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Immunoglobulin (GM and KM) allotypes in the Sikh population of India.

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AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 75:31-35 (1988)
Immunoglobulin (GM and KM) Allotypes in the
Sikh Population of India
L. LEIGH FIELD, SIRA SURJE, AND AJIT K . RAY
Division of Medical Genetics, Department of Pediatrics, University of
Calgary and Alberta Children’s Hospital, CaZgary T2T 5C7 (L.L.83 and
Department ofAnthropobgy, University of Toronto, Toronto M5S I A l
(A.K. R.),Canada
KEY WORDS
Sikhs, Gm, Km, Population genetics
ABSTRACT
The populations of India are genetically diverse, both within
and between geographic regions; immunoglobulin (GM) allotypes provide important information on genetic differences between populations, since the
frequencies of combinations of allotypes (termed “haplotypes”) vary dramatically among ethnic groups. As part of a project to assess genetic diversity
among defined Indian populations, we have examined eight GM allotypes in a
sample of 101 unrelated Sikhs who have migrated to Toronto, Canada: Glm(1,
2, 3, 17) and G3m (5, 15, 16, 21). Sikhs are a religious group that arose in the
Punjab about 1500 A.D.; most of the original converts are believed to have
been middle to upper-middle caste Hindus. Gm allotyping showed that six Gm
haplotypes occurred at polymorphic frequencies (>0.01) in Sikhs: Gm3;5,
,nm1,17;21 ~ ~ 1 , 2 , 1 7 ; 2 ~1 ~ 1 , 1 7 ;~5~ 1 , 1 7 ; 1 5 , 1 6
,
, and Gm1>3;5. These haplotypes
have all been previously reported in Indian populations. The frequencies of the
first four haplotypes resembled the published frequencies for lower-caste Hindus of NW India more than upper-caste Hindus. However, the last two haplotypes have been found only in upper-caste Hindus. The frequency of one of
these, Gn1,17;15316was higher in Sikhs (0.09) than has been reported in any
Indian population with the exception of Parsis (who are descended from Iranians). We speculate that the high frequency of this haplotype may have been
characteristic of some of the Hindu castes in the Punjab from which Sikhs are
descended.
5
7
The populations of India are genetically
diverse, both within and between geographic
regions. Endogamous mating is the rulethat is, spouses are chosen only from within
cultural groups (primarily defined by religion), and often only from within specific
subgroups of these (for example, Hindu
castes). As part of an ongoing project to assess the genetic diversity among strictly defined Indian populations, we previously
reported the GM immunoglobulin allotype
frequencies of upper-caste Hindus from Bengal in northeast India (Ray and Field, 1981).
We now report GM and KM allotype frequencies in the Sikh population of northwest India. Sikhs are a religious sect that arose in
the Punjab about 1500 A.D. Most of the original converts are believed to have been middle to upper-middle caste Hindus, and they
0 1988 ALAN R. LISS. INC.
now comprise more than 10 million people
(Singh, 1983).
GM allotypes are genetically determined
variants in the structure of the heavy
(gamma) chains of the IgG immunoglobulin
class, and KM allotypes are variants in the
structure of the kappa light chains of all immunoglobulin classes. There are only two
common KM allotypes [Km(l, 311, compared
to 18 GM allotypes. Four of the GM allotypes
occur on gamma-1 chains [Glm(l, 2, 3, 17)],
one on gamma-2 chains [G2m(23)],and 13 on
gamma-3 chains [G3m(5,6, 10, 11, 13, 14, 15,
16, 21, 24, 26, 27, 28)1. The locations of the
allotypes are indicated by the prefixes Glm,
G2m, and G3m for gamma-1, gamma-2, and
Received April 2, 1987; revision accepted July 21, 1987.
32
L.L. FIELD, S. SURJE, AND A.K. RAY
gamma-3 chains, respectively. Genes encoding allotypes at each of the three gammachain loci are inherited together in units,
called GM haplotypes. The frequencies of
these GM haplotypes vary dramatically
among ethnic groups (Steinberg and Cook,
1981); and within each ethnic group, only
some of all possible haplotypes that could
arise by recombination between the three loci
actually occur, suggesting that the distribution of haplotypes may reflect the long-term
operation of natural selection. Further support for this suggestion is provided by the
many studies that have shown associations
between GMKM allotypes and susceptibility
to specific diseases, or immune responsiveness to specific antigens (for review, see
Whittingham and Propert, 1986).In the present study, we were interested in GM allotypes as indicators of population genetic
diversity.
