The varying frequencies of five DNA polymorphisms of X-linked coagulant factor IX in eight ethnic groups.

Five RFLPS of X-linked coagulation factor IX were evaluated in more than 500 normal persons (723-804 X chromosomes) of both sexes who belonged to eight ethnic groups: Anglo-Americans, Basques, Swedes, African-Americans, East Africans, East Indians, Chinese, and Malays. The polymorphisms, 5' to 3', were BamHI, XmnI, TaqI, MnlI, and HhaI. A PCR procedure was developed for three previously described RFLPs-XmnI, TaqI, and MnlI; a PCRP procedure was developed for BamHI, and a PCRP which had been described by others was used for HhaI. Europeans were the most polymorphic, African-Americans and East Africans were intermediate, and Orientals were the least polymorphic. Extragenic 3' HhaI was highly polymorphic in most groups, and extragenic 5' BamHI was polymorphic only in persons with African ancestry. Two major haplotypes predominated among 247 men, and the expected and observed heterozygosities were concordant among women. Allelic association was very strong between the three intragenic PCRPs; it was present but weak between 5' extragenic BamHI and XmnI. No association was found between 3' extragenic HhaI and MnlI.     

Restriction fragment length polymorphism (RFLP) at the DNF15S2 locus in three ethnic groups of Singapore

Three different ethnic groups from Singapore comprising 79 Chinese, 34 Malays and 23 Indians of Dravidian origin, were investigated for the HindIII RFLP at the DNF15S2 locus. The three populations had very similar allele frequencies and the frequency of rarer(S) allele was significantly (p less than 0.01) lower (0.21) in these ethnic groups compared to that in Caucasians (0.41). The phenotypic distributions were at Hardy-Weinberg equilibrium.     

Population genetics of the Malm? polymorphism of coagulation factor IX.

The distribution of 1,198 Malm? alleles was examined in 822 men from 16 indigenous populations and 188 women from 7 of the ethnic groups. Subjects were from several European countries, the Mediterranean, East Asia, and the USA (Anglo- and African-Americans). The frequencies of the rarer (Malm? B) allele were approximately equal across Europe, the highest frequencies (0.36) being in the French and Anglo-Americans; no population was observed with clearly the highest frequency. They diminished slightly at moderate distances from Europe (Tunisia, Ethiopia) and greatly at longer distances (East Asia and West Africa). In Orientals, the frequencies ranged from 0.07 (East Indians) to 0.03 (the Chinese) and from 0.0 to 0.15 in African-Americans. Assuming selective neutrality, the data are consistent with the European origin of the 'B' allele when the population was small and outward spread.     

alpha1-Antitrypsin variants in different racial groups in Malaysia.

In a study of Malaysians of different racial groups, 1,510 sera (908 from Malays, 371 from Chinese and 231 from Indians) were identified for their protease inhibitor (Pi) types. The gene frequencies for the alleles PiM, PiS and PiX in Malays were, respectively, 0.979, 0.015, and 0.007. In Chinese, the frequencies were 0.981, 0.019 and 0.000, and in Indians they were 0.976, 0.24, and 0.000. It is interesting that the usually rare PiX type is found in appreciable frequency in the Malays. Two different types with unusual behavior and obscure origin were also found.     

Four DNA polymorphisms on the short arm of the X chromosome: allele frequencies in a German and in a Turkish population

Four restriction fragment length polymorphisms, revealed by cloned arbitrary X chromosome segments (L1.28, RC8, pD2, 754) were studied in samples (50 individuals each) of a German and a Turkish population. All previously reported alleles of these polymorphisms were found in both populations, except the infrequent RC8 allele B3 (3.0 kb fragment), which was absent in both groups. The observed minor alleles were found to be rarer in the German series than in the Turkish group, but there was no conclusive evidence of essentially different allele frequencies in either population. However, the frequencies of the RC8 allele B2 (5.3 kb fragment) were differing at the 5% significance level. The allele frequencies of the four polymorphisms are presented and compared with those reported from other European regions.     

