SNPs linked to HLA-DR types in Europeans/Caucasians [Archive]

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Maciamo

24-01-16, 13:52

The HLA gene (https://en.wikipedia.org/wiki/Human_leukocyte_antigen) regulates our acquired immune system (https://en.wikipedia.org/wiki/Adaptive_immune_system). It is what helps our body identify foreign antigens (bacteria, fungi, viruses) and determine what type of white blood cells and antibodies should be produced. Depending on our HLA type we are more or less resistant to certain diseases and infections. HLA also influences our risk of developing autoimmune diseases like diabetes, multiple sclerosis, rheumatism, arthritis, hypothyroidism, psoriasis, Celiac disease, Crohn's disease, fibromyalgia, and so on.

Class I HLA (A, B and C) deal with intracellular immunity, i.e. mostly viruses and some bacteria (e.g. Chlamydia, Rickettsia, Mycobacteria, Mycoplasma). Class II HLA (DM, DO, DP, DQ, DR) fight off extracellular pathogens - mostly bacteria and fungi. HLA DM to DQ have little diversity, so the main determinant of extracellular immunity between individuals is above all HLA-DR. HLA-DR is subdivided in HLA-DRA (3 variants) and HLA-DRB (439 variants), but all useful variations are found within HLA-DRB, which has 23 types usually in European/Caucasian people. The short-hand HLA-DR always refers to HLA-DRB.

You can compare the distribution of HLA-DR alleles by country (http://www.eupedia.com/genetics/HLA-DR_allele_frequencies_by_country.shtml) to get a better idea of where each type is more common. To better visualize regional variations, I have started making maps for each HLA-DR type. Here are those that I have already made: HLA-DR1 (http://www.eupedia.com/forum/threads/31178-HLA-DR1-distribution-map-subtypes-SNPs-and-associated-medical-conditions), HLA-DR3 (http://www.eupedia.com/forum/threads/31882-HLA-DR3-distribution-map-subtypes-SNPs-and-associated-medical-conditions), HLA-DR4 (http://www.eupedia.com/forum/threads/31146-HLA-DR4-distribution-map-subtypes-frequencies-and-associated-medical-conditions), HLA-DR7 (http://www.eupedia.com/forum/threads/31899-HLA-DR7-distribution-map-subtypes-SNPs-and-associated-medical-conditions), HLA-DR11 (http://www.eupedia.com/forum/threads/31145-HLA-DR11-distribution-map-subtypes-frequencies-and-associated-medical-conditions), HLA-DR15 (http://www.eupedia.com/forum/threads/31884-HLA-DR15-distribution-map-subtypes-SNPs-and-associated-medical-conditions), HLA-DR16 (http://www.eupedia.com/forum/threads/31877-HLA-DR16-distribution-map-subtypes-SNPs-and-associated-medical-conditions).

You can know your HLA types through a blood test, i.e. serotype (ask your doctor), or checking the raw from your DNA, i.e. genotype, if you tested with 23andMe, and in some cases also with Geno 2.0 or FamilyFinder. Some alleles are not tested by any of the three companies though. I have found a list of SNPs for all common European types, but unfortunately I do not know which allele is positive for some SNPs. If some of you have more information, make sure to share it.

There are subtypes for each HLA-DR type, although most of them have only one common subtype in Europe. HLA-DRB*0101 means essentially the same as HLA-DR1. To be more accurate it is subtype 1 of HLA-DR1, but it is the only subtype found in Europe. The highest diversity of subtypes in found within HLA-DR4, although non-Mediterranean Europeans usually belong to HLA-DRB*0401. The positive allele is indicated in brackets/parentheses. You will need to be positive for all SNPs listed in the same row to belong to one HLA-DR type. Each person normally belongs to two HLA-DR types (although it is possible to have twice the same). The most common subtypes are indicated in bold.

I have tried to geographically match the colours of HLA types to the colours I used for Y-DNA haplogroups. For example, HLA-DR9 is most common in North Asia and among Finno-Ugric people, so I used purple like for Y-haplogroup N1c. HLA-DR11 peaks in West Asia, Greece and Italy, so I used green like for Y-haplogroup J2. I couldn't always find a correlation with Y-DNA, so I sometime used colours used for mtDNA or autosomal maps, as in HLA-DR15 which is orange like the ANE admixture.

HLA-DR Type

SNP 1
SNP 2
SNP 3

HLA-DRB*0101

rs4947332 (T)
rs6457614 (G)

HLA-DRB*0301

rs2040410 (http://www.snpedia.com/index.php/Rs2040410) (A)

HLA-DRB*0401
rs6910071 (http://www.snpedia.com/index.php/Rs6910071) (G)
rs3817964 (http://www.snpedia.com/index.php/Rs3817964) (A)
rs660895 (http://www.snpedia.com/index.php/Rs660895) (G)

HLA-DRB*0402

rs3130071 (T)
rs416352 (T)

HLA-DRB*0403
rs7454108 (http://www.snpedia.com/index.php/Rs7454108) (C)
rs206765
rs399604

