Need help deciphering genetic risk

[jumpinjiminy]

I should just stay away from these in depth articles. They're probably going to get me in trouble someday. There is this study on developing an algorithm for genetic risk in MS based on 16 alleles from larger studies that are highly correlated with MS.

Someone I know, but won't mention any names, had their genome mapped and just for giggles found this interesting way of adding up the risk, which came out to 3.75 total for whatever risk alleles were there. It seemed pretty straightforward at first until getting farther down in the study where this person's eyes began to cross due to the long-forgotten statistical terminology involved.

If anyone is good with statistics, it would be interesting to know if this weighted genetic risk of 3.75 could indicate being part of the high risk category? I think that's what it means, but I'm not confident in interpreting it that way and would like other opinions if anyone is willing.

The link addy: http://www.ncbi.nlm.nih.gov/pmc/arti...9/?tool=pubmed

[onlyairfare]

I'm way too tired to read a scientific article this late at night and attempt to translate into English, though I will try later on to do that.

I recall that a North Carolina major university had a major research center focusing on genetics of MS. I think it was Duke University. If I were worried about "the real genetic risk," I'd ask about consulting a doctor there.

Don't forget that lots of studies are done, some are valid and get published in respected journals, but then after that, other medical studies have to be able to more testing with similar results in order to validate the findings.

Don't rush to any conclusions...yet

[jumpinjiminy]

Thanks, airfare. Any help I can get with this is appreciated. I'm not sure whether to bring it up with the neuro next week or not. There was another study I found that the additive odds risk came out to be something like 16, where they used 7 different SNPs from the study linked above.

Then there are the environmental risk factors, tobacco use, EBV titres, and vitamin D levels that all have relative odds ratios to add in.

It looks like there is one copy of a protective allele, and this one appears to play a role with the smoking. But the study didn't specify whether being heterozygous or homozygous modified the risk in any way. If a person lacks the protective alleles along with carrying the HLB DRB1*15 susceptibility gene, the odds ratio was 13 if they smoked vs. 4.9 in non-smokers.

That's a pretty significant jump in risk. In either case, it's pretty fascinating reading. I can see why it's an exciting time to be an MS researcher, or any medical researcher for that matter. The more datasets that get developed, the more powerful these studies will get.

[Tawanda]

I have M.S. My mother had M.S. I have 3 first cousins on my mother's side with guess what condition? M.S.! I don't need any fancy studies to tell me anything I don't already know. At least it takes personal responsibility off of me!

Now all I can do is pray that my daughter does not one day develop this MonSter. I freak out whenever her foot falls asleep (which seems like a lot!). She also has a mysterious re-appearing foot fungus I worry about, and women are more likely to "inherit" M.S. then men. I didn't know I had the disease when I had her, but once I was diagnosed, I knew that we had no choice but to be a "one, and done!" type of family. My genes are lethal.

Incidentally, we are considered a "cluster" family and are part of an ongoing genetic study at UCSF.

Good luck getting your answers.

[jumpinjiminy]

Thanks, Tawanda. And thank you for participating in the genetic studies. I so hope your daughter doesn't develop it either. They seem to think that keeping the vitamin D level up there in the early years might prevent developing it. Who knows, but it's worth trying for.

My grandfather had MS, a very similar pattern to what my whatchamacallit is displaying. I think my dad has a little something going on as well, but very mild. I've noticed his tremors come and go. His toes are numb, but they don't know why, and he lost the use of one arm for a couple of months and now it's fine. That's it for him, but it makes me suspicious. Maybe he inherited more protective genes, or fewer susceptibility genes? It's a very curious thing.

The more I'm reading about these genetic factors involved, the more it makes me think there are as many combinations of genes and environmental interactions as there are different expressions of it. So far, the studies are not connecting the dots between genetic combinations and MRI patterns or severity. They have found some correlation for age of onset, and that's about it.

[jumpinjiminy]

There's another group from the UK that wrote a scathing report as to why doing all of these genome wide association studies is likely to be unfruitful in terms of diagnosis, yet they mention 9 non-MHC loci that have widespread acceptance as risk alleles. At every loci, you have two alleles. A person could have 18 risk alleles for these 9 loci. I have 12.

I've compared the risk of this with the risk of other autoimmune diseases based available information from these genome wide association studies. In comparison, these other conditions aren't even in the race.

I'm shocked, really, that I have so many of these genetic red flags for MS. As mild as this whatchamacallit has been over the years, I would have expected just a few.

[meeegun]

how would one go about getting tested for these genes? i am extremely interested in knowing if i have any of these alleles, partly because i would like to have as much information as i can about my genetics and what i could potentially pass on if i were to have children, and also because i am incredibly nerdy and find stuff like this extremely interesting. would i have to be a part of some kind of research study in order to get the testing?

[salamandertom]

As far as there being differences in hetero vs homozygous I know a LOT about that. More than I will bore anyone with. But, there is a significant difference in being homozygous vs heterozygous. I assume that the risk factors are listed for homozygous recessive and that the protective allele is dominant. I did not read the article, but you can be either homozygous recessive or homozygous dominant. (or of course heterozygous)

If I am correct in my assumptions I would say that heterozygous individuals *should* have the same protection as the homozygous recessive people. This is a widely disputed thing though - look up symptomatic carriers and you will find an eyefull.

