Distribution of red cell phosphoglucomutase-1 subtypes in several Mongoloid populations of East Asia

The distribution of red cell phosphoglucomutase (PGM) subtypes was determined by starch-gel electrophoresis and isoelectric focusing in a group of 2,484 unrelated individuals from ten Mongoloid populations of East Asia. The sample comprised 998 Chinese from various localities--Singapore, 325; Malaysia, 270; Taiwan, 276; Hong Kong, 67; Fouzhou, 60--as well as 342 Koreans; 252 Filipinos; 529 Thais; 336 Malays, and 27 Indonesians. Altogether 15 phenotypes controlled by four common and five rare alleles at the PGM1 locus were observed in these populations. The frequency of the most frequent allele (PGM1+) varied from 0.56 to 0.74, with the highest frequency observed in the Singapore Chinese and the lowest in the Malays. Within the Chinese from different localities a significant degree of heterogeneity was observed at the PGM1 locus. The rare allele (PGM17)6 was observed only among the Chinese, Thais, and Malays, while the PGM1 was lacking in the Filipinos. A new allele with ahigh pI (6.5) was observed in a low frequency in all the populations but the Malays.     

Polymorphism of complement component I in Mongoloid populations: a new genetic variant IF A2

The genetic polymorphism of the complement component I (IF) was investigated in 282 Chinese, 239 Koreans and 198 Japanese. The 3 common IF phenotypes (A, AB and B) and a new rare IF phenotype (BA2) were observed. The obtained allele frequencies are as follows: IF*A = 0.0993 and IF*B = 0.9007 in Chinese; IF*A = 0.0921 and IF*B = 0.9079 in Koreans; IF*A = 0.0985, IF*B = 0.8990 and IF*A2 = 0.0025 in Japanese. These 3 Mongoloid populations showed a much higher degree of IF polymorphism than Caucasian populations.     

Plasma alpha 1B-glycoprotein allele frequencies in Finns and Swedish Lapps: evidence for a new alpha 1B allele

A new allele (A1B*5) of human plasma alpha 1B-glycoprotein (alpha 1B) was reported. alpha 1B phenotyping was done by two-dimensional agarose gel (pH 5.4)-horizontal polyacrylamide gel (pH 9.0) electrophoresis followed by protein staining. The alpha 1B phenotypes 1-1, 1-2, 1-5 and 2-2 were observed in Finns and phenotypes 1-1, 1-2, 1-5 and 2-5 in Swedish Lapps. The respective frequencies of A1B*1, A1B*2 and A1B*5 were 0.9575, 0.0350, 0.0075 in Finns and 0.8922, 0.0653, 0.0425 in Swedish Lapps. The Swedish Lapps showed a higher degree of alpha 1B polymorphism (polymorphism information content = 0.19) than other Caucasian populations that have been studied.     

Further studies of the plasma alpha 1 B-glycoprotein polymorphism: two new alleles and allele frequencies in Caucasians and in American blacks

Two new alleles (A1 B*3 and A1 B*4) of human plasma alpha 1 B-glycoprotein (alpha 1 B) were reported. alpha 1 B phenotyping was done by using either a simple method of two-dimensional (2-D) agarose gel-horizontal polyacrylamide gel electrophoresis (PAGE) followed by protein staining or by one-dimensional horizontal PAGE and immunoblotting. Seven different alpha 1 B phenotypes (1-1, 1-2, 1-3, 1-4, 2-2, 2-3 and 3-3) were observed; phenotypes 1-3 and 1-4 were differentiated from each other only by the 2-D method. The respective frequencies Af A1 B*1, A1 B*2, A1 B*3 and A1 B*4 alleles in the studied populations were estimated as follows: American Blacks (New York) 0.732, 0.204, 0.064, 0; American Whites (New York) 0.947, 0.053; Czechs (M?lník) 0.964, 0.034, 0, 0.002; Slovaks (Bratislava and Trencin) 0.977, 0.023, 0, 0. The population of American Blacks showed a much higher degree of alpha 1 B polymorphism (polymorphism information content = 0.37) than the Caucasian populations that have been studied.     

