HIGH-RESOLUTION HLA-DRB1 ALLELE FREQUENCIES IN A ROMANIAN COHORT OF STEM CELL DONORS
Caragea ĚŔ, Ursu IR, Visan DL, Maruntelu I, Iordache P, Constantinescu A, Tizu M, Tălăngescu A, Constantinescu I
*Corresponding Author: Lect., MD, PhD Radu-Ioan Ursu, Carol Davila University of Medicine and
Pharmacy, Department of Medical Genetics, Bucharest, Romania, Str. Batistei 12, Bucharest, Romania; tel.: 0040736167020; e-mail: dr.radu.ursu@gmail.com
page: 43
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DISCUSSIONS
The most frequent HLA-DRB1 alleles identified
through the current research (frequencies >10%) were
HLA-DRB1*16:01:01 (12.6%), HLA-DRB1*11:04:01
(12.1%), DRB1*03:01:01 (12%). The other more com-
mon variants detected (frequencies 5% - 10%) were
HLA-DRB1*07:01:01 (9.3%), HLA-DRB1*01:01:01
(7.3%) and HLA-DRB1*11:01:01 (6.3%) and HLA-
DRB1*13:01:01 (6%), while HLA-DRB1*15:01:01 was
observed in approx. 4.4% of all tested individuals and
HLA-DRB1*13:02:01 and HLA-DRB1*04:01:01 being
at approximately a 3% frequency.
When adding the frequencies of all the variants for
each HLA-DRB1 allele, the most common alleles are
DRB1*11 (19.38%), DRB1*16 (13.95%), DRB1*03
(12.10%), DRB1*13 (10.99%), DRB1*04 (9.51%),
DRB1*07 (9.26%), DRB1*01 (8.40%), DRB1*15
(5.93%), DRB1*14 (5.31%), while the other 5 detected
HLA-DRB1 alleles (DRB1*10, DRB1*12, DRB1*02,
DRB1*05, DRB1*09) had low combined frequencies
(1.73% or lower).
In Europe, on average, the most common HLA-
DRB1 variants are HLA-DRB1*07:01, followed by the
DRB1*03:01, DRB1*15:01, DRB1*01:01, DRB1*11:01,
DRB1*13:01, DRB1*04:01 and DRB1*16:01 alleles
(listed in the descending order of their frequencies) [7].
The frequency observed for the most common HLA-
DRB1 allele identified in our analyzed Romanian cohort
(HLA-DRB1*16:01:01, 12.6%), if confirmed through
further studies on wider populations, would be the sec-
ond highest detected in all populations worldwide, only
Bulgarians reveal higher frequencies for this allele (AF
15.5%) [7, 14]. The next population group, in descending
order of allele frequencies for this HLA-DRB1 variant,
would be Polish (8%) and then certain Russian populations
(Belgorod and Nizhny Novgorod Russians and Bashkor-
tostan Bashkirs) (AF 3.3% - 4.9%), but with much lower
percentages for this allele [7].
Similarly, to HLA-DRB1*16:01:01, the frequency
detected for the second most common allele in our cohort
(HLA-DRB1*11:04:01, 12.1%), would also, if confirmed,
be the second highest worldwide, being surpassed, again,
only by the Bulgarian population (AF 15.5%) [7, 20]. The
next high frequencies can be observed in the Paraguayan/
Argentinian Guarani population (AF 10%) and different
Russian populations (Russians from the Belgorod and
Vologda regions and Tatars from Bashkortostan) (AF
5.54% - 5.88%), but also the Portuguese Madeira popu-
lation (5.5%) [7].
The other more common HLA-DRB1*11 variant,
HLA-DRB1*11:01, was observed in only approx. 6.3%
of all analyzed Romanian individuals, almost half the
frequency of HLA-DRB1*11:04. Similar findings were
observed in continental and Crete island Greeks, Bulgar-
ians, Macedonians, Croatians, Turks, and Italians, where
HLA-DRB1*11:04 predominated over HLA-DRB1*11:01
[7, 21-30]. In contrast, the two alleles displayed equal or
opposite frequencies in Central and Western European countries, where the HLA-DRB1*11:01 allele is widely
more prevalent [7].
Both the HLA-DRB1*16:01:01 and the HLA-
DRB1*11:04:01 variants appear to be more specific for
the populations belonging to or historically tracing back
from the Eastern European, Caucasus, Black Sea and Bal-
kan regions.
