Associations of epithelial sodium channel genes with blood pressure: the GenSalt study.

In order to investigate the associations of SCNN1A, SCNN1G and SCNN1B genes with blood pressure (BP) in the Han Chinese population, we included 2880 participants did not use antihypertensive medication in the month prior to the baseline survey in the current analysis. Forty-four tag-single-nucleotide polymorphisms (SNPs) in epithelial sodium channel (ENaC) genes were selected and genotyped, and nine BP measurements were obtained during the 3-day examination. In the single-marker analyses, we identified significant associations of SCNN1A marker rs13306613 with diastolic BP (DBP) and SCNN1B marker rs12447134 with systolic BP (SBP) under codominant model after Bonferroni's correction (P=2.82 × 10(-5) and 4.63 × 10(-4), respectively). In addition, five SNPs in SCNN1G and four SNPs in SCNN1B achieved nominal significance for SBP, DBP or mean arterial pressure (MAP) under the additive model. For example, the minor C allele of rs5735 in SCNN1G gene was associated with decreased SBP, DBP and MAP (P=0.016, 5.41 × 10(-3) and 4.36 × 10(-3), respectively). Gene-based results showed significant associations of SCNN1G and SCNN1B with BP levels. This study suggested that ENaC genes have important roles in BP regulation in the Han Chinese population. Future studies are warranted to replicate these findings, and functional studies are needed to identify true causal variants in ENaC genes.

Genetic correlation of blood pressure responses to dietary sodium and potassium intervention and cold pressor test in Chinese population.

We examined the genetic association between blood pressure (BP) responses to dietary sodium and potassium intervention and to cold pressor test (CPT) in a large family-based dietary feeding study. The dietary intervention and CPT were conducted among 1906 participants in rural China. The dietary intervention included three 7-day periods of low-sodium feeding (51.3 mmol per day), high-sodium feeding (307.8 mmol per day) and high-sodium feeding plus potassium supplementation (60 mmol per day). BP responses to high-sodium intervention had strong genetic correlations (ρ(G)) with both BP responses to low sodium (ρ(G)=-0.43 to -0.54, P-values=0.0005 to 0.03) and to potassium supplementation (ρ(G)=-0.41 to -0.49, P-values=0.001 to 0.005) interventions. Most environmental correlations between BP responses to various dietary interventions were significant. The ρ(G) between BP responses to CPT and to high-sodium intervention and potassium supplementation were statistically significant. For example, the ρ(G) between maximum BP responses to CPT and BP responses to high-sodium intervention was 0.37 (P=0.006) for systolic BP (SBP) and 0.41 (P=0.002) for diastolic BP (DBP). The ρ(G) between maximum BP responses to CPT and BP responses to potassium intervention was -0.42 (P=0.001) for SBP and -0.46 (P=0.001) for SBP. Our study suggests that there are common genetic determinants that influence BP responses to dietary sodium and potassium interventions and to CPT.

Multivariate and multilocus variance components method, based on structural relationships to assess quantitative trait linkage via SEGPATH.

A general-purpose modeling framework for performing path and segregation analysis jointly, called SEGPATH (Province and Rao [1995] Stat. Med. 7:185-198), has been extended to cover "model-free" robust, variance-components linkage analysis, based on identity-by-descent (IBD) sharing. These extended models can be used to analyze linkage to a single marker or to perform multipoint linkage analysis, with a single phenotype or multivariate vector of phenotypes, in pedigrees. Within a single, consistent approach, SEGPATH models can perform segregation analysis, path analysis, linkage analysis, or combinations thereof. SEGPATH models can incorporate environmental or other measured covariate fixed effects (including measured genotypes), genotype-specific covariate effects, population heterogeneity models, repeated-measures models, longitudinal models, autoregressive models, developmental models, gene-by-environment interaction models, etc., with or without linkage components. The data analyzed can have any missing value structure (assumed missing at random), with entire individuals missing, or missing on one or more measurements. Corrections for ascertainment can be made on a vector of phenotypes and/or other measures. Because of the flexibility of the class of models, the SEGPATH approach can also be used in nongenetic applications where there is a hierarchical structure, such as longitudinal, repeated-measures, time series, or nested models. A variety of specific models are provided, as well as some comparisons with other linkage analysis models. Particular applications demonstrate the importance of correctly accounting for the extraneous sources of familial resemblance, as can be done easily with these SEGPATH models, so as to give added power to detect linkage as well as to protect against spuriously inferring linkage.

