RESUMEN
BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2×10(-4)). Examination of genotype-sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10×10(-4) and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41×10(-4) and 1.55×10(-4), respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low-sodium intervention (P = 1.22×10(-4) and 4.44×10(-5), respectively). Ten variants from 3 independent SELE loci displayed significant genotype-sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56×10(-3) to 1.00×10(-4)). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Dieta Hiposódica , Endotelio Vascular/fisiología , Variación Genética/genética , Sodio en la Dieta/farmacología , Adolescente , Adulto , Alelos , Amidohidrolasas/genética , Pueblo Asiatico , Presión Sanguínea/fisiología , Selectina E/genética , Femenino , Colágenos Asociados a Fibrillas/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Adulto Joven , Factor de von Willebrand/genéticaRESUMEN
OBJECTIVE: Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans, followed by single nucleotide polymorphism (SNP) fine mapping of candidate genes in the linked chromosomal region. METHODS: We used nonparametric methods to test for linkage of microsatellites with hypertension and BP measures in smokers, nonsmokers, and the combined group. To begin fine mapping of a major quantitative trait locus (QTL) for systolic blood pressure (SBP) on chromosome 15q that showed strong evidence for GxS interaction, we genotyped 55 SNPs in nine candidate genes for association studies using two population-based statistical methods. RESULTS: The strongest evidence for GxS interaction (P = 0.0004) was found for SBP on chromosome 15q, where a major QTL (LOD = 3.36) was identified only in nonsmokers. Follow-up studies identified three SNPs in three genes (ANPEP, IGF1R, and SLCO3A1) that showed associations with SBP only in nonsmokers, cumulatively accounting for a 7 mmHg increase in SBP. However, conditional linkage analyses that accounted for phenotypic effects of these SNPs only slightly reduced the original LOD score. CONCLUSION: The detection of a major QTL on chromosome 15q for SBP in nonsmokers indicates the presence of loci that influence BP via GxS interactions. However, identification of the genes that underlie such QTL effects remains a challenge. Although we found three candidate genes that showed significant associations with SBP in nonsmokers, further studies are required to identify the gene(s) that underlie the chromosome 15q QTL that influences SBP via GxS interactions.