Faina Schwartz

Evidence for Linkage Between Essential Hypertension and a Putative Locus on Human Chromosome 17

Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location of the blood pressure QTL.

Autosomal dominant orthostatic hypotensive disorder maps to chromosome 18q.

Familial orthostatic hypotensive disorder is characterized by light-headedness on standing, which may worsen to syncope, palpitations, and blue-purple ankle discoloration, and is accompanied by a marked decrease in systolic blood pressure, an increase in diastolic pressure, and tachycardia, all of which resolve when supine. We ascertained three families in which this disorder is inherited as an autosomal dominant trait with reduced penetrance. A genomewide scan was conducted in the two largest families, and three regions with multipoint LOD scores >1.5 were identified. Follow-up of these regions with additional markers in all three families yielded significant evidence of linkage at chromosome 18q. A maximum multipoint LOD score of 3.21 in the three families was observed at D18S1367, although the smallest family had negative LOD scores in the entire region. There was significant evidence of linkage in the presence of heterogeneity at 18q, with a maximum LOD score of 3.92 at D18S1367 in the two linked families. Identification of the gene responsible for orthostatic hypotensive disorder in these families may advance understanding of the general regulatory pathways involved in the continuum, from hypotension to hypertension, of blood pressure.

Maternal influence on blood pressure suggests involvement of mitochondrial DNA in the pathogenesis of hypertension: the Framingham Heart Study.

Objective To investigate the contribution of the mitochondrial genome to hypertension and quantitative blood pressure (BP) phenotypes in the Framingham Heart Study cohort, a randomly ascertained, community-based sample. Methods Longitudinal BP values of 6421 participants (mean age, 53 years; 46% men) from 1593 extended families were used for analyses. In analyses of BP as a continuous trait, a variance components model with a variance component for maternal effects was used to estimate the mitochondrial heritability of the long-term average BP adjusted for age, sex, body mass index, and hypertension treatment. For analyses of BP as a categorical trait, a nonparametric test sensitive to excessive maternal inheritance was used to test for mitochondrial effect on long-term hypertension, defined as systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg or use of antihypertensive medication in one-half or more of qualifying examinations. This test was based on 353 pedigrees comprised of 403 individuals informative for mitochondrial DNA contribution. Results The estimated fraction of hypertensive pedigrees potentially due to mitochondrial effects was 35.2% (95% confidence interval, 27–43%, P < 10−10). The mitochondrial heritabilities for multivariable-adjusted long-term average systolic BP and diastolic BP were, respectively, 5% (P < 0.02) and 4% (P = 0.11). Conclusion Our data provide support for a maternal effect on hypertension status and quantitative systolic BP, consistent with mitochondrial influence. Additional studies are warranted to identify mitochondrial DNA variant(s) affecting BP.

Identification of a polymorphic glutamic acid stretch in the α2b-adrenergic receptor and lack of linkage with essential hypertension

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the alpha- and beta-adrenergic receptors, are obvious candidates. The alpha2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the alpha2B receptor and essential hypertension, we scanned the alpha2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the alpha2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Maternal component in the familial aggregation of hypertension

To assess maternal versus paternal contributions to the familial aggregation of hypertension, we examined family history data from 344 hypertensive probands (69 African American, 153 US Caucasian, 122 Greek Caucasian) ascertained without respect to parental hypertension status. The proportion of hypertensive mothers (81.7, 65.0 and 84.8% for African Americans, US Caucasians and Greek Caucasians, respectively) of these probands was significantly greater than the proportion of hypertensive fathers (50.0, 44.9 and 48.3%, respectively) in all three ethnic groups. The lifetime risk of hypertension was significantly greater for mothers compared with fathers of these hypertensive probands (p<0.001). Examination of the probands siblings indicated that maternal history of hypertension was associated with greater lifetime risk for hypertension than paternal history (p<0.01). In conclusion, we observe a consistent maternal component in the inheritance of hypertension. Although we cannot separate a maternal genetic from epigenetic or environmental effect, our findings suggest that genetic research should include studies of the mitochondrial as well as nuclear genome. Furthermore, when assessing a patients risk for hypertension, particular attention should be paid to the maternal family history.

