In the previous part of this mini-series, I had a closer look at the boundaries for the 9p21.3 risk interval for coronary heart disease (CHD) . Today, I will do the same for the type 2 diabetes (T2D) risk associated with the same chromosome region.
The first paper (out of three) describes joint work from the Broad Institute, Lund University and the Novartis Institutes. Similar to the CHD papers discussed yesterday, the authors start with a genome-wide SNP-bases association study , using 386,731 different SNPs and case- and control-groups of almost 1500 subjects each. This looks like a lot of work. After the usual filtering and confirmation experiments, the authors describe novel associations to three different loci: one SNP in the 9p21.3 region near CDKN2A/2B, one in an intron of IGF2BP2, and one in an intron of CDKAL1. IGF2BP2 is not (as stated in the paper) an “insulin-like growth factor 2 binding protein” but rather an “insulin-like growth factor 2 mRNA binding protein”. Can you spot the subtle but important difference? CDKAL1 is a homolog of a published CDK5 inhibitor. I have encountered this protein before, and it clearly deserves a separate posting. In addition to these three novel associations, the authors also confirm previously noted associations to HHEX and SLC30A8.
But let us get back to the 9p21.3 region in question. The association found in this paper relates to the SNP rs10811661. In the current NCBI.36 assembly, this SNP lies at position 22,124,094 which is just outside of the narrow 58 kb region associated with CHD (positions 22,062,301 to 22,120,389). Obviously, the T2D SNP is contained within the more relaxed 190 kb region of the second CHD paper. Unfortunately, none of the CHD papers report on allele frequencies of rs10811661.
The second T2D paper comes from a consortium lead by researchers from the University of Michigan and involves several groups from Finland and the US. Similar to the previous paper, the authors find associations with the CDKN2A/2B region and with the SNPs in the introns of IGF2BP2 and CDKAL1. They confirm the association with HHEX and SLC30A8, and also with other previously reported risk alleles near TCF7L2, PPARG, FTO and KCNJ11. Of the latter ones, PPARG is of particular importance, as it is the target of rosiglitazone. This antidiabetic drug, which is marketed by GSK as Avandia, is currently in trouble (due to heart-related side effects !!), and has been the topic of several blog discussions, e.g. on Dr R.W. , In the pipeline, or dlife. Finally, the authors report on a novel T2D-associated SNP rs9300039 in an intergenic region on chromosome 11p12, miles away (>1Mb) from the next known gene. The association relevant for this post (in the soul region) relates to SNP rs10811661, which is the same one mentioned in the previous paper.
The third T2D paper is from a UK-based consortium with participants from Oxford, Exeter, Bristol, Newcastle and London. The results are again similar to the two previous papers. New associations were found in the soul region on 9p21 and within the IGF2BP2 and CDKAL1 genes. The known associations with HHEX and SLC30A8 are confirmed. As usual, the 9p21 association is to SNP rs10811661, but a second SNP in this region is also discussed: rs564398 is about 100kb telomeric of rs10811661 and thus very close to the CDKN2A/2B genes. The significance of rs564398 is not as good as rs10811661 and it is not replicated in all studies tested. The SNP is reported to show only small linkage disequilibrium with rs10811661, which might mean that the two SNPs represent truly different variants. Interestingly, rs564398 also showed some association with coronary heart disease in one of the two studies: In the McPherson paper, rs564398 was the only SNP shown to have significant association outside of the 58kb critical region. When reading that paper, I wondered why the authors had included this SNP in the figures without ever mentioning it in the text – this might be the reason why.
This is all for today. The next post in this series will compare the critical regions for CHD and T2D. I will speculate on a potential connection between the two risk phenotypes and will have a look at the CDKN2A/2B genes, which appear to be prime candidates for regulation targets.
I should also mention that I have created a thread for this mini-series on my ‘projects page’ .