HLA haplotypes in Singapore: a study of mothers and their cord blood units

During 2005, a total of 174 cord blood units with their paired maternal samples from the Singapore Cord Blood Bank were typed for HLA-A, -B, -C at intermediate resolution and DRB1 at allelic resolution. Analysis of allele segregation in mother and child assigned 185 different four locus (HLA-A, -B, -C, -DRB1) haplotypes in Chinese, 66 in Malays, and 34 in Asian Indians. Very few four locus haplotypes were shared among population groups. To evaluate the frequencies of four locus haplotypes, the Expectation Maximization algorithm was used with HLA assignments from 536 unrelated Chinese volunteers from the Singapore Bone Marrow Donor Program registry. The paired maternal and cord blood study identified 75 different B-C associations in Chinese, 52 in Malays, and 24 in Asian Indians. Common B-C associations may be shared among population groups; for example, B*4001g-Cw*0702g was common in Chinese and Malays, whereas B*1502g-Cw*0801g and B*3501g-Cw*0401g were found in all three groups. The high diversity of four locus haplotypes originates from multiple combinations of both HLA-A and -DRB1 alleles with each B-C haplotype.     

Genetic affinities of north and northeastern populations of India: inference from HLA-based study

India is like a microcosm of the world in terms of its diversity; religion, climate and ethnicity which leads to genetic variations in the populations. As a highly polymorphic marker, the human leukocyte antigen (HLA) system plays an important role in the genetic differentiation studies. To assess the genetic diversity of HLA class II loci, we studied a total of 1336 individuals from north India using DNA-based techniques. The study included four endogamous castes (Kayastha, Mathurs, Rastogies and Vaishyas), two inbreeding Muslim populations (Shias and Sunnis) from north India and three northeast Indian populations (Lachung, Mech and Rajbanshi). A total of 36 alleles were observed at DRB1 locus in both Hindu castes and Muslims from north, while 21 alleles were seen in northeast Indians. At the DQA1 locus, the number of alleles ranged from 11 to 17 in the studied populations. The total number of alleles at DQB1 was 19, 12 and 20 in the studied castes, Muslims and northeastern populations, respectively. The most frequent haplotypes observed in all the studied populations were DRB1*0701-DQA1*0201-DQB1*0201 and DRB1*1501-DQA1*0103-DQB1*0601. Upon comparing our results with other world populations, we observed the presence of Caucasoid element in north Indian population. However, differential admixturing among Sunnis and Shias with the other north Indians was evident. Northeastern populations showed genetic affinity with Mongoloids from southeast Asia. When genetic distances were calculated, we found the north Indians and northeastern populations to be markedly unrelated.     

Molecular diversity of HLA-A*02 in Asian Indians: predominance of A*0211

The North Indians are considered predominantly Caucasoid with an admixture of genes from the Mongoloid and Aryan races. The present study was undertaken to investigate the genetic diversity of HLA-A*02 in the North Indian population and determine the frequency distribution of its molecular subtypes at the population level. The study revealed a high occurrence of A*0211 (33.8%) in this population along with increased frequencies of the common Oriental alleles, A*0206 (7.5%) and A*0207 (32.5%) and also of HLA-A*0205 (15%) commonly observed in negroid populations. HLA-A*0211 has only been reported with very low frequencies among the Ticuna Jews, Thai population, and Colombian Blacks in the malaria endemic areas of Africa. Significantly, we observed an unexpectedly low frequency of A*0201 (3.8%) in contrast to its distribution in Western Caucasians in whom it constitutes 95% of the HLA-A2 repertoire. Prevalence of HLA-A*0211 at very high frequencies among North Indians may be a consequence of the founder effect, racial admixture or selection pressure due to environmental factors in this population.     