A Novel Class of Tests for the Detection of Mitochondrial DNA–Mutation Involvement in Diseases

We develop a novel class of tests to detect mitochondrial DNA (mtDNA)-mutation involvement in complex diseases by the study of affected pedigree members. For a pedigree, affected individuals are first considered and are then connected through their relatives. We construct a reduced pedigree from an original pedigree. Each configuration of a reduced pedigree is given a score, with high scores given to configurations that are consistent with mtDNA-mutation involvement and low scores given to configurations that are not consistent with mtDNA-mutation involvement. For many pedigrees, the weighted sum of scores of the pedigrees is calculated. The tests are formed by comparing the observed score with the expected score under the null hypothesis that only nuclear autosomal mutations are involved. We study the optimality of score functions and weights under the heterogeneity model without phenocopies. We also develop a method to estimate the contribution that mtDNA mutations make if they are involved under a heterogeneity model. Finally, we apply our methods to three data sets: Leber hereditary optic neuropathy, a disease that has been proved to be caused by mtDNA mutations; non-insulin-dependent diabetes mellitus (NIDDM); and hypertension (HTN). We find evidence of mtDNA-mutation involvement in all three diseases. The estimated fraction of patients with NIDDM due to mtDNA-mutation involvement is 22% (95% confidence interval [CI] 6%-38%). The fraction of patients with HTN potentially due to mtDNA-mutation involvement is estimated at 55% (95% CI 45%-65%).

Association of Genetic Variation in the Mitochondrial Genome With Blood Pressure and Metabolic Traits

Elevated blood pressure (BP) is a major risk factor for cardiovascular disease. Several studies have noted a consistent maternal effect on BP; consequently, mitochondrial DNA variation has become an additional target of investigation of the missing BP heritability. Analyses of common mitochondrial DNA polymorphisms, however, have not found evidence of association with hypertension. To explore associations of uncommon (frequency >5%) mitochon drial DNA variants with BP, we identified uncommon/rare variants through sequencing the entire mitochondrial genome in 32 unrelated individuals with extreme-high BP in the Framingham Heart Study and genotyped 40 mitochondrial single nucleotide polymorphisms in 7219 Framingham Heart Study participants. The nonsynonymous mitochondrial single nucleotide polymorphism 5913G>A (Asp4Asn) in the cytochrome c oxidase subunit 1 of respiratory complex IV demonstrated significant associations with BP and fasting blood glucose (FBG) levels. Individuals with the rare 5913A allele had, on average, 7-mm Hg higher systolic BP at baseline (Pempirical=0.05) and 17-mg/dL higher mean FBG over 25 years of follow-up (Pempirical=0.009). Significant associations with FBG levels were also detected for nonsynonymous mitochondrial single nucleotide polymorphism 3316G>A (Ala4Thr) in the NADH dehydrogenase subunit 1 of complex I. On average, individuals with rare allele 3316A had 17- and 25-mg/dL higher FBG at baseline (Pempirical=0.01) and over 25 years of follow-up (Pempirical=0.007). Our findings provide the first evidence of putative association of variants in the mitochondrial genome with systolic BP and FBG in the general population. Replication in independent samples, however, is needed to confirm these putative associations.

Mitochondrial DNA mutations in patients with orthostatic hypotension

We determined the entire sequence of the mitochondrial genome in affected individuals from three families with idiopathic orthostatic hypotension. The disorder in two of these families was recently linked to chromosome arm 18q, while the third family remains unlinked. In all three families, orthostatic hypotension is inherited through the females, suggesting the existence of additional contributing factors, such as genomic imprinting or a mitochondrial modifier. We now report the presence of multiple point mutations in the mitochondrial DNA (mtDNA) in all three families. While most of the changes are common polymorphisms, several novel mutations were found that merit further consideration. In one individual, we detected a T-to-C transition at position 1243 in the 12SrRNA, a change from threonine to alanine at position 67 of the ND1 protein, and from valine to isoleucine at position 197 of the ND2 protein. A second individual harbored a novel substitution of threonine with serine at position 536 of the ND5 protein. Two previously unreported amino acid replacements were detected in a third individual: amino acid 193 of cytochrome b was changed from alanine to threonine, and amino acid 88 of COIII was changed from threonine to alanine. Further studies are required to assess the role of these mutations in blood pressure homeostasis.

The 239AB gene on chromosome 22: a novel member of an ancient gene family

A novel family of genes expressed in human brain has recently been identified. Gene 239FB, transcribed extensively in fetal brain, was isolated from the chromosome 11p13 region associated with mental retardation component of the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome. This report presents a cDNA sequence and expression profile of a related gene, 239AB, isolated from adult brain library, that was mapped to chromosome 22. While similar in structure, the two genes differ in their expression pattern and may have different roles in central nervous system development and function. In contrast to the 239FB, which is expressed predominantly in fetal brain, the 239AB gene is transcribed in adult tissues. Both human genes encode novel proteins of unknown function that are highly conserved from Caenorhabditis elegans to birds and mammals. Phylogenetic analysis suggested that the two lineages of the ancient gene family represented by 239FB and 239AB have been in existence prior to the emergence of modern animals.