methods Urinary MGP was measured in 776 randomly recruited Flemish population (mean age: 51.2 years; 50.9% women) at baseline (during 2005–2010) using capillary electrophoresis coupled with mass spectrometry. Plasma inactive MGP [desphospho-uncarboxylated MGP (dp-ucMGP)] levels were quantified in 646 individuals by ELISA kits. Mortality status was ascertained through the Belgian Population Registry until 2016. The longitudinal association with mortality was determined by the multivariate-adjusted Cox proportional hazards regression models. The multivariate linear regression models were used to identify determinants of urinary MGP level. Results Over the 9.2 years, 47 (6.06%) participants died, including 15 CV deaths. For a doubling of urinary MGP, the hazard ratios (HRs) were 1.31 (95% CI: 1.01–1.69, P = 0.040) for all-cause mortality and 2.05 (95% CI: 1.11–3.79, P = 0.023) for CV mortality with adjustment for covariates, including estimated glomerular filtration rate and urine microalbumin. The addition of urinary MGP to the basic models improved the reclassification as suggested by the increased net reclassification improvement [64.01% (95% CI: 32.64–98.63)] and integrated discrimination improvement [2.33% (95% CI: 0.24–4.71)]. Circulating inactive MGP, total cholesterol, urine microalbumin, and smoking were significantly associated with urinary MGP levels (P ≤ 0.041), independent of sex and age. Conclusion Elevated urinary MGP was associated with an increased risk of all-cause mortality and CV mortality and improved the risk reclassification for all-cause mortality. These findings suggested that urinary MGP might be useful in mortality risk assessment in the general population. However, these observations need to be replicated in larger studies with a longer follow-up time.

Dataset Information

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

Publications

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

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