HLA Class I Antigen and HLA-A, -B, and -C Haplotype

Frequencies in Uruguayans

INES ALVAREZ,1 MILKA BENGOCHEA,1 ROBERTO TOLEDO,1 ELENA CARRETTO,1 AND

PEDRO C. HIDALGO1

Abstract HLA class I antigens were determined for 959 unrelated Uru-
guayans. The predominant HLA alleles were A2, Cw4, and B35, and the most
frequently observed two-loci haplotypes were A2-B44 and B35-Cw4. The
most frequent three-loci HLA haplotype was A2-Cw5-B44. We compared the
Uruguayan sample with similar data from other populations.

Uruguay is situated on the southeast coast of South America and shares borders
with Brazil and Argentina. It covers an area of 176,220 km2 and has a population
of 3,399,237 (2004 estimate; Instituto Nacional de Estadisticas). About half of
the population lives in the capital, Montevideo. Only 14% of Uruguayans live in
rural areas, and the migration rate to the towns is 1.6% per year. The population
is predominantly European in origin, mostly immigrants from Spain, Italy, and
Portugal, with a relatively low proportion of African and Amerindian ancestors
(Sans et al. 1993, 1997; Hidalgo et al. 2005).
In an earlier study the HLA antigen and haplotype frequencies in Uruguay
were reported in a sample mainly from the capital city area (Alvarez et al. 1993).
The aims of the present report are to study a sample that represents the whole
country and to characterize the population in terms of haplotype frequencies and
linkage disequilibrium values. Data were also used to analyze the relationships
with several world populations by measuring the genetic distances among them.

Materials and Methods

Study Sample. The sample was composed of 959 healthy Uruguayans who
participated in paternity studies from March 1998 to June 2001. The studies were
done at the Laboratory of Histocompatibility and Immunogenetics (INDT). The

1
Laboratorio de Inmunogenética e Histocompatibilidad, Instituto Nacional de Trasplante y Donación de
Células, Tejidos y Órganos (INDT), Hospital de Clı́nicas ‘‘Manuel Quintela,’’ Ave. Italia s/n Piso 4, CP 11600,
Montevideo, Uruguay.

Human Biology, August 2006, v. 78, no. 4, pp. 513–525.

Copyright 䉷 2006 Wayne State University Press, Detroit, Michigan 48201-1309

KEY WORDS: HLA CLASS I, HLA HAPLOTYPES, URUGUAY, SOUTH AMERICAN POPULA-
TIONS.

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514 / alvarez et al.

subjects were unrelated Uruguayan adults from all parts of the country. Informed
consent was obtained from all subjects.

Laboratory Analysis. HLA-A, -B, and -C class I antigens were tested by se-
rology using a standard microcytotoxicity method (Terasaki and McClelland
1964; Terasaki et al. 1978); determinations were performed using commercial
HLA-ABC Typing Trays (Pel-Freez, Brown Deer, Wisconsin).

Data Analysis. Allele frequencies were estimated using the maximum-

likelihood method provided in Arlequin, version 2 (Schneider et al. 2000). Two-
locus and three-locus haplotype frequencies and linkage disequilibrium were
calculated according to the method described by Imanishi et al. (1992b). For the
two-locus haplotypes the value of the standardized disequilibrium coefficient
(D⬘) (Lewontin 1964) and the chi-square value were also calculated. The linkage
disequilibrium between two loci was considered statistically significant at the
level of 1%. We tested the goodness of fit for Hardy-Weinberg equilibrium with
the classical chi-square test (Hernandez and Weir 1989).
Gene frequency data at the HLA-A, -B, and -C loci were selected from 28
populations from the available literature to ascertain genetic relationships with
our population (Table 1). The alleles used in the analysis were, for the HLA-A
locus, A1, A2, A3, A11, A28, A29, A30, A31, A32, and A33; for the HLA-B locus,
B7, B8, B13, B14, B17, B18, B27, B35, B37, and B39; and for the HLA-C locus,
Cw1, Cw2, Cw3, Cw4, Cw5, Cw6, and Cw7. We used Nei’s standard genetic
distance (Nei 1972) to evaluate the genetic distances separating all pairwise pop-
ulations. We used the software PHYLIP, version 3.5c (Felsenstein 1993), to con-
struct phylogenetic trees by using Sneath and Sokal’s (1973) unweighted pair-
group method using arithmetic averages (UPGMA). To evaluate the degree of
genetic variation within and between populations, we selected 10 South Ameri-
can urban populations, usually trihybrid. Nei’s measures of gene diversity (Nei
1973) were performed with the DISPAN program (Ota 1993).