Familial resemblance and heritability.

Familial resemblance, which arises when members within families are more similar than are unrelated pairs of individuals, may be estimated in terms of correlations (or covariances) among family members. The magnitudes of such correlations generally reflect both the extent of environmental sharing and the degree of biological relationship between the relatives. Heritability, or more appropriately multifactorial heritability or generalized heritability, quantifies the strength of the familial resemblance and represents the percentage of variance ina trait that is due to all additive familial effects including additive genetic effects and those of the familial environment. However, the traditional concept of heritability, which may be more appropriately called the genetic heritability, represents only the percentage of phenotypic variance due to additive genetic effects. Resolving the sources of familial resemblance entails other issues. For example, there may be major gene effects that may be largely or entirely nonadditive, temporal or developmental trends, and gene-gene (epistasis) and gene-environment interactions. The design of a family study determines which of these sources are resolvable. For example, in intact nuclear families consisting of parents and offspring, the genetic and familial environmental effects are not resolvable because these relatives share both genes and environments. However, extended pedigrees and twin and adoption study designs allow separation of the heritable effects and, possibly, more complex etiologies, including interactions. Various factors affect the estimation and interpretability of heritability, for example, assumptions regarding linearity and additivity of the effects, assortative mating, and the underlying distribution of the data. Nonnormality of the data can lead to errors in hypothesis testing, although it yields reasonably unbiased estimates. Fortunately, these and other complications can be directly modeled in many of the sophisticated software packages available today in genetic epidemiology.

Inhibition of rat passive cutaneous anaphylaxis by 3-(tetrazol-5-yl)quinolines.

Quinoline-3-carboxylic acid (3) was found to have weak oral activity in the rat passive cutaneous (PCA) assay. In an effort to increase activity, the synthesis of structurally related compounds was initiated. This led to substituted 3-(tetrazol-5-yl)quinolines, some of which are equal in potency, when given orally, to doxantrazole. Further work resulted in the synthesis of 4-oxoquinolines, one of which, 8-chloro-1,4-dihydro-4-oxo-3-(tetrazol-5-yl)quinoline (132), is 33-fold more active than disodium cromoglycate (ip) and 32-fold more active than doxantrazole (po).

Antiallergic activity of tetracyclic derivatives of quinoline-2-carboxylic acids. 1.

Substitution of 1,4-dihydro-4-oxoquinoline-2-carboxylic acid by acetyl, benzoyl, and phenylsulfonyl substituents was found to enhance activity in the rat passive cutaneous anaphylaxis assay. A further increase in activity, to equipotency with DSCG, was achieved by incorporation of the 8-benzoyl moiety into a tetracyclic structure to give 1,4-dihydro-4,11(1H,11H)-dioxoindeno[1,2-h]quinoline-2-carboxylic acid (20). In contrast, the reverse isomer 19 was found to have little activity.

Antiallergic activity of tetracyclic derivatives of quinoline-2-carboxylic acid. 2. Some benzothienoquinolinecarboxylic acids.

Some benzothienoquinolinecarboxylic acids were synthesized and tested in the rat passive cutaneous anaphylaxis (PCA) assay as potential antiallergic agents. Many of the compounds showed activity comparable to that shown by disodium cromoglycate (DSFG); two of them, 1,4-dihydro-4,6,6-trioxo-5-chloro[1]benzothieno[2,3-g]quinoline-2-carboxylic acid and 1,4-dihydro-1,7-dioxo[1]benzothieno[3,2-f]quinoline-3-carboxylic acid, showed potency approximately eightfold greater than that of DSCG in the PCA assay.