Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we tested single-nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.95 x 10(-10)) was identified within the regulation of complement activation locus and was centered over a tyrosine-402 --> histidine-402 protein polymorphism in the gene encoding complement factor H. Possession of at least one histidine at amino acid position 402 increased the risk of AMD 2.7-fold and may account for 50% of the attributable risk of AMD.

We have examined the developmental expression of the murine breast and ovarian cancer susceptibility gene, Brca1, to investigate its role in the control of cell growth and differentiation. Specifically, we have analysed Brca1 expression during embryonic development, in adult tissues, and during postnatal mammary gland development, particularly in response to ovarian hormones. Our results suggest that Brca1 is expressed in rapidly proliferating cell types undergoing differentiation. In the mammary gland, Brca1 expression is induced during puberty, pregnancy, and following treatment of ovariectomized animals with 17 beta-estradiol and progesterone. These observations imply that Brca1 is involved in the processes of proliferation and differentiation in multiple tissues, notably in the mammary gland in response to ovarian hormones.

Abstract-The influence of genetic contributors, such as common single nucleotide polymorphisms, on blood pressure and essential hypertension may vary with the gender. We used the power of a large, community-based sample to probe whether gender interacts with genes in contributing to extremes of blood pressure in 611 male and 656 female age-matched white Americans within the top and bottom 5th percentiles of blood pressure among Ͼ53 000 people in a health maintenance program. This approach has Ͼ90% statistical power to detect genes contributing as little as 3% to trait (blood pressure) variation. We scored Ϸ60 000 genotypes in the subjects: 48 single nucleotide polymorphisms at 33 autosomal and 2 X-linked genes in adrenergic and renal pathways that regulate blood pressure. Six individual variants significantly affected blood pressure and demonstrated gene-by-gender interaction, yielding different effects of the single nucleotide polymorphism on blood pressure in males and females. In females, polymorphisms at ␤ 1 -adrenergic receptor and ␣ 2A -adrenergic receptor contributed to blood pressure, whereas in men, polymorphisms at ␤ 2 -adrenergic receptor and angiotensinogen were associated. An ␣ 2A -adrenergic receptor haplotype influenced blood pressure in women, whereas 2 angiotensinogen haplotypes were associated in men. We also detected gene-by-gene, gender-specific interactions (epistasis) in pathophysiological pathways. This study reveals gender-specific effects of single nucleotide polymorphisms, haplotypes, and gene-by-gene interactions that determine blood pressure in white Americans. Such genetic variants may define genetically and etiologically distinct subgroups of men and women with essential hypertension and may have implications for rational treatment selection. Key Words: gender Ⅲ polymorphism Ⅲ epistasis Ⅲ essential hypertension Ⅲ blood pressure Ⅲ adrenergic receptors M any common diseases exhibit gender bias, and gender differences in the development of common multifactorial (or complex) disorders, such as essential hypertension and other cardiovascular diseases, are the subject of considerable attention. 1 Earlier studies pointed to contributions of gender in vascular physiology 2 and in response to adrenergic and antihypertensive drugs, such as ␣ 2 -adrenergic agonists, [3][4][5][6] but the potential interaction of gender and heredity in the determination of elevated blood pressure (BP) is incompletely understood.The gender of a subject is generally accounted for, usually as a covariate, in association studies, but more recently, studies have begun to identify both autosomal genes and genes involved in sexual dimorphism that differentially contribute to multifactorial traits/diseases or are differentially expressed in tissues in males versus females. For example, Nakayama et al 7 identified a genetic variant in the folliclestimulating hormone receptor that may contribute to essential hypertension in females. Peter et al 8 identified evidence of gender-specific contributions of estrogen-related gen...

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Background-Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. Methods and Results-Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by Ϸ47%) and downward deflections (by Ϸ44%), increased cardiac parasympathetic index (by Ϸ2.4-fold), and decreased cardiac sympathetic index (by Ϸ26%). Renal norepinephrine excretion was diminished by Ϸ26% and epinephrine excretion by Ϸ34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to Ϸ70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by Ϸ5 to 6 mm Hg, and the polymorphism accounted for Ϸ1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. Conclusions-The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

ABEL, K. (Melpar, Inc., Falls Church, Va.), H. DESCHMERTZING, AND J. I. PETERSON. Classification of microorganisms by analysis of chemical composition. I. Feasibility of utilizing gas chromatography. J. Bacteriol. 85:1039-1044. 1963.-The feasibility of utilizing gas chromatography as a sensitive and rapid method for the analysis of lipids as a natural basis for the classification of microorganisms by chemical composition was investigated. The lipids were extracted and transesterified to component carboxylic acid methyl esters in a single step, after which the methyl esters were resolved by gas chromatography to provide distinctive chromatographic elution patterns. Similarities in the lipid carboxylic acid distribution were noted among selected species of the family Enterobacteriaceae, and significant differences were noted among selected families of the class Schizomycetes.

The human genes BRCA1, conferring susceptibility to early-onset breast and ovarian cancer, has recently been isolated. Here we describe isolation of cDNAs, sequence analysis, and genomic localization of the murine homolog, Brac1. The mouse cDNA sequence predicts a protein of 1812 amino acids; a number of small gaps account for the 51 fewer residues in the mouse protein relative to human BRCA1. While the predicted mouse and human proteins display on the whole a high level of homology (58% identity, 73% similarity), the regions of greatest homology are at the respective amino and carboxyl termini. Most reported disease-associated missense mutations in human BCRA1 occurred within these more highly conserved terminal regions. A predicted zinc-building RING finger domain near the amino terminus lies within a 50 amino acid stretch that is perfectly conserved in both species. The strong conservation during mammalian evolution argues for the importance of this domain, perhaps mediating a role for BRCA1 in DNA and/or protein binding. We have also identified a conserved highly acidic domain in the carboxyl terminal half of the BCRA1 protein resembling acidic transactivation domains of certain transcription factors. Using an interspecific backcross panel, Brca1 was mapped to a region of mouse chromosome 11 that exhibits conserved linkage with 17q21. The sequence and isolated cDNAs will provide useful reagents for studying the expression of Brca1 in the mouse, and for testing the importance of the evolutionarily conserved domains.

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