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Haptoglobin (Hp) is a hemoglobin-binding serum glycoprotein. Some variations in the Hp gene (HP) or Hp-related gene (HPR), including a single-nucleotide polymorphism in intron 2 of HRP, rs2000999, and a complete deletion of the HP gene (HP de l ), one of the rare variants of HP, have been reported to correlate with the serum cholesterol concentration as well as the serum Hp concentration. In this study, we developed a duplex dual-labeled fluorescence probe-based method to simultaneously determine the rs2000999 G > A polymorphism by melting curve genotyping and the zygosity of HP de l by endpoint genotyping. This method was then validated by using the genomic DNA from 94 Japanese subjects for whom genotypes of rs2000999 and HP del zygosity had already been determined. The results obtained with this method were in perfect agreement with the previous ones. Thus, the present method enables us to estimate these two polymorphisms in relatively large-scale groups of subjects, especially in Asian populations where the HP del is distributed., (© 2022 Wiley-VCH GmbH.)

Current studies have suggested that the ABO blood group system is associated with several clinical conditions. For large-scale genotyping of ABO alleles, we developed a triplex fluorescence melting curve analysis (FMCA) to determine five single nucleotide variants (SNVs), c.261delG, c.796C>A, c.802G>A and c.803G>C and c.1061delC, responsible for common ABO phenotypes using dual-labeled self-quenched (TaqMan) probes in a single tube. We accurately determined c.796C>A, c.802G>A, and c.803G>C genotypes using a FAM-labeled probe, c.261delG using a CAL Fluor Orange 560- labeled probe, and c.1061delC using a Cy5-labeled probe. The present genotyping results of five SNVs in 214 subjects of the 1000 Genomes Project were in full agreement with those of the database sequence. The predicted ABO phenotypes using combinations of these five SNVs by this method in 288 Japanese subjects were in complete agreement with those by hemagglutination assay, although we did not find any A2 (alleles containing c.1061delC) or O.02 (alleles containing c.802G>A) alleles. The present triplex probe-based FMCA is a valid and credible method for a considerably accurate large-scale determination of ABO allele genotypes and estimation of phenotypes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Lewis histo-blood group phenotypes are regulated by the action of FUT3-encoded α(1,3/1,4)fucosyltransferase and FUT2-encoded α(1,2)fucosyltransferase. Since Lewis phenotypes are suggested to be associated with various clinical conditions, a method for large-scale FUT3 genotyping is desirable. In worldwide populations, 508G>A and 1067T>A of FUT3 are two of three common causal single nucleotide polymorphisms for Lewis-negative alleles., Materials and Methods: We developed a duplex Eprobe-mediated melting curve analysis for genotyping 508G>A and 1067T>A simultaneously and applied this method to 106 Ghanaian and 140 Japanese subjects., Results: The results of both 508G>A and 1067T>A genotyping by duplex Eprobe-mediated melting curve analysis were completely in agreement with the results of a DNA sequence analysis in 106 Ghanaians and polymerase chain reaction-restriction fragment length polymorphism analysis in 140 Japanese subjects., Conclusion: The present duplex Eprobe-mediated melting curve analysis is valid and credible for large-scale estimation of Lewis-negative alleles., (© 2022 International Society of Blood Transfusion.)