Polymorphism of CYP1A1 and CYP2D6 genes in tundra nentses and European populations of western Siberia

Data on the first examination of the CYP1A1 and CYP2D6 genes' polymorphism in the populations of Tundra Nentsis (Yamalo-Nenetskii Autonomous District) and migrant population of Western Siberia (Novosibirsk oblast and Altaiskii krai) are presented. The frequency of the 2D6*4 mutant allele in Tundra Nentsis, characterized by a two-component Caucasoid and Mongoloid origin, was shown to be intermediate in Caucasoid and Mongoloid populations. The frequencies of the 2D6*4 and 1A1Val* mutant alleles across migrant inhabitants of Western Siberia (Caucasoid populations) were similar to that reported for the Caucasoid populations overall. Distribution of the CYP1A1 genotypes (Ile/Ile, Ile/Val*, and Val*/Val*) in Tundra Nentsis was similar to that found in Mongoloid groups. However, the frequency of the 1A1Val* allele in Tundra Nentsis was 1.5 times higher than that in the Southern Mongoloid populations (Chinese, Koreans, and Japanese).     

The plasminogen polymorphism in South African Negro populations: genetics and anthropogenetics

Summary Genetic polymorphism of human plasminogen (PLG) was investigated in 1252 unrelated individuals from eight South African Bantu-speaking Negro tribes. PLG phenotypes were determined by isoelectric focusing (pH 3.5–9.5 and 5–8 gradients) of neuraminidase-treated samples and subsequent detection by caseinolytic overlay or immunoblotting with specific antibody. No significant difference in the distribution of PLG alleles among the eight ethnic groups was observed. The combined allele frequencies of the common alleles in South African Negroes were 0.6977 for PLG*A, 0.2736 for PLG*B. In addition, six rare alleles were seen: PLG*A3, *A1, *M2, *B1, *B2, *B3. The rare variant PLG*B2 was proven to segregate by autosomal Mendelian inheritance in a family. The combined frequency for the rare alleles was 0.0287. The distribution of phenotypes in the total population sample was found to be in Hardy-Weinberg equilibrium. A striking difference in PLG allele distribution between Negroes from South Africa and published Negroid frequencies from North America could be observed. This difference was also seen in comparison with Mongoloid populations; in contrast, PLG frequencies for South African Negroes were similar or almost identical to known Caucasoid distributions.     

Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA-B17 in different racial groups.

HLA-A, B, and C antigens and the HLA-linked markers BF, C2, and C4 were determined in 1,799 unrelated Caucasians, 140 North American blacks, 140 Chinese, and 66 Japanese. One allele of the C4A locus (Rodgers), C4A*6, was found to code for a functionally inactive product in HLA-B17 (Bw57)-positive individuals, but for a functionally active product in HLA-B37- or HLA-B27-positive individuals. Further studies revealed that the functionally inactive C4A*6 gene product was found only in one subtype of HLA-B17, namely, 17.1 (Bw57, long). In addition, it was found that the frequency of the other subtype of HLA-B17, namely, 17.2(Bw58, short) varies greatly in different populations and that HLA-Bw58 is associated with either C4A*3,B*1 or C4A*3,B*Q0.     

Identification of a null allele of cytochrome P450 3A7: CYP3A7 polymorphism in a Korean population

Cytochrome P450 3A7 (CYP3A7) is expressed in the human fetal liver and plays a role in the metabolism of hormones, drugs, and toxic compounds. Genetic variants of CYP3A7 are associated with serum estrone level, bone density, and hepatic CYP3A activity in adults. We analyzed the genetic variations of CYP3A7 in a Korean population. From direct sequencing of all exons and flanking regions of the CYP3A7 gene in 48 Koreans, we found five genetic variants, including three novel variants. One variant, a thymidine insertion in exon 2 (4011insT), causes premature termination of CYP3A7 translation, which may result in a null phenotype. The novel variant was assigned to the CYP3A7*3 allele by the CYP allele nomenclature committee. For further screen of this novel variant in other ethnic populations, we used pyrosequencing to analyze an additional 185 Koreans, 100 African Americans, 100 Caucasians, and 159 Vietnamese for the presence of this variant. The variant was not found in any other individuals, except for one Korean subject. The frequencies of two known functional alleles, CYP3A7*2 and CYP3A7*1C, were 26 and 0%, respectively, in Koreans. The frequencies of the functional CYP3A7 polymorphisms in Koreans were significantly different from those in Caucasians and African Americans. This is the first report of a null-type allele of the CYP3A7 gene. It also provides population-level genetic data on CYP3A7 in Koreans to reveal the wide ethnic variation in CYP3A7 polymorphism.     