Further data on the microsatellite locus D12S67 in worldwide populations: an unusual distribution of D12S67 alleles in Native Americans

We report the frequencies of alleles at the microsatellite locus D12S67 in 2 widely separated ethnic groups of the world: 2 populations from Sulawesi, an island in the Indonesian archipelago, and 5 Native American tribes of Colombia, South America. The allele frequencies in the Minihasans and Torajans of Sulawesi are similar to each other (but the modal class allele is different) and in general agreement with those reported in mainland Asian groups, but different from both Europeans and Chinese Han of Taiwan. The 5 Native American tribes (Arsario, Kogui, Ijka, Wayuu, and Coreguaje) display different allele frequencies from those seen in Sulawesi populations, in other groups from Europe and mainland Asia, and in Chinese Han of Taiwan. Native Americans exhibit a bimodal distribution of alleles, unlike other groups, with significant differences among the tribes. The Arsario and Kogui have no admixture with Europeans or Africans and are the most distinctive, while the Wayuu have the most admixture and show most similarity to other groups. The data suggest that nonadmixed Native Americans may be quite distinctive with respect to this marker. The most common allele varies across the 5 tribes, from 249 base pairs to 261 base pairs. All samples exhibit Hardy-Weinberg genotype proportions; heterozygosities are lowest in the 2 nonadmixed Native American tribes. Examination of all the available data indicates that some east Asian and southeast Asian groups are characterized by a high frequency of smaller sized D12S67 alleles, while other populations have a greater proportion of the larger sized alleles. The cumulative, though still highly restricted, population data on locus D12S67 demonstrate that it may be of considerable value in anthropological genetic studies of ethnic groups. Data are required on Native Americans outside Colombia before this marker can be used in admixture studies of this group.     

Ethnic differences in allelic associations of the interleukin-1 gene cluster in South African patients with inflammatory bowel disease (IBD) and in control individuals

The allelic frequencies of TaqI, PstI, and variable number of tandem repeat (VNTR) polymorphisms of the IL-1beta, IL-1 receptor (IL-1Re), and IL-1 receptor antagonist (IL-1Ra) respectively, were investigated in black and white patients with inflammatory bowel diseases (IBD) and compared with control individuals. Plasma concentrations of IL-1beta and IL-1Ra were also determined in these individuals. The IL-1beta TaqI(-) allele was significantly more frequent in 50 white IBD patients (60%) compared with 47 white controls (17%), and 20 black patients (20%) (P=0.00001 and P=0.0001, respectively). The IL-1Re PstI(-) allele was significantly more frequent in 20 black patients (75%) compared with 50 white patients (44%) (P=0.0001). The frequency of the IL-1Ra 240-bp allele was lower in black (12%) compared with white controls (25%), (P=0.0151), and the 410-bp allele was more frequent in black (87%) compared with white (73%) controls (P=0.0096). Linkage disequilibrium was found in black individuals homozygous for the 410-bp allele of IL-1Ra, and the PstI(-) allele of IL-1Re (84%) (P=0.0032). There was a significantly increased level of IL-1Ra in black patients compared with white patients and black controls (P=0.0006 and P=0.0008, respectively). The population differences in allelic frequencies of the IL-1 gene cluster and IL-1Ra concentrations suggest that genetic and environmental factors play an important role in susceptibility to IBD.     

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals with deficient enzyme activity appear clinically normal. This “pseudodeficiency” allele commonly found among many reported populations (frequency ∼ 0.10) is associated with two A→G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant. These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa at ∼100 000–200 000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. Received: 23 December 1996 / Accepted: 21 July 1997     

Genetic variants of serum butyrylcholinesterase in Chilean Mapuche Indians

We estimated the frequencies of serum butyrylcholinesterase (BChE) alleles in three tribes of Mapuche Indians from southern Chile, using enzymatic methods, and we estimated the frequency of allele BCHE*K in one tribe using primer reduced restriction analysis (PCR-PIRA). The three tribes have different degrees of European admixture, which is reflected in the observed frequencies of the atypical allele BCHE*A: 1.11% in Huilliches, 0.89% in Cuncos, and 0% in Pehuenches. This result is evidence in favor of the hypothesis that BCHE*A is absent in native Amerindians. The frequencies of BCHE*F were higher than in most reported studies (3.89%, 5.78%, and 4.41%, respectively). These results are probably due to an overestimation of the frequency of allele BCHE*F, since none of the 20 BCHE UF individuals (by the enzymatic test) individuals analyzed showed either of the two DNA base substitutions associated with this allele. Although enzymatic methods rarely detect the presence of allele BCHE*K, PCR-PIRA found the allele in an appreciable frequency (5.76%), although lower than that found in other ethnic groups. Since observed frequencies of unusual alleles correspond to estimated percentages of European admixture, it is likely that none of these unusual alleles were present in Mapuche Indians before the arrival of Europeans.     