Background: The ABO(H) secretor status is controlled by FUT2-encoded α(1,2)fucosyltransferase (Se enzyme) activity. Three SNPs of FUT2, 302C>T (rs200157007), 385A>T (rs1047781), and 428G>A (rs601338), cause three major variants of nonsecretor (se) or weak-secretor (Se w ) alleles. Evidence has been accumulating that suggests the secretor status is associated with various conditions including infectious diseases but a robust multiplex method for assaying relatively large-scale samples to determine the genotype of these three SNPs simultaneously has not been developed yet., Methods: By combined usage of two Eprobes and a dual-labeled fluorescence probe, we developed a real-time PCR, followed by triplex probe-based fluorescent melting-curve analysis (FMCA) for genotyping of 302C>T, 385A>T, and 428G>A of FUT2 in a single tube., Results: Three genotypes of each of three variants of FUT2 were accurately determined by the triplex probe-based FMCA. We then validated this method using genomic DNA samples of 47 Bangladeshis, and the results obtained by using this method were fully concordant with those by previous Sanger sequencing., Conclusions: Since the present single triplex probe-based FMCA is robust, fast, and cost-effective, we are able to effectively estimate the secretor status of subjects on a large scale in many populations around the world., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Objectives: The expression of type 1 chain Lewis blood group antigens is regulated by secretor-type α(1,2)fucosyltransferase, encoded by FUT2, and Lewis α(1,3/1,4)fucosyltransferase, encoded by FUT3. Accumulating evidence has linked Lewis phenotypes or genotypes to various clinical conditions. Thus, in addition to FUT2, large-scale FUT3 genotyping is important. Because FUT3 has two paralogous genes (FUT5 and FUT6) with high DNA sequence similarity, we should select the polymerase chain reaction (PCR) primers carefully for FUT3 genotyping. Previously, we suggested that 13G>A (rs28362458), 59T>G (rs28362459) and 202T>C (rs812936) could be selected as tag single nucleotide polymorphisms (SNPs) for detection of Lewis-negative alleles (le)., Materials and Methods: In this study, three high-resolution melting (HRM) analyses for genotyping these SNPs were developed and applied for 140 Japanese, eight Ghanaians and four Sinhalese subjects., Results: Each of three genotypes of 13G>A (G/G, G/A, A/A), 59T>G (T/T, T/G, G/G) and 202T>C (T/T, T/C, C/C) was discriminated clearly. Although we need to be careful in interpretation of results due to SNPs other than the 59T>G in the amplicon, the results of 59T>G genotyping were in full agreement with the results by a previous PCR-restriction fragment length polymorphism analysis in 140 Japanese. In addition, three heterozygotes of 202C substitution were identified, and no one having a 13A substitution was found in 140 Japanese., Conclusion: The present HRM analyses are useful and reliable methods for large-scale estimation of le alleles., (© 2021 International Society of Blood Transfusion.)

The se del allele is one of the nonsecretor alleles (se) of FUT2 generated by an Alu-mediated recombination event and was first found in Indian Bombay phenotype individuals who have anti-H, anti-A, and anti-B antibodies in their serum. As well as anti-A, and anti-B antibodies, anti-H is clinically significant because it causes sever hemolytic transfusion reactions. Like se del , se 302 having a missense single nucleotide polymorphism (SNP), 302C > T, is characteristic of South Asians with a frequency of 10-30%. We developed a real-time PCR melting curve analysis for detection of se del using a 127-bp amplicon encompassing the breakpoint junction. In addition, by performing duplex PCR by amplifying a 65-bp amplicon of the FUT2 coding region at the same time, we could determine the zygosity of se del in a single tube. We also developed an Eprobe-mediated PCR assay (Eprobe-PCR) for detection of 302C > T of FUT2. These methods were validated by analyzing 58 Tamils and 54 Sinhalese in Sri Lanka. Both the duplex PCR melting curve analysis for determination of se del zygosity and the Eprobe-PCR assay for detection of 302C > T exactly determined three genotypes. In addition, the results of the present methods were in complete agreement with those obtained by previously established methods. The two present methods were reliable and seem to be advantageous for large-scale association studies of FUT2 polymorphisms in South Asian populations., (© 2021. The Author(s).)

FUT2 encodes galactoside 2-α-l-fucosyltransferase 2 which determines the secretor status of ABO(H) blood group antigens. Secretors have at least one functional FUT2 allele (Se), while nonsecretors or weak secretors are homozygous for nonfunctional (non- or weak secretor) FUT2 alleles (se or Se w ). The Se w having the 385A>T missense SNP (rs1047781) is the prevalent nonfunctional allele in East and Southeast Asians. In this study, we developed an unlabeled-probe high-resolution melting (HRM) analysis for genotyping of 385A>T and validated the method by analyzing 72 Japanese whose 385A>T genotypes were confirmed by DNA sequencing. The unlabeled-probe HRM analysis clearly discriminated three genotypes of 385A>T. In addition, the results obtained for the 72 Japanese by this method were fully concordant with previous ones. Estimation of secretor status using this cost-effective method may be useful in East and Southeast Asian populations., (© 2021 Wiley-VCH GmbH.)