Table 1 shows the most common GM haplotypes around the world and the region with
which they are primarily associated. Four of
these haplotypes are polymorphic (frequency
greater than 1%) throughout India: Gm3;5,
~ ~ 1 , 1 7 ; 2~1~ 1 2 , 1 7 ; 2and
1
~ ~ 1 , 1 7 3
field and Kirk, 1981).The frequencies of these
vary in a clinal manner from the northwest
to the southern part of the subcontinent, with
,nm1,17;21 and Gm1*2,17;21increasing in frequency, and Gm3;5 and Gm1.17;5 decreasing
in frequency, as one moves south. The NE
Asian haplotype Gm1,17;15,16 and the SE
Asian haplotype Gm193;5are found a t lower
frequencies and are not found in all populations sampled; the frequency of Km’ does not
show significant variation across India
(Schadield and Kirk, 1981).
grants were from the middle-to-upper economic classes of Indian Sikhs. Since Sikhs
are very conservative in their religious practices, the chance of genetic admixture of nonSikhs into the Indian Sikh population is negligible. We examined eight GM allotypes,
Glm (1,2, 3, 17) and G3m (5, 15, 16, 21), and
one KM allotype, Km(l), in these individuals
using a standard agglutination-inhibition
technique (Steinberg, 1962) adapted for microtitre plates. Allotyping reagents were purchased from the Netherlands Red Cross. Sera
that displayed agglutinating antibodies were
heat-inactivated a t 63°C for 10 min and retyped. Maximum likelihood estimates of GM
haplotype frequencies were calculated by the
computer program MAXLIK (Reed and
Schull, 19681, kindly provided to us by Dr.
T.E. Reed. The gene frequency of Km(1) was
calculated as 1 minus the square root of the
frequency of Km(1) negative individuals.
RESULTS
Two individuals possessed agglutinating
antibodies that could not be heat-inactivated
and were therefore omitted from the analyses. Table 2 shows the GM and KM phenotypes of the remaining 101 individuals. It
also shows the most probable genotypek for
each phenotype, given the results of the haplotype frequency estimation (see below).
In order to estimate haplotype frequencies
efficiently, one must decide which haplotypes
are likely to be present in the sample. The
first five phenotypes listed in Table 2 suggested the presence of the three haplotypes
that are common in Caucasian populations:
Gm3;5 ~ ~ 1 , 1 7 ; 2~1~ 1 , 2 , 1 7 ; (Table
21
1). This is
consistent with Indian populations being
part of a larger “Inao-European” ethnogeoMATERIALS AND METHODS
graphic group. The next three phenotypes
Serum samples were obtained from 103 un- provided ample evidence for the presence of
related Sikhs who have recently migrated the “northeast Asian” haplotype Gm1,17;15,16.
from India to Toronto, Canada. These immi- The phenotypes Gm(1,3,17;5), Gm(1,2,17;5,
9
TABLE 1. GM haplotypes common in various regions
GM haplotype’
~,1,17;5,6,11,24,26
Abbreviation
Predominant
region
Europe
Asia, Europe
Asia, Europe
Asia (NE Asia)
Asia (SE Asia)
Africa
Africa
‘Defined by all known gamma-1 and gamma-3 allotypes (G3m(28) excepted), which are separated by a semicolon
33
GM AND KM ALLOTYPES IN SIKHS
TABLE 2. GM and KMphenotype frequencies in 101 Sikhs
Phenotype'
No.
Probable genotype
21
27
14
Gm (3;5)
Gm (1,3,17;5,21)
Gm (1,2,3,17;5,21)
Gm (1,17;21)
Gm (1,2,17;21)
Grn (1.3.17:5.15.16)
Gm (1,17;15,16,21)
Grn (1,2,17;15,16,21)
Gm (1,3,17;5)
Gm (1,17:5,21)
Gm (1,2,17;5,21)
Grn (1.17:5)
Gm (1;17~5,15,16)
Gm (1,17;15,16)
Grn (1,3;5)
I
,
I
5
9
8
,
7
3
2
0
2
0
1
0
2
TABLE 3. GM haplotype and KM gene frequencies in 101 Sikhs
Haplotypellgene
Estimated
frequency
Standard
error
0.459
0.252
0.149
0.094
0.025
0.021
0.061
0.037
0.031
0.026
0.011
0.021
0.015
Grn3z5
~~1~17.21
~~1,2,17;21
~~1,17;15,16
~~1.17:5
~ ~ 1 3 . 5
Krn'
-
~
'Defined by tested gamma 1 and gamma-3 allotypes, which are separated by a semicolon.