Results
Table 2 shows the HLA antigen and allele frequencies found in the Uru-
guayan population. Departures from Hardy-Weinberg genetic equilibrium at the
single-locus level were not statistically significant, with the only exception of the
HLA-C locus ( p ⬍ 0.01). This exception could be due to the presence of serol-
ogy-undetected alleles included in the blank frequency or to random fluctuations.
The most common two-locus haplotypes whose frequencies were higher
than 1% are shown in Table 3. We observed 21 A-B haplotypes with frequencies
greater than 1%. These 21 haplotypes combined accounted for more than 37.1%
of the haplotypic gene pool. Eleven A-B haplotypes were found to have highly
significant linkage disequilibrium values at the level of 0.1%. The most frequent

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 HLA Haplotypes in Uruguayans / 515

Table 1. Locations, Symbols, and References for the Study Populations

Region and Population Symbola Reference

Europe
Italians ITAL Imanishi et al. (1992a)
Spanish SPAIN Imanishi et al. (1992a)
Portuguese PORT Imanishi et al. (1992a)
Sub-Saharan Africa
Bushmen SAN Imanishi et al. (1992a)
Gambians GAMB Allsopp et al. (1992)
Nigerians NIGE Allsopp et al. (1992)
Zimbabwians ZIMB Imanishi et al. (1992a)
Senegalese SENE Imanishi et al. (1992a)
South African blacks SOAB Imanishi et al. (1992a)
Asia
Buriats BURI Imanishi et al. (1992a)
Kazakhs KAZA Imanishi et al. (1992a)
Japanese JAPA Allsopp et al. (1992)
North and Central America
US blacks AFUS Imanishi et al. (1992a)
North American Indians NOAI Imanishi et al. (1992a)
Mexican Indians (average) MXIN Gorodezky (1992)
Mexican Mestizos (highlands) MXME Gorodezky et al. (2001)
Guatemala GTE Santiago-Delpin (1991)
Panama PAN Santiago-Delpin (1991)
South America
South American Indians SOAI Rothhammer et al. (1997)
Venezuela (Caracas) VEN Makhatadze et al. (1997)
Colombian mestizos (Cali) COME Fleischhauer and Zino (2004)
Colombian blacks (Pacific) COBL Blank et al. (1995)
Ecuador ECU Santiago-Delpin (1991)
Peruvian mestizos (Arequipa) PERU Oliver et al. (2004)
Paraná Brazilian whites PBRW Probst et al. (2000)
Paraná Brazilian mulattos PBRM Probst et al. (2000)
Uruguay URU Present study
Argentina (Buenos Aires) ARG Raimondi (1997)
Chile (Santiago de Chile) CHI Rodriguez et al. (1993)
a. These symbols are used in Table 5 and Figure 1.

A-B haplotype was A2-B44, with a significant linkage disequilibrium value at the
level of 1%. Sixteen B-C haplotypes were found to have highly significant linkage
disequilibrium values. The B35-Cw4, B7-Cw7, and B44-Cw5 haplotypes were
frequent and in strong linkage disequilibrium ( p ⬍ 0.001). We observed 24 A-C
haplotypes with frequencies greater than 1%.
The estimated frequencies and linkage disequilibria for the most frequent
three-locus haplotypes are shown in Table 4. The three most frequent HLA A-C-
B haplotypes were A2-Cw5-B44, A2-Cw4-B35, and A24-Cw4-B35.

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516 / alvarez et al.

