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Objective Adiponectin is an adipocytokine that has been implicated in a variety of metabolic disorders, including T2D and cardiovascular disease. Studies evaluating genetic variants in ADIPOQ have been contradictory when testing association with T2D in different ethnic groups. Design and Methods In this study, 18 SNPs in ADIPOQ were tested for association with plasma adiponectin levels and diabetes status. SNPs were examined in two independent African-American cohorts (nmax = 1,116) from the Insulin Resistance Atherosclerosis Family Study (IRASFS) and the African American-Diabetes Heart Study (AA-DHS). Results Five polymorphisms were nominally associated with plasma adiponectin levels in the meta-analysis (P = 0.035-1.02 × 10−6) including a low frequency arginine to cysteine mutation (R55C) which reduced plasma adiponectin levels to

Objective Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM. Design and Methods Single-nucleotide polymorphisms (SNPs) in ADIPOQ (n = 45), SNPs tagging ADIPOR1 (n = 6), APIPOR2 (n = 8), APPL1 (n = 6) and known rare coding variants in KNG1 (n = 3) and LYZL1 (n = 3) were genotyped in 1220 European Americans from the family-based Diabetes Heart Study. Associations between SNPs and phenotypes of interest were assessed using a variance components analysis with adjustment for age, sex, T2DM-affected status, and body mass index. Results There was minimal evidence of association between SNPs in the adiponectin signaling pathway genes and measures of calcified plaque; eight of the 71 SNPs showed evidence of association with subclinical CVD (P = 0.007-0.046) but not with other phenotypes examined. Nine additional SNPs were associated with at least one of the plasma lipid measures (P = 0.008-0.05). Conclusion Findings from this study do not support a significant role for variants in the adiponectin signaling pathway genes in contributing to risk for vascular calcification in T2DM. However, further understanding the interplay between adiposity, plasma lipids, and inflammation may prove important in the prediction and management of cardiovascular complications in T2DM.

Common genetic variation frequently accounts for only a modest amount of inter-individual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically-mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n=1151) and African American (n=574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency ( 5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (p=1.16×10−47) and 47% (p=5.82×10−20), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV=18% (p= 6.40×10−15) and POV=5% (p=0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV=6% (p=5.44×10−12) and POV=9% (P=1.44×10−10), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.

Six patients with progressive supranuclear palsy (PSP) and 12 age-matched disease-free subjects participated in this study designed to compare rates of ATP production by intact mitochondria from biopsied skeletal muscle. When pyruvate and malate were used as metabolic substrates, rates of ATP production were 0.184 +/- 0.025 mumol/min/U of citrate synthase (CS) activity (a mitochondrial marker) in control subjects and 0.131 +/- 0.051 mumol/min/U of CS in PSP patients. In the presence of succinate, rates of ATP formation were 0.137 +/- 0.02 mumol/min/U of CS in controls and 0.109 +/- 0.04 mumol/min/U of CS in patients. With N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and ascorbate, rates were 0.034 +/- 0.008 mumol/min/U of CS in controls and 0.022 +/- 0.01 mumol/min/U of CS in PSP subjects. Differences between the control and PSP populations reached statistical significance with pyruvate/malate and TMPD/ascorbate. No differences in either muscle histopathology or histochemistry were found between patient and control subjects. Results of this study suggest that oxidative phosphorylation defects occur in muscle mitochondria from patients with PSP.

An alteration within the mitochondrial DNA (mtDNA) has been hypothesized to underlie the deficiencies in mitochondrial complex I activity observed in the platelets, striatal muscle, and brain tissue of individuals with Parkinson's disease. Here we utilized the polymerase chain reaction (PCR) to analyze mtDNA obtained from the platelets of nonmedicated patients with early Parkinson's disease (n = 8) and aged-matched controls (n = 6) for the presence of deletion(s) or addition(s) equal to or greater than 50-100 base pairs. Initial attention was focused upon detecting a 4.977 kb deletion previously found in the brains of parkinsonian patients and some aged controls. Indeed, a large deletion of approximately 5.0 kb was observed in the platelet mtDNA from all parkinsonian individuals. However, this defect was also found in all age-matched controls as well as in a group of young healthy subjects (n = 5). In addition, we searched for the presence of smaller changes in platelet mtDNA from parkinsonian patients by PCR analysis of four mtDNA segments that code for seven of the complex I polypeptides. No large deletions or additions were detected within these four regions of mtDNA in any of the disease or age-matched control samples. We conclude that (a) a 4.977 kb deletion is apparently present in a subpopulation of platelet mtDNA from all individuals, and (b) no macrosequence alteration in mtDNA is likely to underlie the deficiency in complex I activity reported in platelet mitochondria from parkinsonian patients.

Several links exist between the two mechanisms of neuronal degeneration (i.e., oxygen radical production and mitochondrial damage) proposed to have a role in Parkinson's disease. Indeed, mitochondria are critical targets for the toxic injury induced by oxygen radicals, and experimental evidence suggests that mitochondrial damage may cause an increased generation of oxygen radicals. A potentially important link between these two mechanisms of neurodegeneration is glutathione. Because of the scavenging activity of glutathione against accumulation of oxygen radicals, its decrease in the brains of parkinsonian patients has been interpreted as a sign of oxidative stress; however, this change may also result from or lead to mitochondrial damage. It is conceivable therefore that regardless of whether oxidative stress or mitochondrial damage represents the initial insult, these toxic mechanisms may both contribute to neuronal degeneration via changes in glutathione levels.