19 Jul 08

Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome

Posted in General, Genetics at 18:21 by Laci

By B S Brooke, J P Habashi, D P Judge, N Patel, B Loeys and H C Dietz

NEJM 2008;358:2787-2795

Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan’s syndrome. Recent data from mouse models of Marfan’s syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor β (TGF-β) that can be mitigated by treatment with TGF-β antagonists, including angiotensin II–receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan’s syndrome who had severe aortic-root enlargement.

We identified 18 pediatric patients with Marfan’s syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs.

The mean (±SD) rate of change in aortic-root diameter decreased significantly from 3.54±2.87 mm per year during previous medical therapy to 0.46±0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan’s syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan’s syndrome, was not affected by ARB therapy.

In a small cohort study, the use of ARB therapy in patients with Marfan’s syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

10 Feb 08

Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression

Posted in Genetics at 14:14 by Laci

By H Eiberg, J Troelsen, M Nielsen, A Mikkelsen, J Mengel-From, K W Kjaer and L Hansen

Hum Gen 2008;XXX:XXX-XXX

The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation. By linkage analysis of a large Danish family, we finemapped the blue eye color locus to a 166 Kbp region within the HERC2 gene. By association analyses, we identified two SNPs within this region that were perfectly associated with the blue and brown eye colors: rs12913832 and rs1129038. Of these, rs12913832 is located 21.152 bp upstream from the OCA2 promoter in a highly conserved sequence in intron 86 of HERC2. The brown eye color allele of rs12913832 is highly conserved throughout a number of species. As shown by a Luciferase assays in cell cultures, the element significantly reduces the activity of the OCA2 promoter and electrophoretic mobility shift assays demonstrate that the two alleles bind different subsets of nuclear extracts. One single haplotype, represented by six polymorphic SNPs covering half of the 3′ end of the HERC2 gene, was found in 155 blue-eyed individuals from Denmark, and in 5 and 2 blue-eyed individuals from Turkey and Jordan, respectively. Hence, our data suggest a common founder mutation in an OCA2 inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color.

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