HLA-DRB*0404

rs2736157 (G)
rs3115572 (C)
rs2395533

HLA-DRB*0405

rs1057149 (A)

HLA-DRB*0407
rs7774197 (C)
rs417812

HLA-DRB*0701
rs7745002
rs2647087
rs241398

HLA-DRB*0801
rs7743506

HLA-DRB*0901

rs2395185 (T)
rs2516049 (C)

HLA-DRB*1001
rs4148871 (A)
rs2071538 (A)

HLA-DRB*1101
rs434841 (A)
rs1061172
rs5875439 (I)

HLA-DRB*1103
rs4639334 (http://www.snpedia.com/index.php/Rs4639334) (A)
rs412735
rs210180 (A)

HLA-DRB*1104

rs4713607 (G)
rs12664430 (T)

HLA-DRB*1201
rs6901541 (C)
rs6916742

HLA-DRB*1301
rs2395173 (A)
rs2157051 (C)

HLA-DRB*1302
rs4434496 (T)
rs6901541 (C)

HLA-DRB*1303

rs424232 (http://www.snpedia.com/index.php/Rs424232) (T)
rs2050191 (A)

HLA-DRB*1401
rs2763979 (http://www.snpedia.com/index.php/Rs2763979) (T)
rs1794265 (http://snpedia.com/index.php/Rs1794265) (C)

HLA-DRB*1404
rs805262 (T)
rs1794265 (http://snpedia.com/index.php/Rs1794265) (C)

HLA-DRB*1501
rs3135388 (http://www.snpedia.com/index.php/Rs3135388) (T)

HLA-DRB*1601
rs3129891 (A)
rs6923504 (G)

Note that HLA-DR2 doesn't exist anymore. It was split into DR15 and DR16. Likewise HLA-DR5 was split in HLA-DR11 and HLA-DR12, while HLA-DR6 was divided in HLA-DR13 and HLA-DR14.

Depending on reading directions your DNA test, the letters of the alleles might different. Just remember that C=G and A=T.

Angela

24-01-16, 19:04

Maciamo

24-01-16, 20:40

Very interesting, Maciamo. In making my way through the data, I did notice that there seems to be a discrepancy between the 8.7% DR 11 figure for Turkey in the chart and the map showing frequencies in Turkey over 25%.
http://www.eupedia.com/forum/threads/31145-HLA-DR11-distribution-map-subtypes-frequencies-and-associated-medical-conditions

Oops, sorry about that. I checked again the data and 8.7% was only for HLA-DR11:01. The total for DR11 in Turkey is 21% (but 26% in Kurdistan), with a peak of 35% in East Thrace (which also happens to be the region with the highest frequency of J2).

Also interesting that Northern Italy with only 10% J2 still shows the correlation with DR11.
http://www.eupedia.com/europe/european_y-dna_haplogroups.shtml

Perhaps the correlation matches more the West Asian admixture than J2 itself. It makes sense since HLA is an autosomal gene and would spread through both male and female lines, while Y-DNA get skewed according to historical events that impacted male lineages (wars, conquests, royal/noble lineages).

Then it's important to look at the subtypes too. For examples the Kurds and Azeri's DR11 subtype is almost exclusively DR11:03 (20.5% and 18.5% respectively), but DR11:03 is otherwise extremely rare elsewhere. It is only found with a frequency above 2% among the Uyghurs (4%) and in Saudi Arabia (3%), central/northern Italy (2.5%), and Crete (2.5%).

DR11:01 is mostly found mostly in Iran (ethnic Persians especially), Ukraine, Belarus and northern-central Italy. The wide Eurasian distribution, the peak around Ukraine and the fact that DR11:01 was found among Yamna and Corded Ware people strongly hint at an Indo-European dispersal. Proto-Indo-Europeans may have inherited this HLA via their Caucasian admixture, as Georgia is also a hotspot. The higher frequencies in Ukraine, Belarus, Iran and North India suggest that a positive selection for this HLA took place in the Indo-Iranian population (with back migrations to eastern Europe with the Sarmatians and Scythians). In Italy, DR11:01 correlates with R1b-U152. I have made a new map for this subclade to make the explanation clearer.

http://www.eupedia.com/images/content/HLA-DR11_01.png

DR11:04 is the variety found throughout the ancient Greek world and the Levant suggest a link with J2a-dominant Greek and Phoenician civilizations.

http://www.eupedia.com/images/content/HLA-DR11_04.png

Southern Italy, Greece and Turkey have both varieties, about 1/3 Bronze Age DR11:01 and 2/3 Neolithic DR11:04.

I also wonder how the studies which link autoimmune disorders to Neanderthal introgression fit in.

I posted the studies about HLA types inherited from Neanderthals and Denisovans here (http://www.eupedia.com/forum/threads/26737-Do-you-know-your-HLA-types), but the studies only mention HLA A, B and C, not DR. I couldn't find any information about Neanderthalian HLA-DR. However I checked the Denisovan genome and it was homozygous for DRB1*11:03. Both Denisova and one Altaian Neanderthal were also positive for the rs2516049 defining DR09:01 (once again homozygous in Denisova).

