Watch how long you sit!

I recently blogged about the relationship between lack of sleep and disease. Now it looks like a group of investigators in Canada has found some evidence linking sitting time and various chronic diseases. The paper was published recently in the Medicine and Science in Sports and Exercise journal.

Katzmarzyk and his co-workers from the Pennington Biomedical Research Centre in Ontario noted that although moderate-to-vigorous physical activity is related to premature death, the relationship between sedentary behaviors and mortality has not been fully explored and may represent a different paradigm than that associated with lack of exercise. They prospectively examined sitting time and mortality in a representative sample of 17,013 Canadians 18-90 yr of age. Information such as the daily sitting time (almost none of the time, one fourth of the time, half of the time, three fourths of the time, almost all of the time), leisure time physical activity, smoking status, and alcohol consumption were captured at commencement of the study.

The volunteers were then followed prospectively for an average of 12.0 yr. Of the 17.013 volunteers, there were 1832 deaths (759 of cardiovascular disease (CVD) and 547 of cancer). After adjustment for potential confounders, there was a progressively higher risk of mortality across higher levels of sitting time from all causes and CVD but not cancer. Similar results were obtained when stratified by sex, age, smoking status, and body mass index.

Katzmarzyk and his co-workers concluded from their study that their data demonstrate a dose-response association between sitting time and mortality from all causes and CVD, independent of leisure time physical activity. In addition to the promotion of moderate-to-vigorous physical activity and a healthy weight, physicians should discourage sitting for extended periods.

Pharmacogenetics Blog

My colleague here in NUS, Professor Edmund Lee, has started a cool blog on pharmacogenetics.

Go on and have look!

More genomic markers identified for heart attack and coronary artery disease. Surprised?

Time really flies by so quickly!

I have just noted that my last posting was done more than two months ago! There have been several interesting developments in the field of cardiiology, such as the prasugrel episode and identification of new genetic markers. Given my research interest, my attention naturally turns toward the reports related to the genetic studies.

After the publication of a series of papers reporting the association of chromosome 9 with the risk of myocardial infarction (heart attack) and coronary artery disease (artery blockage) last year, the 8 Feb 2009 issue of Nature Genetics published not one, not two, not three, but FIVE papers describing the association of various regions of the genome with MI and CAD. These studies had all used the genome-wide approach (called genome-wide association studies or GWAS), meaning that the entire human genome (23 pairs of chromosomes) were screened instead of looking at certain specific regions only. Though significant, all the reported effects are small, as measured in terms of odds ratios in the range of 1.1 to 1.2.

In the first paper by lead author Dr Jeanette Erdmann (University of Lubeck, Germany) and her team, a new susceptibility locus for CAD on chromosome 3q22.3 was reported following a three-stage analysis of genomewide data in 1222 German individuals with MI and 1298 controls. It appears that when the initial genome-wide scans were done, only the low-hanging fruits, ie chromosomal regions that emitted very strong signals, were picked up. Now, these authors are paying attention to the signals that are of moderate significance, believing that some of them are certainly genuine. They concluded that with their large-scale replication that they have identified 3Q22.3 as a new susceptibility locus for CAD. In addition, they also found suggestive evidence for a second locus on 12q24.31.


In the second study, Dr David-Alexandre Tregouet (University Pierre and Marie Curie, Paris, France) and colleagues reported a new gene cluster—SLC22A3-LPAL2-LPA—as a strong susceptibility locus for CAD. Unlike most genome-wide studies, the novelty of this paper lies in the use of haplotypes – groups of SNPs that are inherited together, rather than analyzing individual differences in DNA sequence called single nucleotide polymorphisms (SNPs). One of the authors for three of the five papers, Dr Nilesh Samani, said in an interview with heartWire that "Tregouet has slowly walked across the chromosomes identifying these haplotypes to see whether the signal was better when looking at the haplotype rather than individual SNPs . . . and one region showed very strong evidence, which was apparent in the individual SNP analysis but wasn't strong enough to be definite. By analyzing it in this way [by haplotype], we found evidence that this locus is strongly associated with CAD. So the findings are twofold: first, we identified a new locus; and second, it shows we can extract more information out of GWAS by doing a slightly more sophisticated analysis."

The third study was conducted by the international Myocardial Infarction Genetics Consortium research and involved using GWAS to test SNPs and copy number variants (CNVs) for association with early-onset MI in 2967 cases and 3075 controls and replicated in an independent sample of 19 492. According to the corresponding author of the paper, Dr Sekar Kathiresan (Massachusetts General Hospital, Boston, MA), this study is the largest GWAS for MI conducted to date and the first to comprehensively test whether CNVs are associated with MI.

CNVs are large chunks of DNA that are either deleted or duplicated, and it has been hypothesized that they might be responsible for some of the inherited component of common diseases. They found no evidence in this new study, however, that any CNVs were associated with MI. However, they did find that SNPs at nine loci reached significance, three of which were new: 21q22, 6p24, and 2q33. The remaining six had previously been observed, including one at 9p21, which is recognized to be the strongest genetic predictor of early MI discovered to date. The nine variants in aggregate identify 20% of the population at 2.25-fold increased risk for MI.

Probably the most surprising of these is the report from Dr David F Gudbjartsson (deCODE Genetics, Reykjavik, Iceland) and his team. They found a link between a high-eosinophil-count gene and MI in 9392 Icelanders and, using the most significant SNPs identified, they studied them further in 12 118 Europeans and 5212 East Asians . Some of the SNPs were associated with asthma but one of them, which is a nonsynonymous SNP at 12q24, was significantly associated with MI in six different populations (6650 cases and 40 621 controls). This raises the question of whether a certain pathway might be common between asthma and MI. With CAD and MI increasingly shown to be of inflammatory nature in their disease origin, such a seemingly remote association might just turn out to be genuine upon further verification.

Japanese researchers Dr Kouichi Ozaki (Center for Genomic Medicine, RIKEN, Yokohama, Japan) and his team have previously reported an association of variants in LGALS2, encoding galectin-2, with MI susceptibility in the Japanese. In the fifth study, they now identify BRCA-1 associated protein (BRAP) as a galectin-2 binding protein and report an association of SNPs in BRAP with MI risk in a large Japanese cohort (OR 1.48, 2475 cases and 2778 controls), with replication in additional Japanese and Taiwanese cohorts [5].

I supposed Dr Eric Topol MD, from the Scripps School of Medicine best sums it up by saying that "there are several pathways that set up a genomic susceptibility to MI. Some are ancestry-specific (such as galectin2-BRAP) and some are unanticipated (eg, eosinophilia). While we see the common phenotype of MI, [it appears] there are many ways to get there at the molecular level."