A global view of the OCA2-HERC2 region and pigmentation

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.     

Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals

Cytochrome P450 (CYP) superfamily members CYP2C8 and CYP2C9 are polymorphically expressed enzymes that are involved in the metabolic inactivation of several drugs, including, among others, antiepileptics, NSAIDs, oral hypoglycemics, and anticoagulants. Many of these drugs have a narrow therapeutic index, and growing evidence indicates a prominent role of CYP2C8 and CYP2C9 polymorphisms in the therapeutic efficacy and in the development of adverse effects among patients treated with drugs that are CYP2C8 or CYP2C9 substrates. In this review, we summarize present knowledge on human variability in the frequency of variant CYP2C8 and CYP2C9 alleles. Besides an expected interethnic variability in allele frequencies, a large intraethnic variability exists. Among Asian subjects, for example, statistically significant differences (p < 0.0001) in CYP2C9*3 allele frequencies between Chinese and Japanese individuals have been reported. In addition, individuals from East Asia present different allele frequencies for CYP2C9*2 and CYP2C9*3 compared with South Asian subjects (p < 0.0001). Among Caucasian Europeans, statistically significant differences for the frequency of CYP2C8*3, CYP2C9*2, and CYP2C9*3 exist (p < 0.0001). This indicates that Asian individuals or Caucasian European individuals cannot be considered as homogeneous groups regarding CYP2C8 or CYP2C9 allele frequencies. Caucasian American subjects also show a large variability in allele frequencies, which is likely to be related to ethnic ancestry. A higher frequency of variant CYP2C8 and CYP2C9 alleles is expected among Caucasian Americans with South European ancestry than in individuals with North European ancestry. The findings summarized in this review suggest that among individuals with Asian or European ancestry, intraethnic differences in the risk of developing adverse effects with drugs that are CYP2C8 or CYP2C9 substrates are to be expected. In addition, the observed intraethnic variability reinforces the need for proper selection of control subjects and points against the use of surrogate control groups for studies involving association of CYP2C8 or CYP2C9 alleles with adverse drug reactions or spontaneous diseases.     

Tissue-type plasminogen activator restriction fragment length polymorphism in the Chinese, Indians and Malays of Singapore

A total of 215 subjects comprising 95 Chinese, 66 Malays and 54 Indians were investigated for restriction fragment length polymorphisms of the tissue-type plasminogen activator (PLAT) gene at an EcoRI site using the probe ptPA-4352. The phenotypic distribution showed a good agreement with the Hardy-Weinberg equilibrium. The gene frequencies of PLAT*1 were found to be 0.47 in the Chinese, 0.52 in the Malays and 0.41 in South Indians.     

Association of Codon 16 and Codon 27 β2‐Adrenergic Receptor Gene Polymorphisms with Obesity: A Meta‐analysis

Objective: To search for an association between the Glu27Gln (rs1042714; B27) and the Arg16Gly (rs1042713; B16) polymorphisms of the β2‐adrenergic receptor (ADRB2) gene and obesity. Methods: Meta‐analysis of published studies, included if subjects were genotyped at either codon 27 (“B27”) or codon 16 (“B16”) of the ADRB2 gene and both obese and nonobese subjects were selected, based on a reported cutoff BMI limit. Initial selection included 14,444 subjects genotyped at B27 (rs1042714) and 6,825 genotyped at B16 (rs1042713). After testing each control group for Hardy‐Weinberg equilibrium, the final selection included 10,404 subjects and 4,328 subjects, respectively. Studies were published before 18 August 2006. Results: The frequency of Glu27 allele carriers, either homozygous or heterozygous, ranged from 6.71% in Aymara American Indians to 78.29% in a Dutch population. The frequency of Arg16 allele carriers varied from 51.4 to 64.6% in Europeans and from 71.1 to 85.6% in East Asians. The summary odds ratio (OR) from overall analyses showed no association between either rs1042714 or rs1042713 and obesity. In race groups with low Glu27 allele frequency (Asians, Pacific Islanders, and American Indians), ORs revealed a significant obesity risk associated with rs1042714. These results were not found in East Asians for rs1042713. Discussion: The presence of the Glu27 allele in the ADRB2 gene appears to be a significant risk factor for obesity in Asians, Pacific Islanders, and American Indians, but not in Europeans. Obesity does not appear to be associated with the Arg16 allele.     