中国汉族两群体HLA-DQA1基因的遗传构成及有关15群体DQA1基因频率的比较分析

以HLA基因的PCR-RFLP分型方法研究了哈尔滨地区(Hans-H,71例)和上海地区(Hans-S,98例)两个汉族群体HLA-DQA1座位的遗传多态性。共检出8种等位基因。两群体均以DQA1*0301频率最高,而*0401最低(哈尔滨群体未检出),频率分布符合Hardy-Weinberg平衡。综合分析华人12群体及日本人、高加索人和尼格鲁人等3群体的HLA-DQA1的基因频率显示:卡方总体检验Hans-H及Hans-S与北方华人其它4群体(除维族)间相互无显著差异(P>0.05)),但逐项检验群体间多存在一个至几个基因频率的显著差异(P<0.05～0.001)。总体检验北方华人6群体(包括Hans-S)与南方5群体间均有显著差异(P<0.05～0.001),但满族与南方汉人3群体总体检验无显著差异(P>0.05),而维族与北方华人6群体则有显著差异(P<0.05～0.001)。另外,华人与异族间总体均有非常显著差异(P<0.001),但相对而言,华人(尤其是北方人)与日本人最为接近,华人与高加索人相似性较大,与尼格鲁人差异最大,而高加索人与尼格鲁人差异也较小。并对上述结果进行了讨论。     

Alpha 1-protease inhibitor (PI) subtypes in seven populations of east Asia

The distribution of serum alpha 1-protease inhibitor (PI) or alpha 1-antitrypsin (alpha 1AT) subtypes was determined by thin-layer isoelectric focusing in a group of 1233 individuals from six Mongoloid populations of East Asia and Dravidian Indians. The sample comprised 385 Chinese from Singapore and 151 Chinese from the Fujien province; 126 Malays; 243 Filipinos; 112 Thais; 56 Koreans and 160 Dravidian Indians. The frequency of PiM1 ranged from 0.65 in the Thais to 0.81 in the Fujien Chinese. The highest frequency of PiM2 was found in the Dravidian Indians (0.28) followed by the Thais (0.25). The frequency of PiM3 was found to vary from 0.03 to 0.07 in these populations. A low frequency of PiF (0.01 to 0.02) and PiS (0.01 to 0.04) was also observed in the Mongoloid populations but absent in the Indians. The PiZ allele was completely absent in all these populations. The phenotypic distribution of PI subtypes was at Hardy-Weinburg equilibrium in all the populations.     

Ethnic variation in the impact of metabolic syndrome components and chronic kidney disease

ObjectiveTo examine the ethnic differences in the association between metabolic syndrome components and CKD in Asian populations.MethodsWe analyzed data from three independent populations in Singapore representing the three major Asian ethnic groups (n = 3167 Chinese, 3082 Malays and 3228 Indians) aged 40–80 years. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m². Factor analysis of metabolic syndrome components was conducted and factor scores were used as independent variables in multivariable logistic regression models.ResultsThe prevalence of CKD was highest among Malays (21.0% vs. 7.4%, 5.9% in Indians and Chinese). Factor analysis identified three factors among Chinese (glycemia, blood pressure [BP], and obesity/lipid) and Malays (glycemia, BP, and lipids) accounting for 70% of the variance and four factors (glycemia, BP, lipids, and obesity) among Indians accounting for 82% of the variance. Glycemia was positively associated with CKD in all three ethnic groups. BP was positively associated with CKD among Malays (OR [95% CI] of 1.16 [1.06–1.28]), whereas it showed an inverse association among Chinese (0.84 [0.71–0.99]) and Indians (0.84 [0.73–0.97]). However, this inverse association lost significance after adjusting for antihypertensive medication use in Chinese and Indians. Obesity/lipids among Chinese and obesity among Indians showed a positive association; lipids showed an inverse association among Malays.ConclusionsThese data suggest that while hyperglycemia was associated with CKD in all three ethnic groups, the impact of BP, lipids, obesity on CKD varies across ethnic groups. Understanding the specific associations may allow greater understanding of how CKD develops in different racial/ethnic groups.     