The expression of ABO antigens in human saliva is regulated by the FUT2 gene, which encodes a secretor type α(1,2)fucosyltransferase. Secretors express ABO substrates in saliva and non-secretors do not. Secretor status is an object of concern, especially for susceptibility to various infectious diseases. A multitude of single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) have been reported, and they show unique distributions among different populations. In this study, we selected 18 uncharacterized FUT2 alleles listed in the Erythrogene database and obtained genomic DNA having these alleles. We experimentally confirmed the haplotypes, but 10 of 18 alleles disagreed with those in the database, which may be attributed to their low frequency. We then examined the activity of the encoded α(1,2)fucosyltransferase for 13 alleles by flow cytometry of H antigen expression. The impact of each nonsynonymous SNP on the enzyme was also estimated by software. We finally identified two non-secretor alleles (se 610 and se 357,856,863 ) and one weak secretor allele (se 262,357 ), while in silico analysis predicted that many alleles impair the function. The present results suggest that correct haplotyping and functional assays are desirable for analysis of the FUT2 gene.

Several genetic polymorphisms of the haptoglobin gene (HP) or haptoglobin-related gene (HPR) were reported to show a population-specific distribution and to be associated with not only serum haptoglobin (HP) but also cholesterol levels. For such association studies, it is important to know the distribution of polymorphisms or their haplotypes in the populations concerned. However, no comprehensive genetic studies have explored this in Latin Americans, and not every human variation or genotype is available in a database. In this study, we determined the genotypes of common HP (HP 1 and HP 2 ), HP del , rs5471, rs5472, and rs2000999 in several Latin American populations. Haplotypes of rs5472-common HP-rs2000999 polymorphisms were estimated. We did not encounter any HP del , and the frequencies of rs5471 A, rs5472 A, HP 1 , and rs2000999 G were higher than their counterpart alleles in studied populations. All of the alleles with higher frequency in the Latin Americans are associated with higher serum HP and lower cholesterol levels. Both A-1-G (probably HP 1S ) and G-1-G (probably HP 1F ) haplotypes were higher in Latin American populations than those in other geographic regions. In addition, the genetic influx from populations of other continents into Peruvians seems to be relatively lower than that into other Latin Americans.

Background: The human FUT2 gene, which encodes a secretor type α(1,2)fucosyltransferase, is reported to have several population-specific single-nucleotide polymorphisms (SNPs) and copy number variations. However, little is known about genetic variation of FUT2 in Native Americans., Study Design and Methods: To detect SNPs and copy number variations of the FUT2 gene in Peruvians, direct sequencing and digital polymerase chain reaction were performed. Haplotypes of observed SNPs were estimated by PHASE software or cloning into plasmids. The functional significance of nonsynonymous SNPs was examined by transient transfection assay., Results: We identified three novel nonfunctional alleles (se 178,357 , se 841 , and se del4 ) due to two nonsynonymous SNPs (178C > T and 841G > A) and a novel long terminal repeat-mediated recombination with a 4.3-kb deletion in 70 Peruvians. The frequency of nonfunctional alleles was relative low (20.7%). Because se 841 has a relatively high frequency (5.7%), it might be a suitable genetic marker for Peruvians., Conclusion: We identified three novel nonfunctional alleles in 70 Peruvians. To our knowledge, this is the first time a long terminal repeat-mediated gene recombination event at the FUT2 locus has been detected., (© 2019 AABB.)