Study of five haemogenetic markers (Gc, C3, Bf, Ag, and GALT) in six Indonesian populations and in 12 subgroups of Balinese

In various ethnic groups of the Indonesian archipelago and of Bali, the polymorphisms of the serum proteins Gc globulin (vitamin D-binding protein), C3 (complement component 3), Bf (complement factor B), Ag x,y (lipoprotein allotypes), and of the red cell enzyme system GALT (galactose-1P-uridyltransferase) were analysed. Among the studied proteins, the Gc system was the most informative one for the anthropologist. Besides considerable differences of frequencies of the common alleles Gc*1F, Gc*1S and Gc*2, a number of rare alleles (1A1, 1A3, 1A8, 1A9, 1A12, 1C2, 1C21, 1C24, and 2C8) and some new ones (1C28, 1C29, 1C30, 2C9) were observed. The presence of Gc*1A1 demonstrates the relationship to the Australo-Melanesian populations, but Mongolian variants (1A3, 1A8, 1A9, 1C2) were also encountered. Within the C3 system a very high frequency of the C3*S allele was observed in all populations. The rare alleles C3*F0.55, C3S1, and C3*S0.5 were observed in some groups. A new allele (C3*F0.35) was detected in a Chinese individual and in a nobleman from Bali. The frequency of the Bf*F allele was rather low in general, and the Bf*S0.7 allele was found in three Indonesian individuals only. The Ag*(x) frequencies were rather high, as it is known for Asiatic populations. Variability among subgroups was not very pronounced. The GALT*2 allele (Duarte variant of the enzyme) was observed very rarely; however, it was present in several populations. Enzyme activities could not be determined, and therefore we cannot tell whether the galactosaemia gene (GALT*0) was present or not.     

Distribution of transferrin subtypes in Tarragona (east Spain).

The distribution of transferrin (TF) subtypes was determined by isoelectric focusing of sera from 284 unrelated individuals from Tarragona (south of Catalonia). The allele frequencies observed, TF*C1 = 0.805, TF*C2 = 0.162, TF*C3 = 0.026 and TF*B = 0.007 were similar to those reported for other Spanish populations.     

CYP2A6 polymorphism reveals differences in Japan and the existence of a specific variant in Ovambo and Turk populations

CYP2A6 is a polymorphic enzyme, and CYP2A6 genotype has been shown to be associated with smoking habits and lung cancer. We investigated CYP2A6 polymorphism in Japanese from four different geographic areas of Japan and in the Ovambo and Turk populations. Using two polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLPs), we identified the functionally important variants of CYP2A6: *1A, *1B, *1F, *1G, *4A, and *4D. In the Japanese population the highest frequencies of the CYP2A6*1A allele were observed in subjects from the Fukuoka (Kyushu Island) and Ehime (Shikoku Island) prefectures, whereas subjects in Shimane and Tottori (both located on the Japan Sea side of Honshu Island) showed the highest frequencies of the CYP2A6*1B allele. In the Tottori and Shimane groups no subject was homozygous for the CYP2A6*4A allele, a whole gene deletion type that is prevalent among Asians. In the Ovambo and Turk populations the CYP2A6*1A allele was predominant. Furthermore, two alleles undetected in the Japanese were observed in these latter two ethnic groups: CYP2A6*1G was found solely in the Ovambos, and CYP2A6*1F was found solely in the Turks. The present study is the first to show interprefecture differences in CYP2A6 polymorphism in Japanese who live in relatively close but distinct geographic areas; this is also the first study to evaluate CYP2A6 variations among these Japanese and the Ovambo and Turk populations. The distribution results of these alleles could help to define the true significance of CYP2A6 polymorphism as a genetic susceptibility marker in worldwide populations.     