Associations between HLA class II alleles in a North Indian population

Abstract: The HLA DR and DQ class II genes are in strong linkage disequilibrium and recombinaton is quite rare. However, many different DR-DQ haplotypes appear to have developed during evolution, giving rise to a variety of combinations with different distributions in populations. In the present report, 138 subjects from North India were studied for the alleles of HLA-DRB1, DRB3, DRB5, DQB1 and DQA1 loci using PCR-oligotyping. The probable haplotypes were constructed based on two-locus associations observed in this population. A frequent haplotype in this population, DRB1*1501-DRB5*0101-DQA1*0103-DQB1 *0601, has been reported very rarely in other ethnic groups. Other DR2 haplotypes, like DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0601, earlier reported in Caucasians, Chinese and Latin Americans, and DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0503, earlier reported in Gypsies, were also observed. A relatively rare haplotype in Caucasians which was earlier reported in Gypsies from the Czech Republic, DRB1*1404-DRB3*0202-DQA1*0101-DQB1*0503, was observed frequently in Indians, suggesting the probable migration of Gypsies from India. The results suggest that the North Indian population contains a mixture of Caucasoid, Black and Chinese genes. Similarities with Gypsies and South-East Asian populations suggest the role of ancient migrations from India.     

Molecular diversity of HLA-A, -B and -C alleles in a North Indian population as determined by PCR-SSOP

We have used molecular methods to determine the frequencies of human leukocyte antigen (HLA)-A, -B and -C alleles in normal, healthy, unrelated individuals from North India using polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes as there is no comprehensive report showing molecular diversity of all the class-I alleles present in North Indians. A*0101, A*0206, A*0301, A*1101, A*6801, A*2401 and A*3101 were the most prevalent alleles of the A locus with 91.11% of the samples showing heterozygosity. At the HLA-B locus a total of 47 B locus alleles were observed and the only allele found with an allele frequency of 15% was B*5801. Other frequent B-locus alleles observed were B*5101, B*3503 and B*4006 with relatively less frequent alleles like B*5201, B*3501, B*0702, B*4403, B*5701, B*1801 and B*5501. Of the samples studied 92.31% were heterozygous for B-locus alleles. Cw*0602 and Cw*0401 were the most frequent C-locus alleles. Other frequent C-locus alleles were Cw*0102, Cw*0302, Cw*0701, Cw*0702, Cw*1202, Cw*1203, Cw*1502 and Cw*1503. HLA alleles common in Africans like B*5801, A*68012, B*5301, B*44032, B*4006 and Cw*1701 were observed in the North Indians besides oriental alleles like B*1301, B*1502 and B*4001 confirming that the genetic make-up of North Indians is Caucasoid with elements of Mongoloid and Negrito races. Some new/rare alleles like B*1802, described as a new allele from Thailand and B*8101, described earlier in a Bubi population were also observed although with low frequencies, showing the diversity of HLA class-I alleles present in the North Indians.     

The TaqIB and -629C>A polymorphisms at the cholesteryl ester transfer protein locus: associations with lipid levels in a multiethnic population. The 1998 Singapore National Health Survey

The Singapore population comprises Chinese, Malays and Asian Indians. Within this population, Asian Indians have the highest rates of coronary heart disease, whereas Chinese have the lowest. Conversely, Indians have the lowest high-density lipoprotein cholesterol (HDL-C) concentrations, followed by Malays and Chinese. We studied the TaqIB and -629C>A polymorphisms at the CETP locus in 1300 Chinese, 364 Malay and 282 Asian Indian men, and in 1558 Chinese, 397 Malay and 306 Asian Indian women, to determine whether these polymorphisms are responsible for the ethnic difference in HDL-C concentration. The frequency of the B2 allele in Chinese, Malays and Indians was 0.384, 0.339 and 0.449 in men, and 0.379, 0.329 and 0.415 in women, respectively (p < 0.001). For the A-629 allele, the relative frequencies were 0.477, 0.423 and 0.592 in men and 0.486, 0.416 and 0.575 in women (p < 0.001). The two polymorphisms were in linkage disequilibrium (D / Dmax= 0.9772, p < 0.00001). The B2 and the A-629 alleles were associated with increased HDL-C concentrations in a dose-dependent manner. The B2 allele continued to show an association with HDL-C concentration, even after controlling for the genotype at position -629. Dietary cholesterol showed a significant interaction with the TaqIB polymorphism in determining HDL-C concentrations in Indians and Malays, but not in Chinese. In conclusion, the high frequencies of these polymorphisms in Asian Indians could not explain the observed ethnic differences in HDL-C concentration. Moreover, we observed an ethnic-specific interaction among dietary cholesterol, the TaqIB polymorphism and HDL-C concentrations.     

