The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease

Philippa J Talmud (1) , David M Flavell , Khaled Alfakih , Jackie A Cooper , Anthony J Balmforth , Mohan Sivananthan , Hugh E Montgomery , Alistair S Hall , Steve E Humphries

1 Medicine

Background: Left ventricular hypertrophy (LVH) is an independent risk factor for coronary heart disease (CHD). During LVH, the preferred cardiac energy substrate switches from fatty acids (FA) to glucose. Lipoprotein lipase (LPL) is the key enzyme in triglyceride hydrolysis and supplies FA to the heart. To investigate whether substrate utilisation influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. Methods and results: In a cohort of 190 hypertensive subjects, LPL X447 was associated with greater LV mass index (SS 85.2±1.7, SX+XX 91.1±3.4, p=0.01), but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with LVH than those without LVH (LVH 0.14, 95%CI 0.08-0.19; non-LVH 0.07, 95%CI 0.05-0.10; Odds Ratio 2.52, 95%CI 1.17-5.40 p=0.02). The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged UK men (n=2716). In the normotensive individuals, compared to S447 homozygotes, X447 carriers were protected from CHD risk (Hazard Ratio [HR] 0.48, 95%CI 0.23-1.00, p=0.05), whilst in the hypertensives, X447 carriers had increased risk (HR: SS 1.54, 95%CI 1.13-2.09, p=0.006; X447+ 2.30, 95%CI 1.53-3.45, p<0.0001) and showed significant interaction with hypertension in CHD risk determination (p=0.007). Conclusions: Hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects.

Mots clés: Medicine

Philippa J Talmud, David M Flavell, Khaled Alfakih, Jackie A Cooper, Anthony J Balmforth, et al.. The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease. Clinical Science, 2007, 112 (12), pp.617-624. ⟨10.1042/CS20060344⟩. ⟨hal-00479356⟩