SNPedia

Thursday, December 20, 2012

Do you see what I MHC?

Two independent SNPs discovered this year, rs2281389 and rs1800795, may indicate that the last decade of inconsistent genome-wide association studies hunting for ways to reduce blood cell transplant failures was not for naught.

Humans have a lot of genetic variation in the human leukocyte antigen (HLA) and this variation creates a somewhat unique signature on the surface of your cells. Your immune system relies on this signature to distinguish its own cells from foreign invaders, and then to target foreigners for attack. This is a great system when you’re trying to fight off a cold, but a problem when you’re trying to find a donor for an organ or tissue transplant. This is why donor registries screen for similar HLA signatures, to minimize the odds of a conflict. There are immune suppressing drugs that lower the odds of rejection, but these come with their own risks. When you’re in need of an organ or tissue donation, you need your immune system working well to help you, not for it to be suppressed.

Graft versus host disease (GVHD) is when the donated cells recognize the recipient as foreign and begin to attack. This affects up to 80% of patients and is a major cause of transplant failure, early complications and death. In the 2012 paper PMID 22837536 researchers looked for SNPs spanning the Major Histocompatibility Complex (MHC) region which didn’t match between 4,000 donor/recipient pairs who were perfectly matched across the 5 major HLA loci. The most significant SNP found, rs2281389, raised the risk and severity of acute GVHD by about 40%. Curiously, it’s the mismatch itself - not any of the possible genotypes - that increases GVHD risk.

Outside the MHC, an independent comprehensive study (PMID 22282500) of 1300 allogeneic hematopoietic cell transplantation (HCT) donors and recipients using previously reported GVHD-associated SNPs concluded that the best replicating - and almost only - variant was IL6 gene SNP rs1800795. This SNP was associated with a 20%-50% increased risk for GVHD, and here, there may be a biological explanation since the rs1800795(G) allele has been associated with increased serum levels of IL-6 and several autoimmune and inflammatory diseases.

Upcoming clinical trials will determine if using these SNPs for improved genetic matching of donors and recipients will lower the incidence of GVHD. And when full genome sequence becomes a routine part of one’s medical record, these type of studies, along with the predictive HLA-typing, will greatly increase the number of potential donors while minimizing rejection risks. As with many Christmas gifts, the new ones will complement and co-exist with the old ones.

Wednesday, December 19, 2012

Christmas in the Heart

rs11591147 is a SNP that warms the heart. This PCSK9 gene SNP has been known since 2005 to be associated with reduced average low density lipoprotein cholesterol (LDL-C), but this year it became the poster child of a set of 9 SNPs used to tackle a key question: to reduce heart disease risk, just how early in life should we start paying attention to LDL-C levels?

The meta-analysis of over 300,000 (!) patients published by Ference et al. [PMID:23083789] concludes that a person who’s lifetime average LDL exposure was reduced by about 40 mg/dl due to one or more of these 9 SNPs has their coronary heart disease risk cut in half. Their models suggest that the earlier you experience lower LDL levels, the better. If you weren’t born with enough of the LDL-lowering variants like rs11591147(T), the sooner you lower your LDL, the better, either by changing your lifestyle (through your diet) or by taking statins. Atherosclerosis isn’t just for old folks – it’s a progressive disease that begins in childhood.

This reminds us of rs4149056, a SNPedia Top 10 SNP pick of 2010. rs4149056(C) alleles and especially rs4149056(C;C) genotypes are associated with higher risk for side effects (muscle pain and degradation) when taking the statin simvastatin. This year, the Clinical Pharmacogenomics Implementation Consortium (CPIC) issued a clinical guideline with dosing recommendations for simvastatin when rs4149056 status is available [PMID: 22617227]. Pharmacogenomics continues to be one of the areas where genomics is directly improving patient health and well-being, and that too warms our hearts.

Tuesday, December 18, 2012

Hurðaskellir

rs63750847 is a rare SNP, but a very good one. According to the Nature paper PMID 22801501 published in August, this variant in the Amyloid Precursor Protein (APP) gene reduces the risk of Alzheimer’s five-fold. It’s present in less than 1% of Icelandic and Scandinavian populations, and even rarer in North Americans. So while most of us aren’t fortunate enough to carry the rare protective allele, seeing such a strong protective effect may suggest new avenues for medicines and treatments.

The finding was published by deCODE, which has made numerous scientific contributions to the field, especially this year. CEO Kari Stefansson has previously expressed frustration that 23andMe’s DTC testing service was given the 2008 Invention of the Year by TIME Magazine, despite deCODE’s extensive research contributions and earlier - by a day or two - DTC launch date.
Perhaps there is some karma here, as deCODE’s latest discovery has won them high praise and was a factor in their $415M acquisition by Amgen. Good research takes time - it took almost 20 years to make the subtle but fundamental shift from the scientific understanding that this SNP was not associated with excessive amyloid deposition [PMID 8170579] to deCODE’s recent conclusion that it actually protects against it. Amgen has stated that it won’t be offering deCODE’s DTC genomic testing, though, so even if 23andMe wasn’t the first DTC genomics testing company, they are the last of the pioneers to still be standing.

