ADD1

Abstract: Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in mammalian cells The entire genomic structure of the human SCAP gene was cloned in a 110-kb region covered by overlapping genomic clones The SCAP gene was localized to chromosome 3p213 by fluorescence in situ hybridization The human SCAP gene is over 30 kb in length and contains 23 exons and 22 introns The transcription initiation site within exon 1 is separate from the initiation codon coded in exon 2 Analysis of exon/intron structure revealed that the gene consists of a mosaic of exons encoding functional protein domains Exon 1 encodes the 5′ non-coding region Exons 2, 3, 7, 8, 9, 10, 11, 13, and 15, respectively, encode each of the eight transmembrane regions Of these, exons 7–11 encode the sterol-sensing domain Exons 15–23 encode the hydrophilic carboxyl-terminal domains containing four copies of a motif called the Trp-Asp (WD) repeats that interact with and regulate SREBP and the site-1 protease Sequence analysis of the 5′-flanking region showed that it comprised a high G/C-rich region and contained adipocyte determination and differentiation-dependent factor 1 (ADD1)/SREBP-1 binding sites in addition to Sp1 and AP2 sites This suggests that SCAP gene expression is under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism Our data establish the basis of investigation for molecular variants in this gene that may result in alterations in plasma lipoprotein levels and/or derangement of intracellular lipid metabolism

Abstract: Background: Essential hypertension is a complex genetic trait. Genetic variant of alpha adducin ( ADD1 ) gene have been implicated as a risk factor for hypertension. Given its clinical significance, we investigated the association between ADD1 Gly460Trp gene polymorphism and essential hypertension in an Indian population. Further, a meta-analysis was carried out to estimate the risk of hypertension. Methods: In the current study, 432 hypertensive cases and 461 healthy controls were genotyped for the Gly460Trp ADD1 gene polymorphism. Genotyping was determined by real time PCR using Taqman assay. Multiple logistic regression analysis was used to detect the association between Gly460Trp polymorphism and hypertension. Results: No significant association was found in the genotype and allele distribution of Gly460Trp polymorphism with hypertension in our study. A total of 15 case-control studies were included in the meta-analysis. There was no evidence of the association of Gly460Trp polymorphism with hypertension in general or in any of the sub group. Conclusions: We found that the Gly460Trp polymorphism is not a risk factor for essential hypertension in a south Indian Tamilian population. However, the role of ADD1 polymorphism may not be excluded by a negative association study. Further, large and rigorous case-control studies that investigate gene-gene-environment interactions may generate more conclusive claims about the molecular genetics of hypertension.

Abstract: It has recently been proposed that primary mutations in genes involved in fatty acid and lipid metabolism may contribute to the pathogenesis of insulin resistance and dyslipidemia often observed in spontaneous forms of hypertension. In the current study in the spontaneously hypertensive rat (SHR), we mapped and sequenced the gene encoding a key transcription factor known as ADD1 (adipocyte determination and differentiation factor 1) or SREBP-1c (sterol regulatory element binding protein-1c) that has recently been identified as a master regulator of genes involved in the hepatic control of lipid and carbohydrate metabolism. We found that (1) the gene for ADD1/SREBP-1c maps to a region of rat Chromosome 10 previously reported to contain a quantitative trait locus involved in the regulation of hepatic cholesterol levels and (2) the SHR harbors a valine-to-methionine substitution in the COOH terminal portion of the ADD1/SREBP-1 protein that is not present in 44 other strains of laboratory rats. These findings, together with previous studies showing that transgenic expression of SREBP-1 isoforms has major effects on hepatic fatty acid and cholesterol biosynthesis, suggest that naturally occurring variation in the gene encoding the SREBP-1 isoforms might contribute to inherited variation in lipid metabolism in the SHR versus other strains of rats. These results should serve to motivate future transfection studies of the effect of the SHR mutant on SREBP-1 expression and activation in vitro, as well as the development of congenic and transgenic strains of SHR to investigate the effects of different variants of SREBP-1 on carbohydrate and lipid metabolism in vivo.

Abstract: Essential hypertension (EH) is the most common risk factor for cardiovascular, cerebrovascular, and renal diseases. It is a complex trait that is heritable and involves multiple quantitative trait loci (QTL) and environmental conditions affecting the underlying physiological mechanisms.1 Genetic linkage studies and genome wide scans have disclosed many possible candidate loci contributing to hypertension. Hypertension has been found to occur more often than expected in families with familial hyperlipidaemia. Because dyslipidaemia is a common finding in hypertensive patients, the lipoprotein lipase ( LPL ) gene is a logical candidate gene that could contribute to the development of hypertension.2 LPL is a crucial enzyme in plasma lipoprotein metabolism, which hydrolyses triglycerides and chylomicrons. Two genetic linkage studies of hypertension in Taiwan suggested some positive linkage signals in or near the LPL gene region with blood pressure (BP).3,4 Because most Taiwanese have consanguinity with Chinese Han people, it is feasible and rational to verify these results in another homogeneous group. Adducin is a membrane skeletal protein that is involved in the regulation of cellular signal transduction and membrane ion transport. Hypertension has also been linked to the α-adducin ( ADD1 ) gene in some human studies.5–7 ### Key points