DNA fragmentation factor beta (DFFB) polypeptide, endonuclease G (EndoG), and Flap endonuclease-1 (FEN-1) are responsible for DNA fragmentation, a hallmark of apoptosis. Although the human homologs of these genes show three, four, and six nonsynonymous single-nucleotide polymorphisms (SNPs), respectively, data on their genotype distributions in populations worldwide are limited. In this context, the objectives of this study were to elucidate the genetic heterogeneity of all these SNPs in wide-ranging populations, and thereby to clarify the genetic background of these apoptosis-related endonucleases in human populations. We investigated the genotype distribution of their SNPs in 13 different populations of healthy Asians, Africans, and Caucasians using novel genotyping methods. Among the 13 SNPs in the 3 genes, only 3 were found to be polymorphic: R196K and K277R in the DFFB gene, and S12L in the EndoG gene. All 6 SNPs in the FEN-1 gene were entirely monoallelic. Although it remains unclear whether each SNP would exert any effect on endonuclease functions, these genes appear to exhibit low degree of genetic heterogeneity with regard to nonsynonymous SNPs. These findings allow us to conclude that human apoptosis-related endonucleases, similarly to other human DNase genes, revealed previously, are well conserved at the protein level during the course of human evolution.

Arsenic causes DNA damage and changes the cellular capacity for DNA repair. Genes in the base excision repair (BER) pathway influence the generation and repair of oxidative lesions. Single nucleotide polymorphisms (SNPs) in human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys; apurinic/apyrimidinic endonuclease (APE1) Asp148Glu; X-ray and repair and cross-complementing group 1 (XRCC1) Arg280His and Arg399Gln in the BER genes were analyzed, and the relationship between these 4 SNPs and the urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations of 100 Vietnamese population exposed to arsenic was investigated. Individuals with hOGG1 326Cys/Cys showed significantly higher urinary 8-OHdG concentrations than did those with 326 Ser/Cys and Ser/Ser. As for APE1 Asp148Glu, heterozygous subjects showed significantly higher urinary 8-OHdG concentrations than did those homozygous for Asp/Asp. Moreover, global ethnic comparison of the allelic frequencies of the 4SNPs was performed in 10 population and previous reported data. The mutant allele frequencies of hOGG1 Ser326Cys in the Asian populations were higher than those in the African and Caucasian populations. As for APE1 Asp148Glu, Caucasians showed higher mutant frequencies than those shown by African and Asian populations. Among Asian populations, the Bangladeshi population showed relatively higher mutant allele frequencies of the APE1 Asp148Glu polymorphism. This study is the first to demonstrate the existence of genetic heterogeneity in a worldwide distribution of SNPs (hOGG1 Ser326Cys, APE1 Asp148Glu, XRCC1 Arg280His, and XRCC1 Arg399Gln) in the BER genes., (Published by Elsevier Inc.)

The single-nucleotide polymorphisms (SNPs) in the human DNase I gene (DNASE1) might be involved in susceptibility to some common diseases; however, only limited population data are available. Further, the effects of these SNPs on in vivo DNase I activity remain unknown. The genotype and haplotype of all the SNPs in DNASE1 were determined in 3 ethnic groups including 14 populations using newly developed methods. Together with our previous data on the nonsynonymous SNPs, two major haplotypes based on the five exonic SNPs were identified; genetic diversity in the Asian population was low. Among 10 SNPs, other than exonic SNPs in the gene, only 3 were polymorphic among all the populations. Haplotype distribution, based on all the polymorphic SNPs, was clarified to be generally varied in an ethnic-dependent manner. Thus, the genetic aspects of DNASE1 with regard to all the SNPs in wide-ranging ethnic groups could be first demonstrated. Further, there was no correlation of all the polymorphic SNPs other than nonsynonymous ones with serum DNase I activity levels. Polymorphic SNPs other than the exonic SNPs might not be directly related to common diseases through alterations in in vivo levels of the activity.