Monday, December 17, 2012

SNPedia’s Nightmare Before Christmas

rs17602729 is the "most prevalent genetic disease mutation" in Caucasians according to PMID 11331279 as it appears to cause muscle pain after exercise for some people. Despite this relatively minor medical impact, it represents SNPedia’s ‘Nightmare before Christmas’.

As our understanding of the genome improves, the scientific community occasionally updates the reference standards. In August 23andMe updated from human reference genome build 36 to build 37.3. If you downloaded your raw data in July, this snp was at position 115037580 but after August it was at 115236057. SNPedia made similar changes back in 2010, but in 2012 we discovered that this snp hadn’t just changed position, it had also changed it's orientation. With this newest assembly, dbSNP flipped the SNP to the opposite strand of DNA, changing the normal G and variant A into normal C and variant T.

Confused? You’re not alone. ClinVar is the new NIH database of variation which affects human health. If you download their raw data and search for rs176027291 you will see that it shows all 4 alleles, with the G as normal. This is probably an artifact of the orientation change, but its likely that someone out there does have each allele. And each one of these nucleotide changes causes a different change to the amino. Since the most common variant is a premature stop codon, the altered aminos are probably viable with subtly different effects. Getting this SNP - and others that are similar challenges - straightened out in 2012 would take a Christmas miracle.

Sunday, December 16, 2012

O come all ye faithful

rs10937823 is one of the nicest gifts given to SNPedia this year. The minor rs10937823(T) allele has been associated with bipolar disorder in at least four independent studies as of last count, albeit with some inconsistency between populations as to which allele is the risk allele.

So why is it a gift? Because of who gave it to us. SNPedia exists and expands thanks in large part to the contributions of a community of people who feel it’s important to make scientific and medical findings about the genome accessible to all. Researchers, professors, physicians, techies, homemakers, students and many more contribute. Some are better at adding papers and p-scores, while others improve the grammar and spelling or rewrite to make the ideas accessible to a wider audience. Everyone contributes a little, and we’re all better off for it.

Our information about rs10937823 was primarily contributed by a med student in Stanford University’s Gene210 class. In this groundbreaking course from Professor Stuart Kim, students analyze their own genomes as they prepare to become doctors and researchers in a post-genome world.

Here’s a big Thank You! to our community – those who believe that if the genome matters, then getting the information out in ways that can be readily used matters too. Everytime a SNPedia page is edited an angel gets its wings.

Saturday, December 15, 2012

(A;A) Christmas Platypus

rs55705857 is strongly associated with the most common form of primary brain cancer, glioma, but it also achieves a distinction of being one of the most strongly cancer-associated SNPs ever found in a SNP survey.

The study published in Nature Genetics this fall [PMID 22922872] by researchers at UCSF and the Mayo Clinic found that rs55705857(G) allele carriers are at 6 times higher risk for glioma formation than non-carriers, and in particular, for subtypes known to harbor IDH1 or IDH2 somatic mutations. It is comforting that while the mutation is common (between 2 - 8% of us harbor this allele), gliomas are rare (diagnosed in around 3 people per 100,000 every year) so most carriers will never develop such tumors. Unfortunately, for those that do, it’s often fatal, as it was for a good friend and colleague, Neil Ghiso.

The chromosomal region (8q24) this SNP is located in has previously yielded SNPs associated with ovarian and prostate cancer, but with much lower odds ratios. And while it’s clear the region is important in some regulatory manner, it’s not yet clear how. Perhaps another one of 2012’s top scientific stories – the first major release by the ENCODE project of data on functional elements in the genome – will help explain this.

And here’s where the platypus comes in. Even though it’s far from a coding region, sequencing shows that the common rs55705857(A) allele is invariant in all mammals, from humans through to, yes, the platypus. Here’s to the Christmas Platypus!

Friday, December 14, 2012

The 12 SNPs of Christmas 2012

It’s been another busy year for SNPedia. More and more folks not only use SNPedia, but along with added features in Promethease, there’s more for every person to learn about themselves. Our genomes become more interesting and informative every year – DNA is the ultimate gift from our parents that keeps on giving.

Like the Christmas carol, for each of the next 12 days we’ll be singing about a SNP that caught our attention in 2012. In some ways this is a Top 12 List, but it’s also a way for us to call attention and thank many of you in our community. So here we go!

On the first day of Christmas … we’ve got to think of Santa and his rs9939609 genotype. This SNP is in the FTO gene, and it has long been associated with obesity, and in some populations, with Type-2 Diabetes. But just last month the Meyre Lab (McMaster Univ.) reported the results of studying over 6,000 patients with depression in their Nature paper [PMID 23164817], and lo and behold, rs9939609 is also associated with resistance to depression. In fact, the minor A allele increases the likelihood of both being obese AND being jolly. Perhaps Santa carries the A allele?! We’ve been unable to get his DNA tested so far, but with the Ho Ho FTO theme in mind, will be leaving him a very special batch of cookies.