HLA-DRB1*16:01:01 is the most frequent in Mace-
donia (AF 14.9%), the second most prevalent in Bulgaria
(after HLA-DRB1*11:04:01), Kosovo (12.9%) and Greece
(HLA-DRB1*16:01, 4 digits, AFs 7.8% – 13.7%), the
fourth in Slovenia, while the HLA-DRB1*16:01 allele
(low resolution) is the third most frequent is among the
population on the Croatian island of Krk (AF 11.2%) (and
the HLA-DRB1*16 has the second highest prevalence with
an AF of 11.8%). This is also possible in high percentages
in Albania, where the second most commonly detected
(low frequency) HLA-DRB1 variant is HLA-DRB1*16
(AF 12.4%), as is in Kosovo (AF 13.75%) [7, 21-30].
The HLA-DRB1*11:04:01 is possibly an even more
ancient populational indicator, being observed in high
frequencies in cohorts from Macedonia (second most fre-
quent allele, AF 13.9%), Bulgaria (most common variant),
Greece (HLA-DRB1*11:04 AFs 13.9% – 19.3%), Turkey
(the most frequent HLA-DRB1 allele), also on the Croatian
island of Krk (13.2%), Israeli Jews of Georgian descent
(24.2%) and Polish Jews (17.8%), Armenia’s combined
Regions (11.5%), in Lebanon’s Kafar Zubian (23.7%) and
Niha el Shouff (17%) (where the DRB1*11:04 allele is the
highest prevalent), Israeli Jews of Libyan descent (17.4%),
Polish (17.8%) and Moroccan Jews (16.4%), or in Kosovo
(10.5%), (HLA-DRB1*11:04 the second most common),
parts of Black Sea Russia, Middle Eastern regions, and
including Spanish Basque areas of Cantabria and Rome
in Italy (the most prevalent variant) [7, 21-30].
A difference, nevertheless, can be observed between
Eastern European countries (where both of these alleles are
highly common) and the other above mentioned popula-
tions, (as are the Krk Island Croatians, the Armenians, the
Spanish Cantabrian Basques and the Italians), where only
HLA-DRB1*11:04:01 (or HLA-DRB1*11:04, depend-
ing on resolution) is the top or the second allele, but the
HLA-DRB1*16:01:01 is one of the least frequent variants
detected.
Both these similarities and differences could find an
explanation in the historical genetic lineage of the peoples
living in these areas, most of them being connected to the
Pelasgians/Thracians/Getae/Dacians populations origi-
nating from these geographical areas (Turkey, Black Sea
countries, Romanian regions, Bulgaria, parts of Albania
and Macedonia, Kosovo, etc.). Also, the presence of the
HLA–DRB1*11:04:01 allele in certain populations only
(Basques, Armenians, Italians) can be explained by com-
mon ancient ancestors (Pelasgians/Thracians/Etruscans)
of these peoples with the populations from the Eastern
Europe and Balkan areas, the HLA-DRB1*16:01:01 vari-
ant appearing to be a mutational event which occurred after
the separation of these groups, with a high specificity for
Eastern Europe/Balkans.
Having reviewed related work, the frequencies of
HLA-DRB1*16:01:01 and HLA-DRB1*11:04:01 were at
a very high frequency compared to the prevalence in most
Central and Western European populations.
In research articles from this European geographical
area, and in the Romanian population as resulted from
previous studies, the most common HLA-DRB1 variants
are HLA-DRB1*03:01:01 and HLA-DRB1*07:01:01
[7,18,21-25]. The frequencies of the HLA-DRB1*07:01:01
and HLA-DRB1*03:01:01 alleles in the tested cohort
were, by contrast, lower than those found in all popula-
tions from Central and Western Europe and also in past
Romanian studies.
The third most common HLA-DRB1 variant in our
studied population, HLA-DRB1*03:01:01 (11.98%), is
one of the frequently identified alleles in various popula-
tions globally. Similar frequencies have been observed in
populations such as USA Caucasians (12.47%), Portuguese
Madeirans (12.2%), Israel Yemenite Jews (12%), Mo-
rocco Settat Chaouya (11.7%) and Atlantic Coast Chaouya
(11.6%), Algerian Oran (11.6%), American citizens of
Italian descent (11.2%) and Polish populations (10.9%).
The highest frequencies worldwide for this variant can be
seen in the Morocco Nador Metalsa (20.2%), Spanish Ca-
nary Islands (Gran Canaria island) (16.3%) and Northern
Ireland (15.4%) populations [7].
Apart from the more frequently detected alleles in
other populations throughout the globe, the current study
also revealed the presence of 4 rare alleles (described
in a maximum of 3 cohorts in published research re-
sults: HLA-DRB1*1:03:01 – 1 previous report; HLA-
DRB1*11:01:02 – 2 reports; HLA-DRB1*04:08:01 – 2
reports; HLA-DRB1*13:0:01 – 3 reports) and also one new
variant, not previously described in the literature (HLA-
DRB1*04:06:02).
Further studies on larger Romanian cohorts need to
be undertaken as to confirm these results and to understand
their clinical, epidemiological, diagnostic, therapeutic or
molecular implications.
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