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Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes ( L3MBTL4  rs403814,  P  meta  = 6.128 × 10 −9 ;  LOC729251 , and  TCEANC ) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that  L3MBTL4  is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of  L3MBTL4  exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically,  L3MBTL4  over-expression could lead to down-regulation of latent transforming growth factor-β binding protein 1 ( LTBP1 ), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed  L3MBTL4  as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention.

Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension