Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.

Summary: Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging‐related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40–89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = –0.41, P < 0.0001) and age‐adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) (r =–0.16, P = 0.007) and urinary 8‐epi‐PGF_2α (r = –0.16, P = 0.005) – an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age‐adjusted TRF length (hypertensives = 5.93 ± 0.042 kb, normotensives = 6.07 ± 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.

The evidence for the existence of genetic susceptibility variants for the common form of hypertension (“essential hypertension”) remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8×10⁻⁷) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1×10⁻⁷). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments. Despite intense research, the genetic risk factors for essential hypertension and blood pressure (BP) regulation have not been identified with consistency. We conducted a genome wide association scan using over 800,000 genetic markers in an African American sample of 1,017 adults in the Washington, D.C., area of the United States. We found evidence to suggest that genetic variants in several genes, including PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H, are significantly associated with systolic BP levels. From our previous knowledge of human physiology, two of these genes have potential roles to play in BP regulation. The evidence for genetic variants influencing diastolic BP levels and hypertension status was weaker and inconclusive. To our knowledge, this is the first study that has used a genome-wide association approach to study hypertension and BP in an African American population, a minority group that experiences hypertension more frequently and more severely than other population groups in the United States. The findings will be useful to other researchers seeking to advance our understanding of the genetic factors that influence BP with the hope that these insights will eventually translate to new and better treatment options for hypertension in African Americans and other global populations.

The editing enzyme double-stranded RNA adenosine deaminase includes a DNA binding domain, Zα, which is specific for left-handed Z-DNA. The 2.1 angstrom crystal structure of Zα complexed to DNA reveals that the substrate is in the left-handed Z conformation. The contacts between Zα and Z-DNA are made primarily with the “zigzag” sugar-phosphate backbone, which provides a basis for the specificity for the Z conformation. A single base contact is observed to guanine in the syn conformation, characteristic of Z-DNA. Intriguingly, the helix-turn-helix motif, frequently used to recognize B-DNA, is used by Zα to contact Z-DNA.

Editing of RNA changes the read-out of information from DNA by altering the nucleotide sequence of a transcript. One type of RNA editing found in all metazoans uses double-stranded RNA (dsRNA) as a substrate and results in the deamination of adenosine to give inosine, which is translated as guanosine. Editing thus allows variant proteins to be produced from a single pre-mRNA. A mechanism by which dsRNA substrates form is through pairing of intronic and exonic sequences before the removal of noncoding sequences by splicing. Here we report that the RNA editing enzyme, human dsRNA adenosine deaminase (DRADA1, or ADAR1) contains a domain (Zα) that binds specifically to the left-handed Z-DNA conformation with high affinity (K_D= 4 nM). As formation of Z-DNAin vivooccurs 5′ to, or behind, a moving RNA polymerase during transcription, recognition of Z-DNA by DRADA1 provides a plausible mechanism by which DRADA1 can be targeted to a nascent RNA so that editing occurs before splicing. Analysis of sequences related to Zα has allowed identification of motifs common to this class of nucleic acid binding domain.