Enzyme activity and distribution of adenosine deaminase types in a population of central Italy

Blood samples from 718 unrelated individuals born in municipalities of the 'Alto Maceratese' region in central Italy were examined for adenosine deaminase (ADA). The allele frequencies for ADA*1 and ADA*2 were 92.48 and 7.45%, respectively. One case of the rare ADA 5-1 phenotype was observed. The observed phenotype distribution agreed well with the one expected assuming a Hardy-Weinberg equilibrium. Enzyme activity was measured in red blood cells from individuals with different phenotypes. The relationships between the enzyme activity of the phenotypes was found to be ADA 1 greater than ADA 2-1 greater than ADA 2 greater than ADA 5-1.     

Polymorphism of HF (beta 1H-globulin) in three Asian populations (Bangladeshis,Tibetans and Indonesians)

The polymorphism of HF (beta 1H-globulin) was investigated in three Asian populations (Bangladeshis, Tibetans and Indonesians) by means of isoelectric focusing and immunoblotting. Phenotypes associated with three common alleles (HF*A, HF*B and HF*Q0) and a rare allele HF*A1 were identified. The observed numbers of phenotypes were in accordance with the numbers expected under the Hardy-Weinberg equilibrium. HF*A1 seems to be a unique allele of the East-Asian Mongoloids including Tibetans and Indonesians.     

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.     

'Smoking genes': a genetic association study

Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (-48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A -1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).     

The frequency and distribution of thiopurine S-methyltransferase alleles in south Iranian population

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Variability in TPMT activity is mainly due to genetic polymorphism. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) were determined in an Iranian population from south of Iran (n = 500), using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. Four hundred seventy four persons (94.8%) were homozygous for the wild type allele (TPMT*1/*1) and twenty five people were TPMT*1/*3C (5%). One patient was found to be heterozygous in terms TPMT*1 and *2 alleles with genotype of TPMT*1/*2 (0.2%). None of the participants had both defective alleles. The TPMT*3C and *2 were the only variant alleles observed in this population. The total frequency of variant alleles was 2.6% and the wild type allele frequency was 97.4%. The TPMT*3B and *3A alleles were not detected. Distributions of TPMT genotype and allele frequency in Iranian populations are different from the genetic profile found among Caucasian or Asian populations. Our findings also revealed inter-ethnic differences in TPMT frequencies between different parts of Iran. This view may help clinicians to choose an appropriate strategy for thiopurine drugs and reduce adverse drug reactions such as bone marrow suppression.     

Origin of the Koreans: a population genetic study.

A population genetic study was undertaken to investigate the origin of Koreans. Thirteen polymorphic and 7 monomorphic blood genetic markers (serum proteins and red cell enzymes) were studied in a group of 437 Koreans. Genetic distance analyses by both cluster and principal components models were performed between Koreans and eight other populations (Koreans in China, Japanese, Han Chinese, Mongolians, Zhuangs, Malays, Javanese, and Soviet Asians) on the basis of 47 alleles controlled by 15 polymorphic loci. A more detailed analysis using 65 alleles at 19 polymorphic loci was performed on six populations. Both analyses demonstrated genetic evidence of the origin of Koreans from the central Asian Mongolians. Further, the Koreans are more closely related to the Japanese and quite distant from the Chinese. The above evidence of the origin of Koreans fits well with the ethnohistoric account of the origin of Koreans and the Korean language. The minority Koreans in China also maintained their genetic identity.     

