Porat M. Erlich

Genetic Variants of WNK4 in Whites and African Americans With Hypertension

Abstract— Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single‐nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P =0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P =0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P =0.027) or without (P =0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Heritability of magnetic resonance imaging (MRI) traits in Alzheimer disease cases and their siblings in the MIRAGE study

Magnetic resonance imaging (MRI) traits can serve as more specific measures of degenerative or cerebrovascular brain injury than can be ascertained through personal history, risk factors, clinical signs, or symptoms. They are potentially useful intermediate phenotypes for genetic studies of Alzheimer disease (AD). Recent studies have estimated heritability of white matter hyperintensity (WMH) among cognitively normal family members to be between 0.55 and 0.73. Persons discordant for AD are expected to have substantially different MRI phenotype distributions; our goal was to determine whether MRI traits in siblings discordant for AD are heritable. We measured cerebral atrophy, medial temporal atrophy (MTA), WMH, and a rating of cerebrovascular disease (CVR) via MRI in 815 participants from 424 families of the Multi-Institutional Research in Alzheimers Genetic Epidemiology Study. Residual heritability after adjustment for covariates ranged from 0.17 (P=0.009) for MTA to 0.57 (P=10−7) for CVR. The number of APOE-ϵ4 alleles was significantly associated with WMH (P=0.01) and CVR (P=0.005) but not cerebral atrophy (P=0.25) or MTA (P=0.83). Heritability remained significant and high after adjusting for APOE genotype, suggesting that a substantial proportion of the additive genetic variation in these MRI traits is explained by other genes. In the Multi-Institutional Research in Alzheimers Genetic Epidemiology Study of AD-discordant siblings, MRI traits are heritable and are potential endophenotypes for genetic association studies.

Magnetic Resonance Imaging Traits in Siblings Discordant for Alzheimer Disease

Magnetic resonance imaging (MRI) can aid clinical assessment of brain changes potentially correlated with Alzheimer disease (AD). MRI traits may improve our ability to identify genes associated with AD‐outcomes. We evaluated semi‐quantitative MRI measures as endophenotypes for genetic studies by assessing their association with AD in families from the Multi‐Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study.

Genetic association between endothelial nitric oxide synthase and Alzheimer disease

Evidence suggests that vascular and inflammatory factors may be important in the etiology of Alzheimer disease (AD). The Glu/Glu genotype at the Glu298Asp variant of the endothelial nitric oxide synthase (NOS3) gene has been tested for association with AD in several Caucasian and Asian populations, with conflicting results. We tested the Glu298Asp variant for association in African American and Caucasian AD patients, unaffected siblings, and unrelated controls from the MIRAGE Study. To explore whether the inconsistent results in previous studies might be due to linkage disequilibrium with a polymorphism or haplotype not previously tested, we genotyped 10 additional NOS3 single nucleotide polymorphisms (SNPs) spanning 25.3 kb. Finally, we compiled results of previous studies of Glu298Asp using meta‐analysis, to determine whether the aggregate studies support an association between Glu298Asp and AD. We found that the Glu298 allele was associated with higher risk of AD in the MIRAGE African American (p = 0.002) but not Caucasian (p = 0.9) groups. None of the additional SNPs were associated with AD in the Caucasians, whereas two showed evidence for association in the African Americans. The meta‐analysis showed a small effect of the Glu298Asp GG genotype on AD risk across all studies (summary odds ratio = 1.15, 95% confidence interval: 0.97–1.35) and significant heterogeneity of this association among studies (p = 0.02).

Genome-wide screen for heavy alcohol consumption

BackgroundTo find specific genes predisposing to heavy alcohol consumption (self-reported consumption of 24 grams or more of alcohol per day among men and 12 grams or more among women), we studied 330 families collected by the Framingham Heart Study made available to participants in the Genetic Analysis Workshop 13 (GAW13).ResultsParametric and nonparametric methods of linkage analysis were used. No significant evidence of linkage was found; however, weak signals were identified in several chromosomal regions, including 1p22, 4q12, 4q25, and 11q24, which are in the vicinity of those reported in other similar studies.ConclusionOur study did not reveal significant evidence of linkage to heavy alcohol use; however, we found weak confirmation of studies carried out in other populations.

Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease

Previous studies have shown association of single nucleotide polymorphisms (SNPs) in 3 contiguous genes (PON1, PON2, and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE study. The odds of AD (adjusted for age, gender, and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all 3 genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from 1 gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic.

Polymorphisms in paraoxonase genes PON1, PON2 and PON3 are associated with late onset Alzheimer disease

Background: Serum paraoxonase isozymes are believed to protect against low density lipoprotein oxidation and thus affect the risk of coronary artery disease. They are encoded by a family of three paralogous genes residing in a cluster on chromosome 7q21 (PON1, PON2 and PON3). Recent evidence suggests an association between SNPs in PON1 and PON2 and Alzheimer disease (AD). Objective: To conduct a comprehensive investigation of association between SNPs in the PON gene cluster and AD. Methods: We genotyped 28 SNPs in the PON gene cluster in DNA specimens obtained from participants of the MIRAGE AD Study, including 267 Caucasian AD cases and 317 of their non-demented sibs and 238 African American AD cases and 172 of their non-demented sibs. SNPs were selected for genotyping based on their minor allele frequencies, predicted function, predicted haplotype representation and validation. Data for individual SNPs were evaluated using family-based association tests, generalized estimating equations and chi square tests of proportion. Haplotype analysis was conducted using HBAT. Conclusions: We observed association between AD and several SNPs and haplotypes throughout the PON gene cluster. In both Caucasians and African Americans a peak of significant association in the coding regions of PON2 and PON3 was found (p-values ranged between p 0.01 to p 0.0002). In Caucasian families a significant association was observed for a SNP in the promoter of PON1. This is the first comprehensive high-density SNP association study of paraoxonase genes and AD. Our results confirm and extend those of previous reports, which evaluated single SNPs in smaller datasets. Like APOE, paraoxonase is involved in the physiological pathway of lipidtransport. Our study highlights the importance of this pathway and, possibly, its related vascular pathologies (e.g. atherosclerosis) in the etiology of late onset AD. Further studies are needed to identify the functional variants in the PON gene cluster responsible for this association.