Table 2. Distribution of HLA Class I Antigens and Gene Frequencies in Uruguayans

Antigen Frequency (%) Gene Frequency

HLA-A
A1 17.2 0.092
A2 44.0 0.249
A3 17.7 0.092
A9 1.8 0.010
A10 2.0 0.010
A11 9.6 0.048
A19 2.3 0.011
A23(9) 5.5 0.028
A24(9) 18.9 0.100
A25(10) 2.4 0.012
A26(10) 3.9 0.020
A28 10.3 0.053
A29(19) 10.1 0.052
A30(19) 6.6 0.034
A31(19) 9.0 0.046
A32(19) 6.6 0.033
A33(19) 6.7 0.034
A34(10) 1.8 0.009
A66(10) 0.6 0.003
A68(28) 0.3 0.002
A69(28) 0.5 0.003
A74(19) 0.7 0.004
ABL 0.055
HLA-B
B5 0.4 0.002
B7 11.5 0.059
B8 8.9 0.045
B12 0.8 0.004
B13 2.9 0.015
B14 7.4 0.038
B15 1.1 0.006
B16 0.7 0.004
B17 1.6 0.008
B18 9.4 0.048
B21 1.8 0.009
B22 0.5 0.003
B27 5.9 0.029
B35 25.3 0.136
B37 1.4 0.007
B38(16) 4.0 0.019
B39(16) 7.3 0.038
B42 0.8 0.004
B44(12) 23.1 0.121
B45(12) 2.5 0.013
B46 0.1 0.001
B47 1.0 0.005
B48 0.7 0.004
B49(21) 3.8 0.019

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 HLA Haplotypes in Uruguayans / 517

Table 2. (Continued)

Antigen Frequency (%) Gene Frequency

B50(21) 3.9 0.020
B51(5) 13.6 0.069
B52(5) 1.2 0.006
B53 0.9 0.005
B54(22) 0.1 0.001
B55(22) 1.6 0.008
B56(22) 1.0 0.005
B57(17) 5.3 0.027
B58(17) 2.1 0.010
B60(40) 7.1 0.036
B61(40) 3.2 0.016
B62(15) 10.5 0.055
B63(15) 0.8 0.004
B64(14) 0.4 0.002
B65(14) 2.2 0.011
B70 2.6 0.013
B73 0.1 0.001
B75(15) 0.7 0.004
B81 0.2 0.001
BBL 0.057
HLA-C
Cw1 8.4 0.043
Cw2 13.0 0.068
Cw3 19.3 0.103
Cw4 33.7 0.193
Cw5 11.5 0.060
Cw6 16.6 0.089
Cw7 32.6 0.186
Cw8 7.3 0.037
CwBL 0.221
BL, blank.

As can be seen in Table 5, the mean genetic distance between Uruguay and
European populations is lower (0.027 Ⳳ 0.005) than that obtained considering
sub-Saharan Africans (0.128 Ⳳ 0.03), American Indians (0.124 Ⳳ 0.034), and
Asian populations (0.089 Ⳳ 0.026), favoring a mostly European contribution to
the present Uruguayan’s gene pool.
The dendrogram in Figure 1 summarizes the affinities among the selected
populations. The Uruguayan sample is located in a principal cluster that includes
European populations and also some other South American populations (Argen-
tina, Venezuela, and Paraná whites from Brazil); curiously, Paraná mulattos and
Mexican mestizos also grouped within this cluster. Regional and historical rela-
tionships are evident in the tight cluster formed by Uruguay, Argentina, and
Spain.

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Table 3. HLA Two-Locus Haplotype Frequencies and Linkage Disequilibrium in Uru-