Population genetics of the vitamin D binding protein (GC) subtypes in the Asian-Pacific area: Description of new alleles at the GC locus

Isoelectric focussing (IEF) in thin layer polyacrylamide gels pH range 4-6.5 has been used to analyse the GC phenotypes of 4233 individuals from 28 different population groups in the Asian, Pacific, and Australian area. Because this technique reveals subtypes of the common GC*1 allele, there is almost a two-fold increase in the mean heterozygosity at the GC locus using IEF compared with conventional electrophoresis. The highest frequency (above 50%) of the GC*1S allele was encountered in Indian populations, reflecting genetic affinities with Europeans. By comparison, east and south east Asians are unique offing maximum values of the GC*1F allele (50%). With the exception of a few Pacific populations which show similar frequencies to east Asians, all other groups in the Pacific area, including Australia, have values of GC*1F similar to GC*1S ranging from 27% to 40%. The GC*2 frequency in most populations varies from 20% to 30%. However, some Polynesian groups have values up to 40% and Australian Aborigines less than 10%. Among other alleles, GC*1A1 is found to be widely distributed among Australian Aborigines and Melanesians and occurs sporadically in Polynesians, Micronesians, and in the Lesser Sunda Islands. Four new alleles, GC*1C24, GC*1C35 Aborigine, GC*1A21, and GC*1A22 are described. The gene frequency data at the GC locus has been used to calculate Nei genetic distances between the populations studied.     

Population genetics of alpha-1-antitrypsin polymorphism in US whites, US blacks and African blacks.

An isoelectric focusing (IEF) procedure in an ultra-narrow pH range, 4.2-4.9, has been utilized to detect alpha 1-antitrypsin or alpha 1-protease inhibitor (PI) allele products in 2 US white and 3 US black populations as well as 1 native African black population. In addition to the 3 common alleles PI*M1, PI*M2 and PI*M3, products of the 4th allele PI*M4 have been identified in US whites at low-level frequency. The presence of the PI*S, PI*Z and PI*I alleles has also been verified in our population samples. While the PI*S allele is present at a polymorphic level in US whites, it is only present sporadically in US blacks and is completely absent in African blacks. The PI*Z allele was not detected in the black populations tested. The PI allele frequency data have been used to calculate white admixture in US blacks.     

High Resolution Human Leukocyte Antigen Class I Allele Frequencies and HIV-1 Infection Associations in Chinese Han and Uyghur Cohorts

Background

Host immunogenetic factors such as HLA class I polymorphism are important to HIV-1 infection risk and AIDS progression. Previous studies using high-resolution HLA class I profile data of Chinese populations appeared insufficient to provide information for HIV-1 vaccine development and clinical trial design. Here we reported HLA class I association with HIV-1 susceptibility in a Chinese Han and a Chinese Uyghur cohort.

Methodology/Principal Findings

Our cohort included 327 Han and 161 Uyghur ethnic individuals. Each cohort included HIV-1 seropositive and HIV-1 seronegative subjects. Four-digit HLA class I typing was performed by sequencing-based typing and high-resolution PCR-sequence specific primer. We compared the HLA class I allele and inferred haplotype frequencies between HIV-1 seropositive and seronegative groups. A neighbor-joining tree between our cohorts and other populations was constructed based on allele frequencies of HLA-A and HLA-B loci. We identified 58 HLA-A, 75 HLA-B, and 32 HLA-Cw distinct alleles from our cohort and no novel alleles. The frequency of HLA-B*5201 and A*0301 was significantly higher in the Han HIV-1 negative group. The frequency of HLA-B*5101 was significantly higher in the Uyghur HIV-1 negative group. We observed statistically significant increases in expectation-maximization (EM) algorithm predicted haplotype frequencies of HLA-A*0201-B*5101 in the Uyghur HIV-1 negative group, and of Cw*0304-B*4001 in the Han HIV-1 negative group. The B62s supertype frequency was found to be significantly higher in the Han HIV-1 negative group than in the Han HIV-1 positive group.

Conclusions

At the four-digit level, several HLA class I alleles and haplotypes were associated with lower HIV-1 susceptibility. Homogeneity of HLA class I and Bw4/Bw6 heterozygosity were not associated with HIV-1 susceptibility in our cohort. These observations contribute to the Chinese HLA database and could prove useful in the development of HIV-1 vaccine candidates.