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Objective A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. Methods Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium ( n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium ( n = 85,274). Results In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing ( P −4 ). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD ( P = 5.4 × 10 −7 ). Conclusion These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.

Functional single nucleotide polymorphisms within the ectoplasmic domain of the Toll-like receptor 4 (TLR4) gene have been shown to result in an endotoxin-hyporesponsive phenotype and aberrant signal transduction for bacterial agonists. TLR4 is in proximity to a genome-wide linkage peak in 9q32-33. Given the proposed function and location of TLR4, we examined the association of 2 functional variants of TLR4 in patients with ankylosing spondylitis (AS) in Newfoundland.In total, 101 AS patients and 100 ethnically matched controls were genotyped, using the Sequenom MassArray platform, for 2 functional variants in the TLR4 gene: Asp299Gly (A/G polymorphism) and Thr399Ile (C/T polymorphism).The minor allele frequency for the Asp299Gly variant (G) was significantly higher in AS cases compared to controls (7.5% vs 2.6%, respectively; OR 3.10, p = 0.037). The minor allele frequency for the Thr399Ile variant (T) for cases and controls was 7.4% vs 3.0% (OR 2.59, p = 0.071). Haplotype analysis using Haploview noted a higher proportion of GT in the cases (for GT, chi-squared p = 0.023).Given the functional role of TLR4 variants in the innate immune system, larger studies are now warranted to elucidate the association of TLR4 variants in AS.

To examine the association of single nucleotide polymorphisms (SNP) in the NFKB1 gene, as well as 2 genes in the nuclear factor (NF)-kappaB functional complex (RelA and NFKBIA), in patients with psoriatic arthritis (PsA) from Newfoundland.Patients with PsA and controls were genotyped for one 4-base insertion/deletion and 5 SNP in NFKB1, 4 SNP in RelA, and 7 SNP in NFKBIA by time-of-flight mass spectrometry, using the Sequenom platform. Chi-square analysis was used to test the single locus associations between SNP in the NF-kappaB complex and PsA. Associations between multi-locus haplotypes and case or control status were tested using the software PHASE.Two hundred and twenty-four patients with PsA (52% male) and 88 ethnically matched controls (64% male) were genotyped. No association was noted with any of the SNP tested for the single locus associations in NFKB1, RelA, and NFKBIA or with multi-locus haplotypes. In particular, the allele frequency for the NFKB1 -94delATTG was 41.7% in cases and 41.6% in the controls (p = 0.97).No association between the NFKB1 -94 ins/delATTG promoter polymorphism or with other NF-kappaB complex SNP in patients with PsA from Newfoundland was observed.

Non-invasive prediction of aluminum bone disease in hemo- and peritoneal dialysis patients. Between October 1987 and October of 1989, we conducted a prospective study to evaluate non-invasive test strategies for predicting aluminum bone disease (ABD) in a group of largely unselected dialysis patients based on their deferoxamine (DFO) test alone, or the combined results of their DFO test and intact 1-84 parathyroid hormone (PTH) levels. These test parameters were evaluated against the pathological diagnosis of ABD based on bone biopsy (“gold standard”). A total of 445 patients in three dialysis centers in Toronto were serially followed for their clinical, laboratory and risk parameters for renal osteodystrophy during the study, and 259 (142 PD and 117 HD) patients underwent a series of investigations which included the DFO test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Serum aluminum ([A]) level ≥ 3700nM (or 100 µg/liter) had a positive predictive value (PPV) of 75% for ABD in our PD and 88% in our HD patients, but its sensitivity was low (10 and 37%). Delta [Al] (that is, incremental rise of serum [Al] from baseline post-DFO) was useful in predicting ABD in our PD but not HD patients. Test combination based on delta [Al] ≥ 5550nM (or 150 µg/liter) and PTH level < 20 pM (or 200 pg/ml) yielded the best PPV ≥ 95% for ABD in both PD and HD patients. This test cut-off would remain highly predictive of ABD even if the prevalence of ABD decreases to as low as 5% for the PD patients and 10% for the HD patients. However, for patients who have discontinued their aluminum gels for ≥6 months these test strategies would not be useful due to a very high frequency of false-negative cases (or low sensitivity). Thus, the main utility of these non-invasive strategies will be in those patients who continue to require treatment of aluminum gels for their phosphate control.Non-invasive prediction of aluminum bone disease in hemo- and peritoneal dialysis patients. Between October 1987 and October of 1989, we conducted a prospective study to evaluate non-invasive test strategies for predicting aluminum bone disease (ABD) in a group of largely unselected dialysis patients based on their deferoxamine (DFO) test alone, or the combined results of their DFO test and intact 1-84 parathyroid hormone (PTH) levels. These test parameters were evaluated against the pathological diagnosis of ABD based on bone biopsy (“gold standard”). A total of 445 patients in three dialysis centers in Toronto were serially followed for their clinical, laboratory and risk parameters for renal osteodystrophy during the study, and 259 (142 PD and 117 HD) patients underwent a series of investigations which included the DFO test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Serum aluminum ([A]) level ≥ 3700nM (or 100 µg/liter) had a positive predictive value (PPV) of 75% for ABD in our PD and 88% in our HD patients, but its sensitivity was low (10 and 37%). Delta [Al] (that is, incremental rise of serum [Al] from baseline post-DFO) was useful in predicting ABD in our PD but not HD patients. Test combination based on delta [Al] ≥ 5550nM (or 150 µg/liter) and PTH level < 20 pM (or 200 pg/ml) yielded the best PPV ≥ 95% for ABD in both PD and HD patients. This test cut-off would remain highly predictive of ABD even if the prevalence of ABD decreases to as low as 5% for the PD patients and 10% for the HD patients. However, for patients who have discontinued their aluminum gels for ≥6 months these test strategies would not be useful due to a very high frequency of false-negative cases (or low sensitivity). Thus, the main utility of these non-invasive strategies will be in those patients who continue to require treatment of aluminum gels for their phosphate control.

In occupational cancer epidemiology, many studies are carried out without access to information on smoking and other potential confounding variables. It is unclear whether such deficiencies are likely to cause serious bias in estimates of cancer-occupation associations. An empiric investigation was carried out to determine the effect of inclusion or exclusion of three variables--smoking, ethnic group, and socioeconomic status--on estimates of odds ratios (OR) between 25 occupations and three types of cancer--lung, bladder, and stomach. Of the 75 associations studied, only one OR was distorted by more than 40% when comparing unadjusted with adjusted estimates; three were distorted by between 30% and 40%; four others by between 20% and 30%. Of the eight associations which were distorted by more than 20%, seven involved lung cancer and one involved bladder cancer; none involved stomach cancer. An additional analysis was carried out on the 25 lung cancer-occupation associations to determine whether the nature of the stratification on smoking (ie, whether crude or "precise" categories were used) gave different OR estimates. The differences in ORs induced by different parametrizations of the smoking variable were relatively small. Our results support the view that relative risks between lung cancer and occupation in excess of 1.4 are unlikely to be artifacts due to uncontrolled confounding. For bladder and stomach cancer, the corresponding cut point may be as low as 1.2. In studies of occupation and cancer, uncontrolled confounding due to smoking and social class may not be as serious a threat to the integrity of results as is sometimes feared.