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

Yang WY, Petit T, Thijs L, Zhang ZY, Jacobs L, Hara A, Wei FF, Salvi E, Citterio L, Delli Carpini S, Gu YM, Knez J, Cauwenberghs N, Barcella M, Barlassina C, Manunta P, Coppiello G, Aranguren XL, Kuznetsova T, Cusi D, Verhamme P, Luttun A, Staessen JA - BMC Genet. (2015)

Bottom Line: 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).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 %).

View Article: PubMed Central - PubMed

Affiliation: Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Kapucijnenvoer 35, Box 7001, BE-3000, Leuven, Belgium. wenyi.yang@med.kuleuven.be.

ABSTRACT

Background: 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).

Results: 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 %).

Conclusions: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

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Related in: MedlinePlus

CHD Incidence by genotype for six MEOX2 SNPs (Panels a-f). Estimates were standardised to the mean of the distributions of sex and age in the whole study population. Vertical bars denote the standard error. P-values refer to the difference between minor allele carriers and major allele homozygotes. Cumulative incidence did not differ between minor allele homozygotes and heterozygotes (0.23 ≤ P ≤ 0.98 [a, c-f]), except for rs12056299 (P = 0.014 [b]). Median follow-up was 15.2 years. Tabulated data are the number of participants at risk by genotype at 6-year intervals
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Fig1: CHD Incidence by genotype for six MEOX2 SNPs (Panels a-f). Estimates were standardised to the mean of the distributions of sex and age in the whole study population. Vertical bars denote the standard error. P-values refer to the difference between minor allele carriers and major allele homozygotes. Cumulative incidence did not differ between minor allele homozygotes and heterozygotes (0.23 ≤ P ≤ 0.98 [a, c-f]), except for rs12056299 (P = 0.014 [b]). Median follow-up was 15.2 years. Tabulated data are the number of participants at risk by genotype at 6-year intervals

Mentions: The sex- and age-standardised incidence rates of coronary events associated with the MEOX2 SNPs appear in Additional file 1: Table S4. Compared with major allele homozygotes, minor allele carriers experienced a higher CHD incidence except for rs6959056. The sex- and age-adjusted cumulative incidence of coronary events (Fig. 1) showed significant association (P ≤ 0.012) with the MEOX2 SNPs except for rs1050290 (P = 0.058). There were no differences in these estimates between homozygous and heterozygous minor allele carriers (0.23 ≤ P ≤ 0.98) except for rs12056299 (P = 0.014). For all coronary events combined, the sex- and age-standardised incidence rates (0.11 ≤ P ≤ 0.39) and the sex- and age-adjusted cumulative incidence (0.11 ≤ P ≤ 0.71) did not differ among minor allele carriers and major allele homozygotes of the four TCF15 SNPs.Fig. 1


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

Yang WY, Petit T, Thijs L, Zhang ZY, Jacobs L, Hara A, Wei FF, Salvi E, Citterio L, Delli Carpini S, Gu YM, Knez J, Cauwenberghs N, Barcella M, Barlassina C, Manunta P, Coppiello G, Aranguren XL, Kuznetsova T, Cusi D, Verhamme P, Luttun A, Staessen JA - BMC Genet. (2015)

CHD Incidence by genotype for six MEOX2 SNPs (Panels a-f). Estimates were standardised to the mean of the distributions of sex and age in the whole study population. Vertical bars denote the standard error. P-values refer to the difference between minor allele carriers and major allele homozygotes. Cumulative incidence did not differ between minor allele homozygotes and heterozygotes (0.23 ≤ P ≤ 0.98 [a, c-f]), except for rs12056299 (P = 0.014 [b]). Median follow-up was 15.2 years. Tabulated data are the number of participants at risk by genotype at 6-year intervals
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4591634&req=5

Fig1: CHD Incidence by genotype for six MEOX2 SNPs (Panels a-f). Estimates were standardised to the mean of the distributions of sex and age in the whole study population. Vertical bars denote the standard error. P-values refer to the difference between minor allele carriers and major allele homozygotes. Cumulative incidence did not differ between minor allele homozygotes and heterozygotes (0.23 ≤ P ≤ 0.98 [a, c-f]), except for rs12056299 (P = 0.014 [b]). Median follow-up was 15.2 years. Tabulated data are the number of participants at risk by genotype at 6-year intervals
Mentions: The sex- and age-standardised incidence rates of coronary events associated with the MEOX2 SNPs appear in Additional file 1: Table S4. Compared with major allele homozygotes, minor allele carriers experienced a higher CHD incidence except for rs6959056. The sex- and age-adjusted cumulative incidence of coronary events (Fig. 1) showed significant association (P ≤ 0.012) with the MEOX2 SNPs except for rs1050290 (P = 0.058). There were no differences in these estimates between homozygous and heterozygous minor allele carriers (0.23 ≤ P ≤ 0.98) except for rs12056299 (P = 0.014). For all coronary events combined, the sex- and age-standardised incidence rates (0.11 ≤ P ≤ 0.39) and the sex- and age-adjusted cumulative incidence (0.11 ≤ P ≤ 0.71) did not differ among minor allele carriers and major allele homozygotes of the four TCF15 SNPs.Fig. 1

Bottom Line: 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).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 %).

View Article: PubMed Central - PubMed

Affiliation: Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Kapucijnenvoer 35, Box 7001, BE-3000, Leuven, Belgium. wenyi.yang@med.kuleuven.be.

ABSTRACT

Background: 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).

Results: 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 %).

Conclusions: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Show MeSH
Related in: MedlinePlus