New HLA-C alleles identified in minority populations

Twenty new human leukocyte antigen C alleles identified in 2200 minority individuals characterized by sequence-based typing.     

Polymorphism and distribution of HLA-DR2 alleles in Mexican populations

DRB1*15/16 nucleotide polymorphism was analyzed in 68 DR2 positive individuals (18 Mexican Mestizos, 30 Mazatecans and 20 Nahuas), carrying a total of 75 DR2 haplotypes. HLA-DR2 was one of the most frequent specificities detected in Mazatecans and Nahuas with gene frequency (gf) of 0.232 and 0.141, respectively. In these populations DRB1*16 was the most frequent DR2 split (gf = 0.183 in Mazatecans and gf = 0.135 in Nahuas), whereas in Mexican Mestizos the most frequent was DRB1*15 (gf = 0.065). Four DRB1-DQB1 combinations in Mexican Mestizos, two in Mazatecans and one in Nahuas were in linkage disequilibrium. In spite of the restricted polymorphism, there were differences on DRB1*15/16 alleles found in Mexicans. DRB1*1501 a Caucasian allele was predominant in Mexican Mestizos, whereas DRB1*1602 an Amerindian allele was characteristic on Indian populations. An important difference was detected among the Amerindian populations studied since DRB1*1502 was only present in Mazatecans. This data corroborates the restricted polymorphism of DRB1*15/16 and the high frequency of DRB1*16 subtype in autochthonous American populations and suggest that the differences in gene frequencies of DRB1*15/16 alleles could be helpful in distinguishing each of these population.     

Novel thymidylate synthase enhancer region alleles in African populations

Thymidylate synthase (TS) regulates the production of DNA synthesis precursors and is an important target of cancer chemotherapy. A polymorphic tandem repeat sequence in the enhancer region of the TS promoter was previously described, where the triple repeat gives higher in vitro gene expression than a double repeat. We recently identified ethnic differences in allele frequencies between Caucasian and Asian populations. We now describe assessment of genotype and allele frequencies of the TS polymorphism in 640 African (African American, Ghanaian and Kenyan) and Caucasian (UK, USA) subjects. The double and triple repeat were the predominant alleles in all populations studied. The frequency of the triple repeat allele was similar between Kenyan (49%), Ghanaian (56%), African American (52%), American Caucasian (54%) and British Caucasian (54%) subjects. However, two novel alleles contained 4 and 9 copies of the tandem repeat. These novel alleles were found at a higher allele frequency in African populations (Kenyan 7%, Ghanaian 3%, African American 2%) than Caucasians (UK 1%, USA 0%). The novel alleles identified in this study decrease in frequency with Western migration, while the common alleles are relatively stable. This is a unique example suggesting the influence of multiple selection pressures within individual populations. Hum Mutat 16:528, 2000.     

Life expectancy in British Marfan syndrome populations

A total of 206 patients with Marfan syndrome were ascertained throughout genetic clinics in Wales and Scotland during the period 1970–1990. There were 45 deaths representing 22% of the cohort. Mean age at death was 45.3 ± 16.5 years. 50% median cumulative survival in the total cohort (n = 206) was 53 years for males and 72 years for females. Multivariate analysis confirmed severity as the best independent indicator of survival. These findings and survival curves will assist in the counselling of British families and individuals with Marfan syndrome.     

Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

The evolutionary origin of genetic diversity in the SLAM/CD2 gene cluster, implicated in autoimmune lupus susceptibility in mice, was investigated by sequence analysis of exons from six members of the cluster in 48 wild mouse samples derived from the global mouse population. A total of 80 coding region SNPs were identified among the six genes analyzed, indicating that this gene cluster is highly polymorphic in natural mouse populations. Phylogenetic analyses of these allelic sequences revealed clustering of alleles derived from multiple Mus species and subspecies, indicating alleles at several SLAM/CD2 loci were present in ancestral Mus populations prior to speciation and have persisted as polymorphisms for more than 1 million years. Analyses of nonsynonymous/synonymous ratios using likelihood codon substitution models identified several segments in Cd229, Cd48 and Cd84 that were impacted by positive diversifying selective pressures. These findings support the interpretation that selection favoring the generation and retention of functional polymorphisms has played a role in the evolutionary origin of genetic polymorphisms that are predisposing to autoimmunity.     

