HLA-DR4 : distribution map, subtypes frequencies and associated medical conditions

[Maciamo]

Here is a map showing the allele frequency of HLA-DR4. The maximum frequencies are observed among Murmansk Saami, Norwegians, Welsh, Southwest English, Belgians and Armenians.

Subtypes

DR4 has over 100 subtypes (subclades). Here is the distribution of the 10 most common.

DRB1*04:01: peaks in Siberia (max. 35%), followed by Scandinavia and Eastern Europe (± 15%), but also Jordan, Lebanon and Tunisia

DRB1*04:02: peaks in the Middle East and North Africa (4-15%)

DRB1*04:03: most common in Polynesia, Melanesia, Columbia and Venezuela, but also found in Lebanon and Palestine (9%), Iranian Kurdistan (7%) and Saudi Arabia (6%).

DRB1*04:04: found mostly among Native Americans and Siberians, but also a bit in western Europe (3-5%)

DRB1*04:05: found at high frequencies in Melanesia, Austronesia, Japan and Korea, but also in Sardinia (20%), and at low frequencies (1-4%) around southern Europe and the Near East.

DRB1*04:06: found mostly in Northeast Asia (1-7%)

DRB1*04:07: found among Native Americans (5-60%) and Northwest Spain (15%)

DRB1*04:08: found at low frequencies (1-6%) between northern Europe and Mongolia and in Native North Americans.

DRB1*04:10: found at low frequencies (1-7%) in the Pacific rim, from Alaska and eastern Siberia to Melanesia via Japan.

DRB1*04:11: found at varying frequencies (2-70%) in Central and South America


In Scandinavia, over 90% of the DR4 is DRB1*04:01.

In Western and Central Europe DRB1*04:01 is the most common (usually over 50%), followed by DRB1*04:04, but other types (2, 3, 5, 6, 7, 8) are also found at low frequencies.


Medical associations

This HLA type is associated with alopecia areata (baldness) and quite a few autoimmune diseases, depending on the subtype, including among others:

DRB1*04:01: multiple sclerosis, rheumatoid arthritis, type 1 diabetes, lyme disease induced arthritis

DRB1*04:02: type 1 diabetes

DRB1*04:03: polycystic ovary syndrome

DRB1*04:04: autoimmune hepatitis

DRB1*04:05: autoimmune hepatitis, rheumatoid arthritis, type 1 diabetes

DRB1*04:06: caspase-8 autoantibodies silicosis-systemic sclerosis (SSc)-systemic lupus erythematosus (SLE)


Role in autism ?

Various studies have also linked HLA-DR4 (as well as DR11) to autism spectrum disorder (ASD). The subtypes most strongly correlated to autism were DRB1*0401 and DRB1*0404, i.e. the variants most common in western, northern and eastern Europe as well as Siberia.

Interestingly, both DR4 and DR11 are associated with a risk for rheumatoid arthritis, so it seems that both could (dys)function in a similar way.


SNP's

You can verify if you carry HLA-DR1 by checking your raw data from 23andMe, Geno 2.0 or FamilyFinder. The positive allele is in brackets/parentheses. You normally need to be positive for all alleles defining your subtype.

- HLA-DRB*0401 : rs6910071 (G), rs3817964 (A) or rs660895 (G)

- HLA-DRB*0402 : rs3130071 (T) or rs416352 (T)

- HLA-DRB*0403 : rs7454108 (C means DR4 and/or DQ8), rs206765 or rs399604

- HLA-DRB*0404 : rs2736157 (G), rs3115572 (C) or rs2395533

- HLA-DRB*0405 : rs1057149 (A)

- HLA-DRB*0407 : rs7774197 (C) or rs417812

 

[Maciamo]

I have made a map of the mostly North European DRB1*04:01 subclade to show the contrast with other subclades. It appears to be essentially Germanic and East Slavic. I can't explain the isolated hotspot in Jordan. Maybe a sample bias as the sample size is small (n=146).

 

[I1a3_Young]

I read a health study regarding susceptibility to rheumatoid arthritis for *0401 and *0404 because of a protein blocker that stops swelling in joints. The interesting bit was that they said there's a 75% risk of this protein blocker of you are both *0401 and *0404 (50% if *0404 alone).

Can you be both at once? Heterozygous? Or do you have to be homozygous for one HLA by definition?

 

[I1a3_Young]

I read a health study regarding susceptibility to rheumatoid arthritis for *0401 and *0404 because of a protein blocker that stops swelling in joints. The interesting bit was that they said there's a 75% risk of this protein blocker of you are both *0401 and *0404 (50% if *0404 alone).

Can you be both at once? Heterozygous? Or do you have to be homozygous for one HLA by definition?

You get one from each parent for each HLA type (A,B,C,DQ,DR). Siblings have a 1 in 4 chance of getting the same combination as each other.

 

[Ds7511]

Maciamo, thank you for the information,

All of my family on 23andMe are like this, for *0401: - HLA-DRB*0401 : rs6910071 (A/A), rs3817964 (T/T) , and rs660895 (A/A), except for my dad and myself who are instead: rs6910071 (A/G), rs3817964 (T/T), and rs660895 (A/A).

Given the one G allele at rs6910071, could that indicate that he and I carry one copy of *0401, or likely not ? (If so, we are apparently the only two in my family who do carry it). I have read before some studies and such saying that the G allele at rs6910071, and/or the G allele at rs660895 can be tags for *0401. thanks.