The Distribution of HL—A Leukocyte Antigens in Singapore Chinese, Malays, and Indians

The distribution of 19 HL—A antigens was studied in three ethnic groups in Singapore: Chinese, Malays, and Indians. Two antigens (one from each HL—A locus) were found to be significantly more frequent in each ethnic group when compared to the other two ethnic groups. These antigens were HL—A11 and W10 in Chinese, HL—A9 and W15 in Malays, and HL—A1 and W17 in Indians. The antigens HL—A10, HL—A8, and W14 had a low frequency in the three ethnic groups. The virtual absence of HL—A1 in Chinese, low frequency in Malays, and high frequency in Indians support the suggestion that this antigen is a "Caucasian" antigen.
The presence of linkage disequilibrium between the two HL—A loci was investigated by the calculation of delta values. No significant delta values were found in the Malays whereas the Chinese and Indians showed significant values for the antigen combinations HL—A2.12, HL—A9.5, HL—A9.W17, HL—A11.W15 (Chinese) and HL—A1.W17, HL—A2.W17, HL—A3.W5 (Indians).
It is suggested that the HL—A system of leukocyte antigens should be an important genetic marker in the study of origins and relationships between ethnic groups.     

洛阳地区汉族HLA—DRB1^＊04等位基因的PCR—SSO分型

对河南洛阳地区汉族进行了ＨＬＡ－ＤＲＢ１＊０４等位基因的ＰＣＲ－ＳＳＯ分型，采用第１２届国示组织相容性专题讨论会推荐的引物和序列特异性寡核苷酸探针，可检测１７个ＤＲＢ１＊０４组特异性等位基因，在１１６份无血缘关系健康人ＤＮＡ村洒中有１６份为ＤＲＢ１＊０４，其中１份为纯合，ＤＲＢ１＊０４的基因频率为０．０７１５。ＤＲＢ１＊０４等位基因分布于５个不同的型别，分别是ＤＲＢ１＊０４０１、０４０３、０４０４     

DISTRIBUTION OF HLA-A*28 ALLELES IN A SPANISH POPULATION

DNA oligotyping was used to determine HLA-A28 subtypes in 25 unrelated Caucasian individuals living in or around Seville, Spain. Results showed that HLA-A*6802 was the most frequent allele, found in 14 individuals (53.8%), followed by HLA-68.3, which was present in eight subjects (30.8%), and both combined represented 84.6% of A28⁺ individuals in the area. The HLA-A*6801 allele was found in three individuals (11.5%), whereas HLA-A*6901 was present in one subject only (3.8%). Results indicate that the distribution of HLA-A28 alleles can vary among different Caucasoid populations. In this way, the high frequency obtained for A*6802 supports previous studies suggesting that the HLA-A*6802 allele was prevalent in people of the Mediterranean basin, in contrast to A*6801, prevalent in northern European populations.     

DQB1 Exon2 and promoter allele frequencies and haplotypes in native American Indians and a German Caucasoid population.