Several SNPs in the deoxyribonuclease I-like 1 (DNase 1L1) and DNase 1L2 were investigated. In the present study, the genotype distributions of three synonymous SNPs (V59V, rs1050095; P67P, rs1130929; A277A, rs17849495) in the DNase 1L1 gene and four non-synonymous SNPs, V122I (rs34952165), Q170H (rs6643670), and D227A (rs5987256) in the DNase 1L1 gene, as well as D197A (rs62621282) in the DNase 1L2 gene were investigated in 13 populations. In all the populations, no variation was found in four SNPs (V59V, Q170H, D227A, and A277A) in DNASE1L1 or in D197A in DNASE1L2. As for V122I, only the German population showed a low degree of polymorphism. The SNP V122I in DNASE1L1 was monoallelic for the G-allele in all of the Asian and African populations examined, with no polymorphism being evident. Since the A-allele in SNP V122I was distributed in only the Caucasian populations, not in the other ethnic groups, it was confirmed that the A-allele in SNP V122I was Caucasian-specific. On the other hand, only P67P in DNASE1L1 was polymorphic among three synonymous SNPs. The effect of nucleotide substitution corresponding to polymorphic SNP P67P on DNase 1L1 activity was examined: the corresponding nucleotide substitution in polymorphic SNP P67P has little effect on the DNase activity.

A reduction of deoxyribonuclease I (DNase I) activity levels in the serum of patients with autoimmune diseases has been reported. The objectives of this study were to clarify genetic and biochemical aspects of 12 non-synonymous SNPs in the human gene (DNASE1), potentially giving rise to an alteration in the in vivo DNase I activity levels. Genotyping of all the non-synonymous SNPs was performed in healthy subjects of three ethnic groups including 15 populations using newly developed methods. Among them, only four SNPs, R-21S, Y95S, G105R, and Q222R were polymorphic in all or some populations; Asian group showed a relatively low genetic diversity of these SNPs. Furthermore, the distribution pattern of the common SNP Q222R was classified into three ethnic groups. The activity levels of the amino acid-substituted DNase I forms derived from SNPs R-21S, G105R, P132A, and P197S were significantly high compared with that of the wild-type; the polymorphic SNPs R-21S and G105R gave rise to a high activity-harboring DNase I isoform. On the other hand, activity levels from Q35H, R85G, V89M, C209Y, Q222R, and A224P were significantly low, but these SNPs, except Q222R, were not distributed in any of the populations. However, since these SNPs may produce potentially low levels of in vivo DNase I activity, a minor allele in each SNP will be served as a genetic risk factor for autoimmune diseases. These findings on non-synonymous SNPs in DNASE1 may provide a biochemical-genetic basis for the clarification of a possible relationship between DNase I and the diseases., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: To validate the association of a single nucleotide polymorphism (SNP) of the connective tissue growth factor gene (CTGF) with susceptibility to systemic sclerosis (SSc) in the Japanese population., Methods: 395 Japanese patients with SSc, 115 patients with rheumatoid arthritis and 269 healthy Japanese volunteers were enrolled in the study. An SNP (rs6918698) at -945 bp from the start codon in the promoter region of the CTGF gene was determined by allelic discrimination with the use of a specific TaqMan probe., Results: The G allele showed a significantly higher frequency in patients with SSc than in controls (p<0.001; odds ratio 1.5; 95% confidence interval 1.2 to 1.9). In particular, the clinical subsets of SSc showed a more significant association between the G allele and diffuse cutaneous SSc (p<0.001) and the presence of interstitial lung disease (p<0.001), the presence of anti-topoisomerase I antibody (p<0.001) and anti-U1RNP antibody (p = 0.010). Association analyses using the genotype of the SNP yielded results similar to those of analyses using the allele., Conclusions: This study confirms the association between an SNP in the CTGF gene and susceptibility to SSc, especially in the presence of diffuse cutaneous SSc, interstitial lung disease and anti-topoisomerase I antibody. The results strongly suggest that this SNP may be a powerful indicator of severe skin and lung involvement in patients with SSc.

