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Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.

The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100,000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in approximately 3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population.

Epidemiological studies have identified elevated low density lipoprotein (LDL) and diminished high density lipoprotein (HDL) cholesterol levels as risk factors for coronary artery disease. The major protein component of HDL is apoprotein A-I (apo A-I), a polypeptide of 243 amino acids of known primary amino acid sequence. This apoprotein serves as a cofactor for the plasma lecithin-cholesterol acyltransferase (LCAT) enzyme responsible for the formation of most cholesteryl esters in plasma, and also promotes cholesterol efflux from cells. The primary translation product of apo A-I contains both a pre and a pro segment, and post-translational processing of apo A-I may be involved in the formation of the functional plasma apo A-I isoproteins. Defective apo A-I processing may be the underlying problem in Tangier disease, in which patients have low plasma HDL and apo A-I levels despite normal apo A-I synthesis. Patients have been reported with conditions distinct from Tangier disease in whom severe deficiency or absence of apo A-I has been associated with very low HDL levels and severe coronary artery disease. We have now examined the apo A-I gene in two such patients and their first degree relatives. These patients have been reported to have skin and tendon xanthomas, corneal clouding and severe premature coronary atherosclerosis associated with very low HDL levels and deficiencies of two apoproteins, apo A-I and apo C-III. We show that both probands are homozygous for a defect in the apo A-I gene locus.

Endothelial cells play a critical role in thromboregulation by virtue of a surface-connected fibrinolytic system. Cultured endothelial cells synthesize and secrete tissue-type plasminogen activator (t-PA) which can bind to at least two discrete sites on the cell surface. These binding sites preserve the catalytic activity of t-PA and protect it from its physiological inhibitor (PAI-1). N-terminal glutamic acid plasminogen (Glu-PLG), the main circulating fibrinolytic zymogen, also interacts specifically with the endothelial cell surface. Binding is associated with a 12-fold increase in catalytic efficiency of plasmin generation by t-PA which may reflect conversion of Glu-PLG to its plasmin-modified form, N-terminal lysine plasminogen (Lys-PLG). Lipoprotein(a) is an atherogenic lipoprotein particle which contains the plasminogen-like apolipoprotein(a) bound to low density lipoprotein. We report here that lipoprotein(a) interferes with endothelial cell fibrinolysis by inhibiting plasminogen binding and hence plasmin generation. In addition, we demonstrate lipoprotein(a) accumulation in atherosclerotic lesions. These findings may provide a link between impaired cell surface fibrinolysis and progressive atherosclerosis.

It has recently been suggested that polymorphisms in the human apolipoprotein A-I (apo A-I) gene locus may be related to the development of premature atherosclerosis and hypertriglyceridaemia. To understand if and how these polymorphisms affect apo A-I gene expression, we studied the genomic sequences flanking the apo A-I gene. Here we show the presence of another apolipoprotein gene, apolipoprotein C-III (apo C-III), approximately 2.6 kilobases (kb) downstream of the 3' end of the apo A-I gene. We also show that the apo A-I and apo C-III genes are convergently transcribed and that a polymorphism previously reported to be associated with hypertriglyceridaemia may be due to a single base pair substitution in the 3'-noncoding region of apo C-III mRNA.

Apolipoprotein A-I (apo A-I) is the major protein constituent of high-density lipoprotein (HDL). The study of the apo A-I gene is of interest because plasma levels of HDL have been inversely correlated with the development of coronary artery disease and because polymorphisms related to this gene have been associated with hypertriglyceridaemia and premature atherosclerosis. We have recently isolated and characterized the human apo A-I gene and have shown that apo A-I and apolipoprotein C-III (apo C-III) genes are physically linked and that a polymorphism (of unknown frequency in the general population) of the apo A-I gene is inherited as a mendelian trait linked to premature atherosclerosis in an affected family (not the same polymorphism as has previously been reported to be associated with hypertriglyceridaemia). Here we report that this polymorphism is due an at least 6.5-kilobase (kb) DNA insertion in the coding region of the apo A-I gene and that there is no detectable alteration (as determined by limited genomic blotting analysis) of the apo C-III gene of these patients.