In order to investigate the distribution of the DQB1 promoter (QBP1) alleles and their linkage with the structural portion of the DQB1 gene, a comparative population-based study in native American Indians (Zapotecs) and a German Caucasoid population was carried out by PCR-SSO and -SSP typing. 215 healthy, unrelated German individuals and 66 healthy Zapotecs were analysed for the distribution and linkage of DQB1 and QBP1 alleles. Among the Zapotec population 9 out of 12 known QBP1 alleles were found. In 6 Zapotec individuals unsual hybridisation patterns suggestive of new QBP1 alleles were observed. In Zapotecs as well as in Germans a tight linkage between the promoter region and exon 2 of DQB1 was observed. Exceptions were seen for DQB1^*0501, ^*0603 and ^*0604 in Germans and ^*0501 in Zapotecs. Marked differences in allele frequencies between Germans and Zapotecs are seen mainly for DQB1^*0201, ^*0602, ^*04 and ^*0302. It is concluded that population-specific differences in haplotype frequencies exist, while linkage disequilibrium is maintained.     

Genetic Association in Myocardial Infarction: Ethnicity; ABO, Rh, Lea, Xga Blood Groups; G6PD Deficiency; and Abnormal Haemoglobins

Four hundred and eighty-six patients with myocardial infarction of both sexes comprising 213 Chinese, 53 Malays, 199 Indians, and 21 Europeans, resident in Singapore were investigated for differences in relative incidence, and for the ABO, Rh, Le^a, and Xg^a blood groups, G6PD deficiency, and haemoglobin types. Relative incidence of myocardial infarction was appreciably higher among Indians than Chinese and Malays in all age groups, more so in younger people. There was no significant difference in the distribution of the genetic markers between patient and control series in either Chinese, Malays, or Indians.     

Inference from the relationships between linkage disequilibrium and allele frequency distributions of 240 candidate SNPs in 109 drug-related genes in four Asian populations

The extensive nucleotide diversity in drug-related genes predisposes individuals to different drug responses and is a major problem in current clinical practice and drug development. Striking allelic frequency differences exist in these genes between populations. In this study, we genotyped 240 sites known to be polymorphic in the Japanese population in each of 270 unrelated healthy individuals comprising 90 each of Malaysian Malays, Indians, and Chinese. These sites are distributed in 109 genes that are drug related, such as genes encoding drug-metabolizing enzymes and drug transporters. Allele frequency and linkage disequilibrium distributions of these sites were determined and compared. They were also compared with similar data of 752 Japanese. Extensive similarities in allele frequency and linkage disequilibrium distributions were observed among Japanese, Malaysian Chinese, and Malays. However, significant differences were observed between Japanese and Malaysian Chinese with Malaysian Indians. These four populations were grouped into two genetic clusters of different ancestries. However, a higher correlation was found between Malaysian Malays and Indians, indicating the existence of extensive admixture between them. The results also imply the possible and rational use of existing single nucleotide polymorphism databases as references to assist future pharmacogenetic studies involving populations of similar ancestry.     

The allele frequencies of three polymorphisms in genes involved in homocysteine metabolism in a group of unrelated healthy Singaporeans

The cystathionine β-synthase (CBS) 844ins68 polymorphism, methionine synthase (MS) A2756G SNP, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T SNP are associated with homocysteine (Hcy) level in humans. Elevated Hcy level is considered a risk factor for atherosclerotic diseases among Asian populations. Therefore, the three polymorphisms may vary the risk for developing such diseases in Singaporeans. In this study, the three polymorphisms were determined in a group of unrelated healthy Singaporeans (273 Chinese, 127 Indians, and 156 Malays). Regarding allele frequencies, Indians had the highest frequencies of the CBS insertion allele (2.0%) and the MS 2756G allele (26.4%), while Chinese had the highest MTHFR 677T allele frequency (27.5%). In addition, the MTHFR 677T allele was found significantly lower in Chinese males than in their female counterparts. As the CBS insertion allele was suggested to be associated with lower Hcy level, whereas the MS 2756G allele and the MTHFR T/T genotype were related to higher Hcy level, the MS A/G or G/G genotype and the MTHFR T/T genotype were considered double genetic risk factors for elevated Hcy level. The frequency of such double genetic risk was 0.7% (4 subjects) in the total population consisting of 3 Chinese (1.1%) and 1 Malays (0.6%). No MTHFR T/T genotype was found in Indians. Such results suggested that Chinese could have higher Hcy levels than Malays while the situation for Indians was complicated. Since human Hcy levels are also affected by environmental factors, further studies are required to better evaluate the association between these three polymorphisms and Hcy levels and/or disease susceptibilities in Singaporeans.     