Diversity of alleles encoding HLA-B40: relative frequencies in united states populations and description of five novel alleles

The frequency of each B*40 allele was determined by DNA sequencing in four major United States populations: Caucasians, African Americans, Asians/Pacific Islanders, and Hispanics. Thirty-two individuals from each ethnic group, who were previously described serologically as B40, B60, or B61, were randomly selected out of a pool of 82,979 unrelated individuals for allele characterization. Out of nine different B*40 alleles identified in this study, B*4001 and B*4002 were the two most frequent B*40 alleles in all the population groups. B*4001 was the primary B*40 allele seen in Caucasians (83%) and African Americans (76%), while B*4002 was found in the majority of Hispanics (62%). The distributions of both alleles were comparable in the Asian/Pacific Islander population. These two alleles were the only B*40 alleles detected in Caucasians while four to five additional B*40 alleles were seen in the other population groups. The other B*40 alleles detected in this study included: B*4003 and B*4010 in Asian/Pacific Islanders; B*4012 and B*4016 in African Americans; and B*4004, B*4006, and B*4027 in Hispanics. Analysis revealed significant differences between Hispanics and all other groups as well as between African Americans and Asian/Pacific Islanders. This report also describes five novel B*40 alleles: B*4019, B*4020, B*4024, B*4027, and B*4028.     

ABH secretion in populations of the British Isles

Saliva specimens were collected from 163 Manx and 994 Cumbrian individuals and tested for secretor group. The findings confirm the pattern of variability in non-secretor frequencies reported in populations of the British Isles. A possible explanation for this distribution of secretor groups is suggested. The Cumbrian sample is also examined for intra-regional heterogeneity.     

Distribution of HLA alleles and haplotypes in Jinuo and Wa populations in Southwest China

The frequencies of human leukocyte antigen (HLA) alleles HLA-A, -B, and -DRB1 alleles and A-B-DRB1, A-B, and B-DRB1 haplotypes were studied in Jinuo and Wa populations in Southwest China using the polymerase chain reaction-Luminex (PCR-Luminex) typing method. A total of 12 A, 22 B, and 16 DRB1 alleles were found in the Jinuo population, and 10 A, 28 B, and 18 DRB1 alleles were found in the Wa population. The A*110101-B*1502-DRB1*120201 was the predominant haplotype in both the Jinuo and Wa populations; A*110101-B*1301-DRB1*120201 and A*24020101-B*1502-DRB1*120201 were common in the Jinuo population, whereas A*110101-B*1532-DRB1*1504 and A*110101-B*350101-DRB1*1404 were common in the Wa population. Phylogenetic tree and principal component analyses based on HLA-A, -B, and -DRB1 allele frequencies suggested that both the Jinuo and Wa populations belong to the Southeast Asian group, whereas Wa population is still maintaining its original genetic character and a great distance from other populations because of a founder effect and subsequent geographic isolation. A close relationship among Jinuo, Wa, Thai, and Vietnamese was also suggested.     

Distribution of ITPA P32T alleles in multiple world populations

Dose-limiting toxicity from azathioprine treatment affects up to 37% of patients. Screening for thiopurine methyltransferase (TPMT) polymorphisms will prospectively identify approximately 10% of patients. Recently, a polymorphism in the inosine triphosphate pyrophosphatase gene (ITPA) has been associated with severe azathioprine toxicity. We demonstrate here that this proline to threonine substitution at codon 32 in the ITPA gene is found at low frequency in Central/South American populations (1–2%), at a constant frequency across Caucasian and African populations (6–7%), and is highest in Asian populations (14–19%). This data is consistent with previously described allele frequencies in other Caucasian (7%), African (5%), and Asian (11–15%) populations. This data provides a foundation on which prospective screening studies can be planned to identify patients at risk for severe toxicity from azathioprine therapy.     

Prevalence of clinically relevant UGT1A alleles and haplotypes in African populations

Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8) )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n) . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.     