Multiple sclerosis is a very complex disease. They are JUST starting to gather information on the genetics. I wouldn't really put much stock into any information there is currently about alleles and risks. This disease is far too complex, and this information is quite new. I would think in about 10 years they will have a very good handle on it.

I hope that helped.

[maitrimama]

meeegun - Most of my family had their DNA analyzed last year for fun. My sister has done extensive genealogical work and was interested to see what would show up and if it would support her work which has gone all the way back to Charlemange (on the illegitimate side We did find out some interesting info that some of us have higher probabilities of diseases we have and have not seen in our family.

The company we used is called 23andMe and was all done by mail and results come online and are updated often with new information. It is probably worth a look to see if the can provide what you are looking for.

Good luck!

[jumpinjiminy]

Meegun, mine was done through the 23andme service. There are other services that can be ordered through your doc to test for certain specific traits - like drug metabolism. I'm thinking of bringing this up with my GP since this test showed a couple of slow pathways.

Maitrimamma, my mother is also very interested in geneology and our lineage traces back to Charlemaine, too. When you get there, someone has kept records back to 6AD. It's a fascinating travel through time. If you follow the record alongside a window with European history, you get to see how people migrated into different areas during specific historical events where they intermingled.

Salamandertom, thank you for the input. The GWAS study above just mentions the 'risk allele,' the one that was present across thousands of samples comparing those with the disease to the controls without. Many of them have been repeated across other studies. They assume the risk alleles to have an additive quality in combination with each other.

I'm not sure about the dominant or recessive inheritance factor involved. Some of the studies mention the minor allele (least frequently seen) and major allele (most commonly seen), and the odds risk of carrying the minor allele as well has how frequently it was seen in the study populations.

You're right. They have a long way to go with this, and this is why I was asking about the relative significance of it all.

[maitrimama]

jumpinjiminy - my family got a kick out of some of the info. Being as my dad's side is predominately Irish it probably comes as no surprise that there has been alcoholism sprinkled through out the generations. I am a recovering/sober alcoholic who hasn't drank in many years. Out of the three of us I was the wild child and my brother & sister have never had any problems with alcohol but I am the one that has the least chance of becoming an alcoholic. I took away from that that in most cases genetics is not and exact science.

[Tawanda]

Genetic testing = Scary business!

how would one go about getting tested for these genes? i am extremely interested in knowing if i have any of these alleles, partly because i would like to have as much information as i can about my genetics and what i could potentially pass on if i were to have children, and also because i am incredibly nerdy and find stuff like this extremely interesting. would i have to be a part of some kind of research study in order to get the testing?

As for myself, I might be a bit curious, but how scary would it be to have our children tested? If something as bad as M.S. is coming down the turnpike for my daughter, I don't think any of us really want to know (unless there was some preventive measure we could do now, which there isn't - maybe put her in a plastic bubble??) Personally, I'm glad that I didn't know what the future held for me when I was in my 20s or 30s. I would have freaked out about everything and life-quality would definately be diminished. I would just hope that my daughter marries someone who really takes the "in sickness and in health" part of the wedding vows VERY seriously...just in case, and is smart with her career and financial planning (something that I was not). This is good advice for any young person starting out (oh yeah, and have one charge card for emergencies only!)!

I also wonder if you could have every red flag going on as far as your genetic disposition and STILL go your whole life without developing M.S., but have children who take on the risk and develop M.S. This is why I'm not only worried about my DD, but my nieces and nephews as well. Again, this is out of my hands and worrying never does any good.

[jumpinjiminy]

jumpinjiminy - my family got a kick out of some of the info. Being as my dad's side is predominately Irish it probably comes as no surprise that there has been alcoholism sprinkled through out the generations. I am a recovering/sober alcoholic who hasn't drank in many years. Out of the three of us I was the wild child and my brother & sister have never had any problems with alcohol but I am the one that has the least chance of becoming an alcoholic. I took away from that that in most cases genetics is not and exact science.

It's not an exact science yet. I think it has the potential to be once they have everything figured out. It might take a century or two, given the amount of data being generated. LOL

The funny thing is, the report you get from the company doesn't give that much information. It's when you start digging through the research on pubmed and comparing your SNPs to those collected in various GWASs that things get really interesting.

To make things even more fun, there's a handy little add-on for Firefox that you can link to your downloaded DNA profile on your computer. It can be enabled or disabled while searching the web. If it's toggled on, whenever you're reading something that displays a SNP number (rsXXXXX), you can hover the cursor over the SNP and it will display which base pairs you have for it (A,T, C, G). It makes digging for info so much faster and easier.

The mitochondrial DNA feature is interesting. It traced my maternal lineage from the far east that migrated to the Turkish and middle eastern region, and then into Europe most recently.

Tawanda, I don't know that I would have wanted to know in my 20s or 30s either. Although, I do remember my quality of life was pretty diminished even then. I remember myself as a fireball of big ideas and dreams with a body that wouldn't cooperate. Everybody thought I was lazy. It was frustrating.

I definitely don't want to know for my kids. It's hard to prepare them for what lies ahead as it is. But on the other hand, if there are preventative actions you or they could take to mitigate the risks, would it be better to know it's there than not?