guayans

Frequency Linkage
Two-Locus Haplotype (2n ⳱ 1,918) Disequilibrium D⬘ ␹2
HLA A-B haplotype
A2-B44 0.041 0.011 0.116 10.72a
A24-B35 0.029 0.016 0.182 44.76b
A1-B8 0.027 0.023 0.561 280.22b
A3-B7 0.025 0.020 0.373 164.87b
A2-B51 0.024 0.007 0.135 7.78a
A3-B35 0.024 0.011 0.144 25.39b
A2-B35 0.023 ⳮ0.011 ⳮ0.316 9.99a
A29-B44 0.023 0.017 0.361 99.28b
A2-B18 0.017 0.005 0.134 5.31
A2-B62 0.016 0.003 0.063 1.34
A2-B60 0.012 0.003 0.106 2.47
A2-B7 0.012 ⳮ0.003 ⳮ0.180 1.29
A24-B62 0.012 0.006 0.130 16.93b
A1-B57 0.012 0.009 0.372 72.85b
A33-B14 0.012 0.010 0.313 168.33b
A23-B44 0.011 0.008 0.309 38.31b
A11-B35 0.011 0.004 0.094 5.43
A31-B35 0.010 0.004 0.104 6.30
A24-B39 0.010 0.006 0.188 23.92b
ABL-B35 0.010 0.002 0.047 1.60
A28-B51 0.010 0.006 0.125 22.39b
HLA B-C haplotype
B35-Cw4 0.114 0.087 0.794 799.92b
B7-Cw7 0.042 0.031 0.638 214.31b
B44-Cw5 0.036 0.029 0.549 265.87b
B62-Cw3 0.031 0.026 0.527 269.05b
B8-Cw7 0.028 0.020 0.547 118.93b
B60-Cw3 0.027 0.024 0.725 333.76b
B14-Cw8 0.026 0.025 0.694 919.59b
B44-Cw4 0.024 0.000 0.003 0.01
B39-Cw7 0.021 0.014 0.442 64.33b
B49-Cw7 0.015 0.011 0.719 83.83b
B27-Cw2 0.014 0.012 0.459 166.43b
B27-Cw1 0.014 0.013 0.467 276.07b
BBL-Cw4 0.014 0.003 0.065 2.07
B18-Cw5 0.014 0.011 0.245 92.17b
B57-Cw6 0.014 0.011 0.458 115.32b
B18-Cw7 0.013 0.005 0.114 5.51
B50-Cw6 0.013 0.011 0.630 155.41b
B13-Cw6 0.012 0.011 0.792 185.24b
B44-Cw7 0.010 ⳮ0.012 ⳮ0.547 18.07b
HLA A-C haplotype
A2-CwBL 0.045 ⳮ0.009 ⳮ0.179 5.80
A2-Cw7 0.042 ⳮ0.004 ⳮ0.085 1.05
A2-Cw4 0.042 ⳮ0.006 ⳮ0.133 2.69
A1-Cw7 0.034 0.017 0.220 41.41b

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 HLA Haplotypes in Uruguayans / 519

Table 3. (Continued)

Frequency Linkage
Two-Locus Haplotype (2n ⳱ 1,918) Disequilibrium D⬘ ␹2
A2-Cw5 0.032 0.017 0.378 52.68b
A2-Cw3 0.030 0.004 0.053 1.85
A24-Cw4 0.025 0.005 0.067 3.96
A24-Cw7 0.024 0.005 0.066 4.08
A2-Cw6 0.023 0.001 0.014 0.11
A3-Cw7 0.023 0.006 0.074 4.69
A24-Cw3 0.021 0.011 0.125 28.94b
A1-Cw4 0.018 0.001 0.006 0.03
A1-Cw6 0.017 0.009 0.113 23.48b
A2-Cw1 0.016 0.005 0.162 6.91a
A3-Cw4 0.016 ⳮ0.002 ⳮ0.092 0.39
A11-Cw4 0.015 0.006 0.150 9.21a
A28-Cw4 0.014 0.004 0.093 3.86
A31-Cw4 0.013 0.004 0.101 3.95
ABL-Cw7 0.012 0.002 0.032 0.52
A28-Cw3 0.011 0.006 0.123 14.04b
A2-Cw8 0.011 0.001 0.049 0.55
A33-Cw8 0.010 0.008 0.255 112.62b
A31-Cw3 0.010 0.005 0.119 11.35b
A32-Cw7 0.010 0.003 0.126 4.59
D⬘: relative linkage disequilibrium. Only haplotypes with frequencies greater than 0.01 are shown.
Haplotypes were sorted from the higher to the lower frequency. BL ⳱ blank.
a. p ⬍ 0.01.
b. p ⬍ 0.001.

The gene diversity in the 10 urban admixed South American populations

are given in Table 6. The coefficient of gene differentiation (GST) was highest for
the HLA-C locus (4.9%) and lowest for the HLA-B locus (1.6%). When all loci
were considered together, the GST coefficient revealed that 97.1% of the total
diversity is retained within populations and only 2.9% is accounted for by the
between-populations component. Locus-by-locus examination of the GST values
showed that the urban South American populations are well differentiated at the
HLA-A, -B, and -C loci.