Background: The FUT3 gene regulates the expression of Lewis blood group antigens. Several lines of evidence suggest association between expression of these antigens and Helicobacter pylori infection or susceptibility to cardiovascular diseases. Single-nucleotide polymorphisms (SNPs) responsible for the Lewis-negative phenotype have been reported, but systematic sequence analyses have not yet been performed., Study Design and Methods: The polymerase chain reaction product containing the whole FUT3 coding region (1086 bp) was sequenced in three human populations, Ghanaians (n = 106), Caucasians (n = 100), and Mongolians (n = 50). Some haplotypes were determined by sequencing cloned inserts, and the other haplotypes were inferred by the free software program PHASE. Also examined was the functional significance of several newly identified SNPs by a transient expression study., Results: Thirty-two SNPs were found, including 15 novel SNPs, in the three populations. The functional impact of three nonsynonymous SNPs that occurred on the Lewis-positive alleles or weakly enzyme-inactivating alleles was examined. A transient expression study suggested that 478C>T and 968G>C are enzyme-inactivating mutations., Conclusion: Sequence analysis identified many SNPs, but most of them are in complete linkage disequilibrium with previously reported SNPs responsible for the Lewis-negative phenotype. 13G>A, 59T>G, and 202T>C seem to be useful as tag SNPs for detection of Lewis-negative alleles in genotyping of Lewis blood groups and large-scale association studies with diseases in many populations.

Background: The single nucleotide polymorphism (SNP) at deoxyribonuclease I (DNase I) in exon 8 (A2317G: Gln222Arg) has been shown to be associated with several diseases., Methods: The allele frequency of the DNASE1 polymorphism in Chinese (Shenyang and Guangzhou in China), Uygurs (Urumqi), Tamils (Sri Lanka), and Tibetans (Katmandu in Nepal) was investigated, and the results were compared with those of other studies., Results: This study revealed that DNASE1*1 is more common in Africans and DNASE1*2 is more common in Caucasians. Expression vectors of DNASE1*1 and DNASE1*2 were constructed and compared to the enzyme properties secreted into a medium from transfected COS-7 cells. The activity of the type-2 enzyme was significantly higher than that of the type-1 enzyme. In addition, the type-1 enzyme was heat-labile when compared to the type-2 enzyme. Moreover, the optimum pH of the DNase I type-2 enzyme was more acidic than that of DNase I type-1., Conclusions: This study revealed that the distribution of Gln222Arg in the DNASE1 gene is different among ethnic groups and that the DNASE1 polymorphism appears to affect the specific activity, heat sensitivity, and optimum pH of the DNase I enzyme.

Background: Many single-nucleotide polymorphisms (SNPs) have been identified in the coding region of the FUT2 locus, which encodes secretor type alpha(1,2)fucosyltransferase. These SNPs are highly population-specific., Study Design and Methods: The 1121-bp polymerase chain reaction (PCR) product containing the whole FUT2 coding region in three human populations, Ovambos (n = 74), Turks (n = 70), and Mongolians (n = 118), was sequenced. The haplotypes consisting of novel SNPs were determined by sequencing cloned inserts, and the haplotypes consisting of already reported SNPs were inferred by free computer software (PHASE). The functional significance of novel SNPs by transient expression study was also examined., Results: Twenty-four SNPs were found including seven novel SNPs (i.e., 4G > A, 244G > A, 442C > A, 489G > A, 569G > A, 665G > A, and 950C > T). A transient expression study suggested that the 244G > A, 569G > A, and 950C > T SNPs are enzyme-inactivating mutations., Conclusion: This study identified 24 SNPs in the FUT2 gene, of which 7 were novel. The frequencies of alleles and genotypes were determined in Ovambos, Turks, and Mongolians. The allelic composition of each population was similar to those of geographically closer populations.

Many single nucleotide polymorphisms (SNPs) have been identified in the coding region of the FUT2 locus, which encodes secretor type alpha(1,2)fucosyltransferase. In this study, we analyzed the sequence variations in the proximal promoter region of FUT2 in several human populations. In African populations, we found two SNPs with intermediate frequency that affected the promoter activity in vitro with a cell type-specific pattern. On the other hand, these two African SNPs were rarely detected outside Africa. Linkage disequilibria (LD) were observed between some haplotypes of the promoter and coding regions, although no characteristic promoter haplotype was linked with the se(428) allele of the coding region, which is estimated to be old. The present results suggest that the pattern of variation in the proximal promoter differs between Africans and non-Africans.