21), and Gm(1,17;5,15,16)suggested the presence of the "African" haplotype Gm1J7;5,
while the phenotype Gm(1,3;5) indicated the
presence of the "southeast Asian" haplotype
Gm1,3;5. All six haplotypes suggested by the
observed phenotypes have been previously reported in Indian populations. We therefore estimated haplotype frequencies allowing for
the presence of these haplotypes. The results
are presented in Table 3; the six GM haplotypes were all polymorphic in this sample of
Sikhs. The observed GM phenotype frequencies (Table 2) did not differ significantly from
the phenotype frequencies expected at HardyWeinberg equilibrium in a population having
the estimated haplotype frequencies (x2(9,
6.8,P= .66).
DISCUSSION
There is only one other published study of
immunoglobulin allotype frequencies in populations of northwestern India that examined as many antigens as the present study
(Schanfeld and Kirk, 1981). The investiga-
tors typed 163 Hindus from the Punjab, Haryana, Delhi, and Western Uttar Pradesh,
broken down into four caste groups: 1) Brahmin (priests), 2) Kshtrya (warriors), which
includes Arora, Khatri, and Rajputs, 3)Vaish
(farmers and merchants), and 4) Shudra
(craftsmen). They suggested that there were
GM differences between castes that mirrored
the north-south frequency gradients of the
subcontinent, with higher castes having
higher frequencies of Gm3;5 and Gm1317;5 and
lower frequencies of Gm1j17;21 and Gm1,2717;21
Since their sample sizes were small, we have
merged the first two castes into a "highercaste" group, and the last two into a "lowercaste" group, for purposes of comparison with
our Sikh sample (Table 4). Sikhs have a
higher frequency of Grn172,17;21 and lower
frequencies of Gm3;5 and Gm1,17;5 than either
of these Hindu samples. Thus, with respect
to these haplotypes, Sikhs resemble the
lower-caste Hindus more than the uppercaste Hindus in the study by Schanfield and
Kirk (1981). Daveau et al. (1980) examined
L.L. FIELD, S. SURJE, AND A.K. RAY
34
TABLE 4. GM hadotvue and KM gene freouencies in Sikhs and other uouulations o f Northwestern India
Sikhs
(n = 101)
(present study)
!,17;21
~~1,17;15.16
~ ~ 1 . 1 7 ; 5
,459
,252
,149
,094
,025
~ ~ 1 , 3 ; 5
,021
Km’
,061
Hindus from NW India’
Higher caste
Lower caste
(n = 98)
(n = 53)
,560
,191
,058
,005
,158
,029
.079
“Punjabis”
(religion not stated)
(n = 101)~
,520
,327
,067
0
,086
0
.087
,396
,279
,142
0
,011
,149
.056
‘Haplotype frequencies for the “higher” and “lower” caste groups were calculated as the mean (weighted by sample size) of the
haplotype frequencies reported in Schanfield and Kirk (1981).
‘Daveau et al. (1980).
GM allotypes in “Punjabis” (religion not
specified),but they did not type the antigens
Glm(17)and G3m(15,16),which help to differentiate the three non-Caucasian haplotypes
from each other (Gm1,’7;15,16, Gm1,17;5,-15-16
when heterozygous with
and ~~1,3,-17;5,-15-16)
the most common haplotype, Gm3;5. Thus,
we do not consider their estimates of the
frequencies of these three haplotypes to be as
reliable as those of Schanfield and Kirk
(1981) or the present study. However, their
frequencies for the common Caucasian haplotypes (Grn3i5, Gm1917i21,and Grn1,2,17;21)and
for Kml were remarkably similar to those we
obtained for Sikhs (Table 4).