Discussion
The Uruguayan gene frequencies show partial overlap with those found in
other Latin American populations, in particular, Venezuela (Makhatadze et al.
1997), Brazilian whites from Paraná (Probst et al. 2000), and Argentina (Rai-
mondi 1997).
Two-loci haplotype data revealed that the most frequent combinations are
characteristic of Northern and Western European populations, all of them with

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520 / alvarez et al.

Table 4. Haplotype Frequencies and Linkage Disequilibrium Values for Three-Locus

Haplotypes

HLA A-C-B Haplotype Frequency (2n ⳱ 1,918) Linkage Disequilibrium

A2-Cw5-B44 0.029 0.027
A2-Cw4-B35 0.024 0.018
A24-Cw4-B35 0.022 0.019
A29-CwBL-B44 0.020 0.019
A3-Cw4-B35 0.019 0.017
A3-Cw7-B7 0.018 0.017
A2-CwBL-B51 0.018 0.014
A1-Cw7-B8 0.017 0.016
A2-Cw3-B60 0.011 0.010
A24-Cw3-B62 0.011 0.011
A2-CwBL-B44 0.011 0.004
A11-Cw4-B35 0.011 0.010
A24-CwBL-BBL 0.011 0.009
A2-Cw3-B62 0.010 0.008
Only haplotypes with frequencies greater than 1% are shown. Haplotypes were sorted from highest
to lowest frequency. BL ⳱ blank.

significant linkage disequilibrium. The A30-B18 haplotype is found in Basques,

Spaniards, Algerians, and Sardinians. It has been considered a paleo-Iberian-
North African marker (Arnaiz-Villena et al. 1995). A33-B14 association is also
found in Basques, Iberians, and Mediterranean populations (Arnaiz-Villena et al.
1995). However, some common African haplotypes (Imanishi et al. 1992a) were
found at low frequencies, such as A30-B35, A2-B70, and B53-Cw4, indicating a
low level of African admixture in our population.
Haplotype A2-Cw5-B44 was the most common three-locus haplotype in
the Uruguayan sample, and it is also frequent in Western Europe. The second
most frequent haplotype in Uruguayans, A2-Cw4-B35, is also common in Euro-
pean as well as African populations. Some haplotypes, such as A23-Cw4-B44
and A11-Cw1-B27, common in Basques and Catalans (Comas et al. 1998), were
also found in our sample.
The Uruguayan population is most closely related to European populations
(Spaniards, Portuguese, and Italians), as demonstrated by the UPGMA tree and
by the closest genetic distance values. The relationship between Uruguay and
Argentina reveals a common European background with important Spanish and
Italian components (Oddone 1966). However, the presence of some haplotypes
commonly found in Africans and American Indians reveals admixture in our
population. This shows that, as well as other admixed Latin American popula-
tions, the Uruguayan population received contributions from European, native
American Indian, and African ancestries. Thus the broad heterogeneity of origins
may have contributed to the level of genetic differentiation among the South
American populations, showing complex processes of gene admixture.

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 Table 5. Genetic Distances (⳯10) Computed by the Method of Nei (1972)

SAN GAMB NIGE ZIMB SENE BURI KAZA JAPA ITAL SPAIN PORT SOAI NOAI MXIN AFUS
GAMB 4.11
NIGE 3.01 0.69
ZIMB 2.80 0.62 0.64
SENE 3.67 0.26 0.37 0.48
BURI 5.33 0.75 1.00 1.23 0.64
KAZA 5.70 1.06 1.30 1.59 0.78 0.22
JAPA 6.82 1.14 1.76 1.72 1.17 0.36 0.77
ITAL 3.79 1.02 1.21 1.23 0.75 1.09 1.33 1.49
SPAIN 3.82 1.10 1.05 1.06 0.61 0.85 0.89 1.32 0.21
PORT 4.59 0.72 1.08 1.05 0.61 0.76 0.94 1.10 0.20 2.60

................. 16219$
SOAI 6.92 2.48 2.76 3.69 2.00 2.10 1.95 2.59 2.59 2.57 2.40
NOAI 5.10 2.55 2.64 3.22 2.03 2.43 2.53 2.60 1.79 1.96 1.94 0.59
MXIN 5.44 1.83 2.15 2.50 1.40 1.80 1.71 2.30 1.19 1.30 1.13 0.72 0.63