Defining the allelic variants of HLA A19 in the western Indian population

The population of western India is described as Australoid or proto-Australoid (elements) with Indo-Aryan racial admixture. The present study was undertaken to investigate the genetic diversity of human leukocyte antigen (HLA A19) in Western Indians, and to determine the frequency distribution of its molecular subtypes at the population level. The study revealed a high occurrence of A*3303 (56%) in this population along with other common oriental alleles. A*33 has been commonly observed in Asian Indians (18.1%), Hanza-Burush (15.7%), Punjabis (13.9%), and Japanese (11.2%) populations. A*33 has been reported with low frequencies among the Australasians, East European (Czech), North African (Noba), and Eastern Europeans (Slovenian). Significantly we observed a low frequency of A*29 and A*74 when compared with other populations among the A19 repertoire. Prevalence of HLA A*3303 at very high frequencies among Western Indians may be a consequence of the founder effect, racial admixture, or selection pressure due to environmental factors among this population.     

Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups

Systemic lupus erythematosus (SLE) has shown associations with the major histocompatibility complex (MHC) class II DR antigens and class III complement components C2 and C4 in previous studies. The primary susceptibility locus has been difficult to identify, however, on account of linkage disequilibrium within the MHC. We have studied C4A and C4B distributions in 63 Caucasoid, 75 Chinese and 51 Japanese SLE patients. All three populations showed a statistically significant increase in C4A*Q0 (null) alleles when compared with 323 ethnically matched controls. We conclude that complete or partial deficiency of C4A is a genetic determinant of SLE common to these three ethnically distinct populations.     

Genetic variability of Apolipoprotein E in different populations from Venezuela

The genetic variation at the Apolipoprotein E locus (APOE) is an important determinant of plasma lipids and has been implicated in various human pathological conditions. The objective of the present study was to estimate the distribution of APOE alleles in five Venezuelan communities: two Amerindian tribes (Bari and Yucpa), one Negroid population from Curiepe, one Caucasoid population from Colonia Tovar and the Mestizo urban population living in Caracas. The APOE*3 allele was the most common allele in all populations studied. However, a significant increase in the APOE*2 allele frequency in the Mestizo (18.96%) and Negroid (16.25%) populations was found. Similar to results reported in other Native American populations we have found that the APOE*2 allele is completely absent in the Bari and Yucpa Amerindians. Frequencies found in the Colonia Tovar population are in agreement with those reported in the population of Germany, indicating a high degree of relatedness. The results support the notion that the distribution of the APOE alleles shows ethnic variability.     

HLA-DRB1*01 and DRB1*04 alleles in Sardinian rheumatoid arthritis patients

In Sardinia, like in other Caucasoid populations, rheumatoid arthritis (RA) is significantly associated with HLA-DR4 and DR1 antigens. To discover which DR4 and DR1 alleles were associated with the disease we selected 22 Sardinian patients affected by RA. Fifty DR4+ and 28 DR1+ healthy individuals coming from the same geographical area were used as controls. In the Sardinian patients only two DRB1*04 alleles were observed: DRB1*0405 in 11 and DRB1*0403 in three patients. The DRB1*0102 allele was observed in two patients and DRB1*0101 in six patients. Hereditary predisposition to RA in Sardinia therefore seems to be almost exclusively associated with the DRB1*0405 and DRB1*0101 alleles which share the 67LLEQRRAA74-85VG86 epitope in the peptide binding groove.