The presence of the “African” haplotype
GmlJ7;5 in Sikhs deserves comment. While
this haplotype is most common in Africa, it
has been found in previous studies of Indian
populations (Schanfield and Kirk, 1981; Ray
and Field, 1981; van Loghem et al., 1985).
However, since the Gm1?17;5haplotype in India appears to be most often associated with
the Am’ allele at the closely linked AM locus
(Schadield and Kirk, 1981; Ray and Field,
1981),while that in Africa is usually associated with the Am2 allele, the adjective “African” for Gm’317;5may be a misnomer. The
presence of this haplotype in India, and in
populations to the north of India (Schanfield
et al., 1980), may be very ancient and not
indicative of “admixture” with Africans, as
is sometimes stated.
Schanfeld and Kirk (1981) suggested that
in their samples, the Asian haplotypes
Gm1,17;15,’6and Gm’>3;5appeared to be confined to higher-caste Hindus (Brahmin in the
case of Gm1,17;15716
and Kshtrya in the case
of Gm173;5).The presence of Gm’73;5 in Sikhs
may thus support the historical tradition that
the original converts to Sikhism included
Rajputs (Kshtrya caste).
The frequency of the “northeast Asian”
haplotype Gm1,17;15,16 in Sikhs (0.094) is the
highest reported frequency of that haplotype
in any Indian population, with the exception
of Parsis, who are descended from Iranians
and whose Gm1717;15916
frequency was 0.121
in a study by Steinberg and colleagues (1973).
As noted above, Schanfield and Kirk (1981)
found this haplotype in Hindus only amongst
the Brahmin caste. It is not very likely that
the high frequency of GmlJ7;15,16 in Sikhs
was created by a founder effect, since the
number of original converts to Sikhism was
not small. However, it is possible that the
high frequency of this haplotype may have
been characteristic of some of the Hindu
castes in the Punjab from which Sikhs are
descended. Larger samples from the various
Hindu caste groups in that region are needed
to provide more information relevant to that
possibility.
ACKNOWLEDGMENTS
We thank Rose Tobias for performing
the immunoglobulin allotyping and Carol
Sproule for preparing the manuscript.
LITERATURE CITED
Daveau, M, Rivat, L, Lalouel, JM,Langaney, A, Roberts,
DF, and Simons, MJ (1980)Frequencies of Gm and Km
allotypes in the population of Singapore, Sri Lanka
and Punjabis in North India. Hum. Hered. 30:237-244.
Ray, AK, and Field, LL (1981) Immunoglobulin (Gm)
allotypes in a sample of upper-caste Hindus from Bengal, India. Hum. Hered. 31:358-362.
Reed, TE, and Schull, WJ (1968) A general maximum
likelihood estimation program. Am. J. Hum. Genet.
20579-580.
Schanfield, MS, and Kirk, RL (1981) Further studies on
GM AND KM ALLOTYPES IN SIKHS
the immunoglobulin allotypes (Gm, Am, and Km) in
India. Acta Anthropogenet. 6:l-21.
Schanfeld, MS, Alexeyeva, TE, Crawford, MH (1980)
Studies on the immunoglobulin allotypes of Asiatic
populations. VIII. Immunoglobulin allotypes among
the Tuvinians of the USSR. Hum. Hered. 30:343-9.
Singh, H (1983) The Heritage of the Sikhs. Columbia,
MO: South Asia Books.
Steinberg, AG (1962) Progress in the study of genetically
determined human y-globulin types (the Gm and Inv
groups). Prog. Med. Genet. 2 - 3 3 .
Steinberg, AG, and Cook, CE (1981) The Distribution of
35
the Human Immunoglobulin Allotypes. Oxford Oxford University Press.
Steinberg, AG, Undevia, JV,and Tepfenhart, MA (1973)
Gm and Inv studies of Parsis and Irani in India: Report
of a new polymorphic haplotype Grn'93921.
Am. J. Hum.
Genet. 25:302-9.
Van Loghem, E, Tauszik, T, Hollan, S, and Nijenhuis,
LE (1985) Immunoglobulin allotypes in Hungarian
gypsies. J. Immunogenet. 12131-137.
Whittingham, S, and Propert, DN (1986) Gm and Km
allotypes, immune response, and disease susceptibility. Monogr. Allergy 19:52-70.
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