Effects of intragenic variability at 3 polymorphic sites of the apolipoprotein B gene on serum lipids and lipoproteins in a multiethnic Asian population.

We determined the allelic (X+/X-, M+/M-, and E+/E-) distribution frequencies of the XbaI, MspI, and EcoRI restriction fragment length polymorphisms (RFLPs) in the apolipoprotein B gene in a control group of 374 healthy Chinese, Malays, and Indians and in a hyperlipidemic cohort of 131 Chinese patients. Covariability between the RFLPs and serum lipid, lipoprotein, and apolipoprotein concentrations was also studied. We found a lower frequency (average 0.0829) of the X+ allele and higher frequencies of the E+ (average 0.9452) and M+ (average 0.9772) alleles in our study population compared with frequencies reported in other populations. The 3 polymorphic sites did not contribute to significant variations in lipid levels (p > 0.1 in all cases). Also, there was no significant variation in genotype frequencies between the control subjects and the hyperlipidemic subjects. Despite their relative close proximity within the APOB gene sequence, the 3 polymorphic sites did not show any significant linkage disequilibrium. However, the presence of the X+ cutting site was in linkage disequilibrium with the Del allele of the 5' insertion-deletion polymorphism and the E-allele was in linkage disequilibrium with the 3' VNTR located near the 3' end of the coding region of the APOB gene.     

Glucose dehydrogenase polymorphism among ethnic groups of Singapore--with report of two additional alleles (GDH4 and GDH5).

Placental glucose dehydrogenase (GDH; E.C.1.1.1.47) polymorphism was studied in 254 Chinese, 104 Malays, and 47 Indians from Singapore using isoelectric focusing. There is suggestive evidence of two additional anodal alleles (GDH4 and GDH5) in addition to the three alleles described in earlier studies. Altogether, 14 phenotypes have been observed in the present investigation, compared with six phenotypes described in earlier studies. It appears that placental GDH is controlled by five codominant autosomal alleles producing 15 possible phenotypes. The gene frequencies of GDH1, GDH2, and GDH3 in these ethnic groups are significantly different from those reported in Caucasians. There were slight differences in the gene frequencies between the three ethnic groups, with those of Indians being nearer to the frequency in Caucasians. In general, the distribution of GDH phenotypes was at Hardy-Weinberg equilibrium in all three ethnic groups studied.     

ABO and Rh D polymorphism among Tibetans in India

A study of ABO and Rh D polymorphisms was conducted on 923 Tibetans living in exile in four different places (both high and low altitudes) in India. The frequencies of alleles p, q, and r for the ABO blood group system were found to be 0.1295, 0.2544, and 0.6152, respectively, and for alleles D and d of the Rh blood group system the allele frequencies were 0.9428 and 0.0572, respectively, for the total data. No significant difference was found for the allele frequencies among the four places for the two blood group systems. The allele frequencies were in Hardy-Weinberg equilibrium for the ABO blood group system and show East Asian affinity for the Tibetans.     

Genotyping of eight polymorphic genes encoding drug-metabolizing enzymes and transporters using a customized oligonucleotide array

