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Variation in SNX29 and Acute Vasodilator Response in Pulmonary Arterial Hypertension
Jason H Karnes1, Changlei Bao2,3, Shuxin Liang2
1Department of Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson (J.H.K., E.K., K. Banerjee, J.F., K.L.M.).
Background:
Although pulmonary arterial hypertension (PAH) is a rare and fatal disease that is well-characterized, vasodilator-responsive PAH accounts for a minority of cases, with little mechanistic knowledge, but with dramatically improved survival.
Methods:
By assembling national cohorts, we evaluated genetic influences on acute vasodilator drug response, a key determinant of the presence of vasodilator-responsive PAH. Differences between hemodynamics at rest and after a PAH-specific vasodilator were tested in a genome-wide association study. Validated loci were functionally tested in cell culture and in a hypoxic mouse model of pulmonary hypertension.
Results:
Rs8057488 in the sorting nexin 29 (SNX29) gene reached genome-wide significance in the discovery cohort (P=4.00×10-8) and was nominally replicated (P=0.027). Consistent with its predicted function, SNX29 demonstrated an endosomal distribution in PA smooth muscle cells. Silencing SNX29 redistributed stromal interaction molecule proteins to the cell membrane and enhanced store-operated calcium entry. Over-expression of SNX29, in vivo, attenuated hypoxic vasoconstriction in isolated perfused murine lung models.
Conclusions:
The data cumulatively suggest SNX29 may contribute to vasodilation partly through reduced store-operated calcium entry and endosomal trafficking of store-operated calcium entry proteins, advancing our understanding of vasodilator-responsive PAH.
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