Although co-trimoxazole (trimethoprim-sulphamethoxazole) is an effective drug for prophylaxis against and treatment of Pneumocystis pneumonia, patients often experience adverse events with this combination, even at prophylactic doses. With the aim being to achieve individual optimization of co-trimoxazole therapy in patients with systemic lupus erythematosus (SLE), we investigated genetic polymorphisms in the NAT2 gene (which encodes the metabolizing enzyme of sulphamethoxazole). Of 166 patients with SLE, 54 patients who were hospitalized and who received prophylactic doses of co-trimoxazole were included in the cohort study. Adverse events occurred in 18 patients; only two experienced severe adverse events that lead to discontinuation of the drug. These two patients and three additional ones with severe adverse events (from other institutions) were added to form a cohort sample and were analyzed in a case-control study. Genotype was determined using TaqMan methods, and haplotype was inferred using the maximum-likelihood method. In the cohort study, adverse events occurred more frequently in those without the NAT2*4 haplotype (5/7 [71.4%]) than in those with at least one NAT2*4 haplotype (13/47 [27.7%]; P = 0.034; relative risk = 2.58, 95% confidence interval = 1.34-4.99). In the case-control study the proportion of patients without NAT2*4 was significantly higher among those with severe adverse events (3/5 [60%]) than those without severe adverse events (6/52 [11.5%]; P = 0.024; odds ratio = 11.5, 95% confidence interval = 1.59-73.39). We conclude that lack of NAT2*4 haplotype is associated with adverse events with co-trimoxazole in Japanese patients with SLE.

The two genes SLC24A5 and SLC45A2 were recently identified as major determinants of pigmentation in humans and in other vertebrates. The allele p.A111T in the former gene and the allele p.L374F in the latter gene are both nearly fixed in light-skinned Europeans, and can therefore be considered ancestry informative marker (AIMs). AIMs are becoming useful for forensic identification of the phenotype from a DNA profile sampled, for example, from a crime scene. Here, we generate new allelic data for these two genes from samples of Chinese, Uygurs, Ghanaians, South African Xhosa, South African Europeans, and Sri Lankans (Tamils and Sinhalese). Our data confirm the earlier results and furthermore demonstrate that the SLC45A2 allele is a more specific AIM than the SLC24A5 allele because the former clearly distinguishes the Sri Lankans from the Europeans.

Two missense polymorphisms (E272K and L374F) of the AIM1 locus, encoding a melanocyte differentiation antigen, were shown to have a clear association with human ethnicities. These two nonpathogenic single nucleotide polymorphisms (SNPs) may be associated with human pigmentation variation. In this study, we investigated sequence variation in the coding region and exon-flanking sequence and found low genetic variation only in subjects of European descent. All four statistical tests applied to the 7.55-kb region surrounding the L374F polymorphism detected statistically significant deviations from selective neutrality in Europeans. In addition, haplotype analysis revealed that one haplotype carrying 374F was overrepresented in this population, and the low rate of variation, with some features of selective sweeps, was shown to be statistically significant. These results suggest that positive selection recently has been acting or has acted on at least this region of the melanogenic gene and that an advantageous haplotype spread rapidly in Europe.

We have investigated the genetic basis for the Hp0 phenotype amongst 123 randomly selected Ghanaians. A total of 17 individuals were determined to be Hp0 phenotype, based on the classical method for Hp phenotyping of Hb-supplemented plasma. Out of the 17 Hp0 individuals, nine subjects were further classified as ahaptoglobinaemic and eight as hypohaptoglobinaemic by Western blots and double immunodiffusion. We identified three previously known base substitutions (A-55G, A-61C and T-104A) and three new ones (C-101G, T-191G and C-242T) within the 5' flanking region of the Hp gene. The A-61C base substitution significantly decreased transcriptional activity and was associated strongly with Hp2 allele and ahaptoglobinaemia. The C-101G substitution was similar in transcriptional activity to the wild-type and was associated with Hp1S allele and hypohaptoglobinaemia. The Hpdel allele seen in Asian populations was absent. We conclude that the Hp0 phenotype in Ghana has a genetic basis that differs significantly from that seen in Asia.