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RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy

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Abstract

Hypertrophic Cardiomyopathy (HCM) is a disease with variable rate of progression. Young age is an independent risk factor for poor outcome in HCM. The influence of renin–angiotensin–aldosterone (RAAS) genotype on the progression of HCM in children is unknown. Children with HCM (n = 65) were enrolled prospectively across two centers (2001–2005). All subjects were genotyped for five RAAS gene polymorphisms previously associated with LV hypertrophy (pro-LVH): AGT M235T, ACE DD, CMA-1903 A/G, AGTR1 1666 A/C and CYP11B2-344 C/T. Linear regression models, based on maximum likelihood estimates, were created to assess the independent effect of RAAS genotype on LV hypertrophy (LVH). Forty-six subjects were homozygous for <2 and 19 were homozygous for ≥2 pro-LVH RAAS polymorphisms. Mean age at presentation was 9.6 ± 6 years. Forty children had follow-up echocardiograms after a median of 1.5 years. Indexed LV mass (LVMI) and LV mass z-scores were higher at presentation and follow-up in subjects with ≥2 pro-LVH genotypes compared to those with <2 (P < 0.05). Subjects with ≥2 pro-LVH genotypes also demonstrated a greater increase in septal thickness (IVST) and in LV outflow tract (LVOT) obstruction on follow-up (P < 0.05). On multivariate analysis, a higher number of pro-LVH genotypes was associated with a larger effect size (P < 0.05). Pro-LVH RAAS gene polymorphisms are associated with progressive septal hypertrophy and LVOT obstruction in children with HCM. Identification of RAAS modifier genes may help to risk-stratify patients with HCM.

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Acknowledgments

The authors thank Alisa Nakamine, BA, and Claudia Fontes, BA, for help with sample processing for genotyping and Shing Lee for help with statistical analysis. NIH grant RR00645 -GCRC, Office of Clinical Trials Pilot Study Award, Children’s Cardiomyopathy Foundation, and the Syde Hurdus Foundation (SM) and by NIH K08 grant (HL04068), and the Greenberg Award in Cardiovascular Genetics (AJS).

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Correspondence to Seema Mital.

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This work was presented in part at the Annual Scientific Sessions of the American Heart Association, New Orleans, November 2004.

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Kaufman, B.D., Auerbach, S., Reddy, S. et al. RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy. Hum Genet 122, 515–523 (2007). https://doi.org/10.1007/s00439-007-0429-9

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