Angela

24-01-16, 22:36

Thanks again, Maciamo. I was partly just being my normal slightly OCD self. :) Mostly, though, it's just that I have a particular interest in this topic because some auto-immune disorders make a more than average appearance on both my paternal and maternal line.

For what it's worth, my mtDna, as I mentioned in another thread, is U2e, which I don't think is a "Neolithic" clade in Europe. I can't find the study now, but I remember one stating there was a cluster of U2e in southern France, so I'm not surprised there's quite a bit of it in nearby Liguria. Perhaps it, as well as this particular type of HLA marker, came to Liguria with the Celts in the first millennium BC.

Is it known which of these variations is correlated with auto-immune arthritis/lupus versus something like Type One diabetes, for example? We have the first among women of my family, but none of the second. We also have one case of MS, but it might have been inherited from the non-Italian ancestry (which is Irish). From what I've been told Ireland has high rates of MS.

Going back to the frequencies for RA in Europe, any idea why there's such a spike in the Netherlands? Do you know if there's that kind of spike for other auto-immune disorders?

Maciamo

25-01-16, 11:56

For what it's worth, my mtDna, as I mentioned in another thread, is U2e, which I don't think is a "Neolithic" clade in Europe. I can't find the study now, but I remember one stating there was a cluster of U2e in southern France, so I'm not surprised there's quite a bit of it in nearby Liguria. Perhaps it, as well as this particular type of HLA marker, came to Liguria with the Celts in the first millennium BC.

U2e seems to have originated in Russia (Kostenki was U2e 35,000 years ago). It is most common in the North Caucasus and the Volga region, and conspicuously absent in regions last/never settled by the Indo-Europeans (Sardinia, South Italy, Basque country, northern Scandinavia, Southwest Asia, North Africa). So it surely came with the Indo-Europeans, and in northern Italy that could have been the Italics or the Celts, or even maybe later Germanic tribes.

Is it known which of these variations is correlated with auto-immune arthritis/lupus versus something like Type One diabetes, for example? We have the first among women of my family, but none of the second. We also have one case of MS, but it might have been inherited from the non-Italian ancestry (which is Irish). From what I've been told Ireland has high rates of MS.

Yes, if you check the page for DR11 (http://www.eupedia.com/forum/threads/31145-HLA-DR11-distribution-map-subtypes-frequencies-and-associated-medical-conditions), I mentioned the associated autoimmune diseases. But don't forget that you have two HLA-DR types + two HLA-A, two HLA-B and two HLA-C, and all of them play a role in autoimmunity. For example, RA is most closely associated with the northern European HLA-DRB1*04:01 (http://www.eupedia.com/forum/threads/31146-HLA-DR4-distribution-map-subtypes-frequencies-and-associated-medical-conditions), while MS is linked to HLA-DRB1*15:01 (http://www.eupedia.com/forum/threads/31884-HLA-DR15-distribution-map-subtypes-SNPs-and-associated-medical-conditions).

Type 1 diabetes is a bit more complex. The risk factor is a combinations of HLA-DR and HLA-DQ. There are two risk haplotypes:

1) DRB1*03:01-DQA1*05:01-DQB1*02
2) DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*02

People at highest risk of developing type 1 diabetes have one copy of each haplotype.

Going back to the frequencies for RA in Europe, any idea why there's such a spike in the Netherlands? Do you know if there's that kind of spike for other auto-immune disorders?

It's difficult to compare medical statistics across studies as they use different methodologies and sometimes have huge discrepancies in sample sizes (say 50 against 50,000). So it could be that the data for the Netherlands is not relevant (too focused on a specific subpopulation, or too small sample size) as it seems completely out of line with the other figures for northern Europe. But otherwise it is to be expected that RA should be higher in northern Europe as HLA-DRB1*04:01 is higher there.

Maciamo

25-01-16, 14:12

NB: I have added maps and updated the descriptions above fro DR11:01 and DR11:04.

Sile

26-01-16, 10:32

Maciamo

26-01-16, 19:51

I have tried to geographically match the colours of HLA types to the colours I used for Y-DNA haplogroups. ..........confuses me..........which is the T ( ydna )

does this brown text represent T ydna as per your post #1?

I tested

HLA-DRB*1303
rs424232 (http://www.snpedia.com/index.php/Rs424232) (T)

all 3 of us have CC
rs2050191 (A)

rs2050191 (https://www.23andme.com/you/explorer/snp/?snp_name=rs2050191)
A or T
TT
Andrew

AT
Lucien

TT
victor

I tried to match the colours by geographic distribution. However there is no relation whatsoever between the HLA gene (chromosome 6) and Y-DNA or mtDNA. The relation is purely historical. DR13 is grey-brown as it appears to have been spread by Neolithic farmers (Y-DNA G2a, T1a and in Europe also E1b1b). It's not because your belong to Y-haplogroup T that you will be DR13 ! It would be a coincidence. Anyway your results show that you aren't. Keep in mind that contrarily to Y-DNA or mtDNA, everybody has two HLA-DR types. Even if you are of Italian descent, you could have an HLA-DR type that is typical of Siberia (although it's less likely obviously).