HLA-B and HLA-C alleles and haplotypes in the Dravidian tribal populations of southern India

The Dravidians are believed to be the earliest inhabitants of India. Their subsequent migration and admixture with invading racial groups has been of scientific interest for population geneticists. In the present study, seven highly endogamous and extremely isolated colonies of Dravidian tribal populations (n = 105) from Kerala in South India were analysed and compared with random non-tribal Dravidian (RND) samples (n = 78) of southern India using the polymerase chain reaction with sequence-specific primer method for HLA-B and HLA-C typing. The tribal group comprises Adiya, Kanikkar, Kattunaikka, Kuruma, Kurichiya, Malapandaram and Paniya, while the RND group includes Malayalam-speaking individuals from various non-tribal castes of Kerala selected randomly. Some of the most frequent HLA-B alleles in the RND population were similar to the North Indian population and included B*07, B*61 (B*40), B*44, B*51, B*35 and B*52. Although B*61 was the most frequent allele in our total study population, the frequency fluctuated in individual populations. HLA-Cw*14 was one of the most frequent alleles while HLA-Cw*17 was totally absent in all populations studied. The haplotype B*61-Cw*14 was present in all the study groups except in Kurichiya, and the haplotype B*51-Cw*14 was only absent in Kattunaikka. Phylogenetic tree and correspondence analysis indicate that all the Dravidian tribal communities group together as a separate cluster, while the RND group of individuals from South India lie close to the North Indian population. This suggests that the RND population of South India might have a crypto-Dravidian origin, while the smaller Dravidian tribal communities have a distinct Dravidian origin.     

Analysis of the distribution of HLA-A alleles in populations from five continents

The variation and frequency of HLA-A genotypes were established by PCR-SSOP typing in diverse geographically distributed populations: Brazilian, Colombian Kogui, Cuban, Mexican, Omani, Singapore Chinese, and South African Zulu. HLA-A allelic families with only one allele were identified for HLA-A*01, -A*23, -A*25, -A*31, -A*32, -A*36, -A*43, -A*69, -A*80; and with two alleles for HLA-A*03, -A*11, -A*26, -A*29, -A*33, -A*34, and -A*66. Greater variation was detected for HLA-A*02, -A*24, and -A*68 allele families. Colombian Kogui and Mexican Seris showed the least diversity with respect to HLA-A alleles, albeit with small numbers tested, with only four and five HLA-A alleles identified, respectively. It would appear by their presence in all populations studied, either rural or indigenous, that certain alleles are very important in pathogen peptide presentation.     

Analysis of the distribution of HLA-B alleles in populations from five continents

A two stage PCR-SSOP typing procedure, that permitted HLA-B allele assignment, was applied to DNA samples obtained from six diverse populations -Brazilian, Mexican (Series and Mestizos), Cuban (Caucasoid and Mulatto), South African Zulu, Omani, and Singapore Chinese. HLA-B allele frequencies and HLA-A/B two locus haplotype frequencies were compiled for each population.     

Distribution of CGG repeats and FRAXAC1/DXS548 alleles in South American populations

In order to assess the molecular variability related to fragile X (FMR1 locus), we investigated the distribution of CGG repeats and DXS548/FRAXAC1 haplotypes in normal South American populations of different ethnic backgrounds. Special attention was given to Amerindian Wai-Wai (Northern Brazil) and Ache (Paraguay), as well as to Brazilian isolated communities of African ancestry, the remnants of quilombos. Comparison of samples from quilombos, Amerindians, and the ethnically mixed, but mainly European-derived population of S?o Paulo revealed that the 30-copy allele of the fragile X gene is the most frequent in all groups. A second peak at 20 repeats was present in the population of S?o Paulo only, confirming this as a European peculiarity. The distribution of DXS548 and FRAXAC1 alleles led to a high expected heterozygosity in African Brazilians, followed by that observed in the population of S?o Paulo. Amerindians showed the lowest diversity in CGG repeats and DXS548/FRAXAC1 haplotypes. Some rare alleles, for example, the 148-bp (FRAXAC1) or 200-bp (DXS548) variants, which seem to be almost absent in Europe, occurred in higher frequencies among African Brazilians. This suggests a general trend for higher genetic diversity among Africans; these rarer alleles could be African in origin and would have been lost or possibly were not present in the groups that gave rise to the Europeans.     

Characterisation and functional implications of the two new HLA-G alleles found in Amerindian and Caribbean populations

HLA-G polymorphism has been found to be relatively low in all world populations. In the present paper two new HLA-G molecules are described in ancient American natives. A new HLA-G molecule from a Ecuador Amerindian individual (male) showed four codon changes with respect to HLA-G*01:01:01. Silent changes at α1 domain (residue 57, Pro, CCG → CCA) and α2 domain (residue 93, His, CAC → CAT and residue 100, Gly, GGC → GGT) and one productive change in α3 domain (residue 219 changed from Arg to Trp). This α3 change may dramatically alter HLA-G interactions with beta-2 microglobulin, CD8, ILT-2 and ILT-4 ligands present in subsets of T, B, NK, monocytes, macrophages and dentritic cells. Another HLA-G new molecule was found in a woman from Hispaniola Island, Dominican Republic (Sto Domingo): it presented a silent change at α2 domain residue 107, Gly, GGA → GGT and non-silent change at residue 178, Met → Thr (with respect to HLA-G*01:01:01) which is close to class I molecule/clonotypic T cell receptor interaction sites. Functional implications of these findings are discussed.     