$CH9
AFUS 3.47 0.40 0.21 0.42 0.21 0.64 0.95 1.07 0.66 0.55 0.48 2.71 2.41 1.85
MXME 5.03 0.72 0.75 1.23 0.38 0.60 0.75 0.85 0.74 0.57 0.68 1.58 1.61 1.34 0.41
COME 4.81 1.14 1.04 1.24 0.71 0.57 0.74 0.65 0.76 0.49 0.56 1.63 1.32 1.05 0.66
COBL 4.26 0.64 0.36 0.70 0.43 0.97 1.25 1.29 1.58 1.35 1.38 2.76 2.67 2.44 0.34
PERU 6.80 2.96 2.96 3.96 2.27 2.75 2.78 3.42 1.88 2.04 1.88 1.37 1.96 1.14 2.72
PBRW 4.12 0.66 0.97 1.03 0.48 0.53 0.74 0.91 0.19 0.24 1.30 1.80 1.58 0.90 0.48

09-12-06 10:49:00
PBRM 4.00 0.40 0.54 0.70 0.21 0.50 0.68 0.98 0.41 0.38 0.29 1.93 1.84 1.11 0.23
URU 3.50 0.75 0.70 1.10 0.37 0.70 0.78 1.20 0.27 0.22 0.33 1.56 1.29 0.87 0.41

PS
ARG 3.28 0.93 1.01 1.18 0.56 1.03 1.10 1.49 0.20 0.24 0.41 1.72 1.15 0.85 0.65
VEN 4.25 0.64 0.99 0.92 0.41 0.49 0.68 0.68 0.26 0.21 0.21 2.00 1.68 1.10 0.41
ECU 7.09 0.85 1.59 1.75 0.88 0.79 1.00 1.13 0.98 1.13 0.56 1.56 2.19 1.07 1.04
GTE 8.31 1.05 1.94 1.83 1.52 0.94 1.67 0.56 1.89 2.05 1.37 4.14 4.20 3.60 1.20
PAN 5.71 1.10 2.09 1.87 1.52 1.11 1.51 0.83 1.62 1.76 1.35 4.26 4.18 3.61 1.35
CHI 8.45 1.27 2.22 1.65 1.58 1.28 1.72 1.39 1.18 1.42 0.66 3.85 3.80 2.36 1.30
HLA Haplotypes in Uruguayans / 521

PAGE 521
 Table 5. (Continued)
522 / alvarez et al.

MXME COME COBL PERU PBRW PBRM URU ARG VEN ECU GTE PAN
COME 0.51

................. 16219$
COBL 0.57 1.04
PERU 1.90 2.13 3.77
PBRW 0.49 0.41 1.26 1.55

$CH9
PBRM 0.35 0.42 0.63 1.95 0.19
URU 0.30 0.43 0.95 1.46 0.15 0.20
ARG 0.54 0.65 1.29 1.65 0.24 0.40 0.10
VEN 0.32 0.32 1.05 1.92 0.12 0.20 0.21 0.31
ECU 0.84 0.95 1.70 1.17 0.46 0.55 0.78 1.07 0.66
GTE 1.35 1.52 1.39 4.31 1.36 1.25 1.87 2.28 1.28 1.15

09-12-06 10:49:00
PAN 1.62 1.58 1.94 4.12 1.23 1.29 1.55 1.79 1.14 1.49 0.73
CHI 1.63 1.45 2.24 3.02 0.92 1.08 1.65 1.83 1.03 0.64 0.90 1.60

PS
Symbols are explained in Table 1.

PAGE 522
 HLA Haplotypes in Uruguayans / 523

Figure 1. UPGMA dendrogram showing relatedness between Uruguayans and other populations
using HLA-A, -B, and -C allele-frequency data. Symbols are explained in Table 1.

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524 / alvarez et al.

Table 6. Gene Diversity Analysis Among Urban South American Populations

Locus HT HS DST GST

HLA-A 0.8337 0.8171 0.0166 0.0199
HLA-B 0.6651 0.6545 0.0106 0.0159
HLA-C 0.7821 0.7438 0.0383 0.0490
All loci 0.7603 0.7385 0.0218 0.0287

Acknowledgments We are grateful to Mónica Sans for reading the manuscript and for
her invaluable commentaries.

Received 2 May 2005; revision received 14 April 2006.

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