Polymorphisms in drug-metabolizing genes may lead to the production of dysfunctional proteins and consequently affect therapeutic efficacy and toxicity of drugs. Different frequencies of polymorphic alleles among the races have been postulated to account for the observed ethnic variations in drug responses. In the current study, we aimed to estimate the frequencies of 14 polymorphisms in eight genes (TPMT, NQO1, MTHFR, GSTP1, CYP1A1, CYP2D6, ABCB1, and SLC19A1) in the Singapore multiracial populations by screening 371 cord blood samples from healthy newborns. To improve genotyping efficacy, we designed an oligonucleotide array based on the principle of allele-specific primer extension (AsPEX) that was capable of detecting the 14 polymorphisms simultaneously. Cross-validation using conventional polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assays demonstrated 99% concordant results. Measurements on the fluorescent intensity displayed clear distinctions among different genotypes. Statistical analyses showed significantly different allele distributions in several genes among the three races, namely Chinese, Malays, and Indians. Comparing the allelic frequencies in Chinese with previous studies in Caucasian populations, NQO1 609C>T and SLC19A1 80G>A were distinctly different, whereas close similarity was observed for MTHFR 677C>T. We have demonstrated an array-based methodology for rapid multiplex detection of genetic polymorphisms. The allelic frequencies reported in this study may have important therapeutic and prognostic implications in the clinical use of relevant drugs.     

Phylogenetic relationship analysis of Iranians and other world populations using allele frequencies at 12 polymorphic markers

The estimation of genetic distance between populations could improve our viewpoint about human migration and its genetic origin. In this study, we used allele frequency data of 12 polymorphic markers on 250 individuals (500 alleles) from the Iranian population to estimate genetic distance between the Iranians and other world populations. The phylogenetic trees for three different sets of allele frequency data were constructed. Our results revealed the genetic similarity between the Iranians and European populations. The lowest genetic distance was observed between the Iranians and some populations reside in Russia. Furthermore, the high genetic distance was observed between the Iranians and East Asian populations. The data suggested that the Iranians might have relatively close evolutionary history with Europeans, but historically independent from East Asian populations. The evaluation of genetic distance between Indians populations and Iranians was also performed. The Indian groups showed low genetic distance with others, but high genetic distance with the Iranians. This study could provide a new insight into the evolutionary history of the Iranian population.     

Normative genetic profiles of RAAS pathway gene polymorphisms in North Indian and South Indian populations

Population-based genetic association studies, popularly known as case-control studies, have continued to be the most preferred method for deciphering the genetic basis of various complex diseases, even in the post-human genome sequencing era. However, interpopulation differences in allele, genotype, and haplotype frequencies and linkage disequilibrium patterns lead to inconsistent results in candidate gene association studies. Therefore, for any meaningful disease association study, knowledge of the normative genetic background of the baseline population is a prerequisite. In addition, such genetic variation data also provide a ready-made menu of allele frequencies and linkage disequilibrium patterns of various polymorphisms in specific candidate genes in a particular population, which is a useful reference for further genetic association studies. Such genetic variation data are lacking for the Indian population, which represents about one-sixth of the world's population. In the present study we have reported the allele, genotype, and haplotype frequencies, Hardy-Weinberg equilibrium status, and linkage disequilibrium patterns of 12 polymorphisms in six candidate genes from the renin-angiotensin-aldosterone system among Indians. Because of their different history of origin, the Indian population is broadly divided into two subpopulations: North Indians (Caucasian Europeans) and South Indians (Dravidians). Considering this well-documented difference in gene pools, we have presented a comparative account of the normative genetic data of North Indian and South Indian populations with at least four individuals of urban and suburban origin from each of the representative states of northern and southern India.     

MICA polymorphism in South American Indians

We have studied the MICA alleles of 196 unrelated subjects from three South American Indian tribes (Toba, Wichi and Terena). They are members of isolated tribes located in the Gran Chaco area in northeastern Argentina and in Mato Grosso do Sul in South Central Brazil. Of 55 previously known alleles, nine were observed in South American Indians, compared with 16 that were found in North American Caucasians, suggesting a more restricted allelic distribution of MICA in these tribes. In South American Indians, MICA*00201 was the most frequent allele, with a gene frequency of 33% in Toba, 47% in Wichi and 44% in Terena. MICA*00201, MICA*027 (external domain sequence like MICA*008/TM allele A5) and MICA*010 accounted for more than 90% of all the MICA genes in South American Indians. In North American Caucasians, MICA*00801 (*008/A5.1) accounted for 42% of the genes and was the most common allele. We observed a high degree of linkage disequilibrium between certain alleles of MICA and of HLA-B in the South American Indian populations. Phylogenetic trees constructed using gene frequencies of the transmembrane short tandem repeats in the populations reported here, and in other populations taken from published reports, suggest that South American Indians are more closely related to Asians than to Europeans.