Positional Identification of Hypertension Susceptibility Genes on Chromosome 2

Abstract

Abstract-Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (Nϭ461; Nϭ778) and whites (Nϭ550; Nϭ967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.

Sodium Bicarbonate Cotransporter Polymorphisms Are Associated With Baseline and 10-Year Follow-Up Blood Pressures

“…2 The previous findings have been extended by showing that the association is robust longitudinally after 10 years of blood pressure follow-up and that stressed blood pressures also show associations with SLC4A5. Most subjects in the FBPP had hypertension, whereas the Utah pedigree members were generally normotensive.…”

“…[5][6][7] Genotypes were obtained for the 4 SNPs (Celera database: hcv1137521, hcv1137534, hcv1137538, and hcv8941031; dbSNP database: rs828853, rs10177833, rs6731545, and rs1006502) found to be most consistently related to blood pressure in the study from the GENOA network of the FBPP and which had been selected to be typed in 2 of the other FBPP networks. 2 A Roche LightTyper instrument, using melting temperature technology, was used to obtain the genotypes. After genotyping, genotypes were tested for incompatibilities by the PEDCHECK program, 8 and nuclear families identified with incompatibilities had their genotypes set to missing (37 genotypes zeroed out, 0.9%).…”

“…1 The National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), made up of 4 collaborating, multicenter hypertension networks, also found linkage to this region of chromosome 2. 2 Candidate genes under this consensus peak were identified, and single nucleotide polymorphisms (SNPs) within those genes were genotyped to identify polymorphisms responsible for the linkage and to define new pathology leading to elevated blood pressure. The strongest signals for association of hypertension-related traits in the Genetic Epidemiology Network of Arteriopathy (GENOA) network to these candidate genes was with the SLC4A5 gene that encodes a NaHCO 3 transporter that helps control cellular pH.…”

“…The strongest signals for association of hypertension-related traits in the Genetic Epidemiology Network of Arteriopathy (GENOA) network to these candidate genes was with the SLC4A5 gene that encodes a NaHCO 3 transporter that helps control cellular pH. 2 Two other networks within this program confirmed the association with this gene, but the associations were not consistently found for the same SNPs in SLC4A5, nor even with the same blood pressure phenotypes. Nevertheless, 2 of the SNPs in this gene accounted for most of the linkage signal, and the overall association of the SLC4A5 gene with the measured phenotypes in the 3 networks, each with large sample sizes, supported SLC4A5 as a hypertension susceptibility gene.…”

Imputing missing genotypic data of single-nucleotide polymorphisms using neural networks

“…21,22 In this study, we used a subset of 126 SNPs measured on 419 unrelated subjects as a real data example. Overall, 0.92% of the SNP data were missing.…”