The relative frequencies of HLA-DRB1*01 alleles in the major US populations

The frequencies of alleles in the HLA-DRB1*01 family were determined in each of five US populations from a database of 82,979 individuals. Individuals typed as DR1 (or DRB1*01) comprised between 7.6%-21.3% of the individuals in each population group. Fifty-nine DR1 individuals were randomly selected from each group and subjected to high-resolution DNA typing by polymerase chain reaction using sequence-specific oligonucleotide probes. DRB1*0101 was the most common allele in the Caucasian, Asian/Pacific Islander, and Native American groups while the DRB1*0102 allele was found in the majority of African Americans and Hispanics. DRB1*0103 was present at a similar frequency in all populations. DRB1*0104, DRB1*0105, and DRB1*0106 alleles were not observed.     

云南28个群体中含黄素单氧化酶3基因突变频率分布

目的 研究含黄索单氧化酶3(flavin—containing monooxygenase3,FMO3)基因突变频率在云南少数民族群体中的分布。方法 采用聚合酶链反应—限制性片段长度多态性方法对云南24个少数民族的28个群体进行了FMO3基因型分析。结果 FMO3／Stop^148。频率分布范围为0．174～0．803,平均为0．395;FMO3／Lys^158。频率分布范围为0．056～0．414,平均为0．208;FM03／Gly^308频率分布范围为0～0．217,其中布朗族、新平花腰傣、德宏水傣、壮族、德昂族、景颇族、怒族和回族的频率为零,平均为0．046。结论 FMO3基因突变频率不仅民族间有较大的差异,而且同一民族不同群体也不相同。     

The origin of Cretan populations as determined by characterization of HLA alleles

The Cretan HLA gene profile has been compared with those of other Mediterranean populations in order to provide additional information regarding the history of their origins. The allele frequencies, genetic distances between populations, relatedness dendrograms and correspondence analyses were calculated. Our results indicate that the Indoeuropean Greeks may be considered as a Mediterranean population of a more recent origin (after 2000 B.C.), while all other studied Mediterraneans (including Cretans) belong to an older substratum which was present in the area since pre-Neolithic times. A significant Turkish gene flow has not been detected in the Greek or Cretan populations, although Greeks and Turks have two high frequency HLA-DRB-DQB haplotypes in common. It is proposed that Imazighen (Caucasoid Berbers living at present in the North African coast and Saharan areas) are the remains of pre-Neolithic Saharan populations which could emigrate northwards between about 8000-6000 B.C., when desert desiccation began. They also could be part of the stock that gave rise to Sumerians, Cretans and Iberians; this is supported by both linguistic and HLA genetic data.     

Differences in HLA class II alleles of isolated South American Indian populations from Brazil and Argentina

We have studied the HLA class II alleles in 277 South American Indians, which included Argentinian tribes from the Gran Chaco: Toba (n = 135), Toba-Pilaga (n = 19), Mataco-Wichi (n = 49), and Xavantes, a tribe from Central Brazil (n = 74). In the Brazilian tribe, only four DR groups were found: DRB1^*1602 (gf = 0.303), DRB1^*04 including DRB1^*0404 (gf = 0.070) and DRB1^*0407 (gf = 0.077), DRB1^*0802 fgf = 0.265), and DRB1^*1402 (gf = 0.303). The HLA class II allele frequencies were similar among the different Argentinian tribes, and 90% of DRB1 alleles belonged to three families: DRB1^*04 (including DRB1^*0403, DRB1^*0404, DRB1^*0407, DRB1^*0411, and DRB1^*0417), DRB1^*0802, and DRB1^*14 (including DRB1^*1402 and DRB1^*1406). At the DPB1 locus, we found only seven alleles, the most frequent being DPB1^*0402. Comparison of HLA class II alleles with those of North American Indians that we have previously studied shows that the frequency of some HLA class II alleles in Brazilian Xavantes resembles that of North American Indians more than that of the Argentinian Indian tribes. The allele DRB1^*0417 was found exclusively in this population.