Search

Background: The serum haptoglobin (HP) level varies in various clinical conditions and among individuals. Recently, the common HP alleles, rs5472, and rs2000999 have been reported to associate with serum HP level, but no studies have been done on Africans. Here, we explored the relationship of not only these polymorphisms but also rs5470 and rs5471 to the serum HP level in 121 Ghanaians., Methods: Genotyping of rs2000999 was performed by PCR using hydrolysis probes, while the other polymorphisms have been already genotyped. Serum HP level was measured by a sandwich ELISA., Results: We observed a significant association between rs5471 and the serum HP level (p = 0.026). It was also observed within the subgroups of HP 2 /HP 2 and HP 2 /HP 1 . In addition, we detected a trend toward lower HP levels for individuals with the A allele of rs2000999 than those without A, but it was not statistically significant (p = 0.156). However, we did not observe the clear associations between other polymorphisms and serum HP level that were observed for Europeans and Asians because of the small sample size and the complexity of SNPs affecting the HP level., Conclusions: We suggest that rs5471 is a strong genetic determinant of HP levels in Ghanaians, and this seems to be characteristic of Africans. Further investigation using large scale samples will help in understanding the genetic background of individual variability of the serum HP level., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in castration-resistant prostate cancer (CRPC) patients before administration of PPV. Cox regression analysis revealed that mRNA expression of myeloperoxidase, haptoglobin, and neutrophil elastase was significantly associated with overall survival (OS) among vaccinated CRPC patients (adjusted P < 0.01). By promoter sequence analysis of these three genes, we found that rs5472 of haptoglobin (HP), an acute-phase plasma glycoprotein, was strongly correlated to OS of vaccinated CRPC patients (P = 0.0047, hazard ratio 0.47; 95 % confidence interval 0.28-0.80). Furthermore, both HP mRNA expression in PBMCs and protein level in plasma of CRPC patients before administration of PPV exhibited rs5472 dependence (P < 0.001 for mRNA expression and P < 0.05 for protein level). Our findings suggest that rs5472 may play an important role in the immune response to PPV via regulation of HP. Thus, we concluded that rs5472 is a potential prognostic biomarker for PPV.

Three polymorphisms, Paraoxonase 1 (PON1) Q192R (C/G), endothelial nitric oxide synthase (eNOS) E298D (G/T) and eNOS T-786C have been suggested to be potentially associated with coronary artery spasm in Japanese patients. Data on worldwide populations are needed to clarify whether these associations could hold true for other populations. However, few data are available especially in Africans, spasm of which has been suggested to be an aetiology of myocardial infarction. Therefore, these polymorphisms were investigated in three Africans, Ovambos (n = 123), Ghanians (n = 118) and Xhosas (n = 96), together with Japanese (n = 96), by using polymerase chain reaction-restriction fragment length polymorphism analysis. Genotype-distributions of all these SNPs in African populations were significantly different from those in Caucasians, whereas were similar to those in Japanese population. African populations exhibit relatively higher frequency of spasm-associated G192 allele in PON1 Q192R being similar to Japanese population, however frequencies of spasm-associated T298 allele and -C786 allele in SNP eNOS E298D and T-786C, respectively, were conversely lower in Africans than Caucasians. Although healthy subjects have been recruited in this study, these findings may provide genetic background for elucidation of aetiology of spasm., (Copyright © 2011 John Wiley & Sons, Ltd.)

We recently identified a 42bp Variable Number of Tandem Repeats polymorphism in intron 4 of Cold-induced autoinflammatory syndrome 1 gene (CIAS1 42bp-VNTR), which are associated with CIAS1 gene expression and some inflammatory disease. The aim of our study is to investigate whether variability of CIAS1 42bp-VNTR allele is difference among races. A total of 1291 subjects from 7 populations (178 Chinese, 95 Korean, 614 Mongolian, 49 Bangladesh, 72 Sri Lanka, 192 African and 91 European) was genotyped on CIAS1 42bp-VNTR polymorphism, which was also compared to previous genotyping data from 508 Japanese subjects. A total of 11 genotypes and 5 alleles were found in 8 populations. The range of allele frequencies of CIAS1∗6, CIAS1∗7, CIAS1∗9, CIAS1∗12, and CIAS1∗13 were 0.000-0.167, 0.056-0.248, 0.008-0.203, 0.570-0.923, and 0.000-0.104 in eight populations. The CIAS1∗12 was the most common allele among all populations. The longest allele CIAS1∗13 in African population was extremely high frequent at 0.104 compared to other population. While shortest allele CIAS1∗6 was not observed Sri Lankan and African. Frequency (0.924) in the Sri Lankan population. These results showed that the CIAS1 42bp-VNTR polymorphism could represent genetic diversity among different human populations., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Haptoglobin (Hp) polymorphisms have been suggested to be associated with many pathological conditions including cardiovascular diseases, infectious diseases, and type 2 diabetes., Methods: We examined the association between HP genotypes and type 2 diabetes or anthropometric and clinical features in 946 Mongolians. HP genotypes were determined by two methods, TaqMan-based real-time PCR and conventional PCR. Hp phenotyping was also performed by polyacrylamide gel electrophoresis and peroxidase staining in a few selected samples., Results: The 2 HP genotyping methods showed consistent results in 943 of 946 samples. Three samples that showed different results in the 2 PCR methods were determined to be heterozygous for the Hp Johnson allele by phenotyping. We did not find any association between HP genotypes and type 2 diabetes or the anthropometric and clinical features examined in the population studied., Conclusions: TaqMan-based HP genotyping is reliable and will be useful for high-throughput association studies. Further studies of large numbers of subjects and functional differences in Hp types are needed.

Background: The haptoglobin gene (HP) has 2 common codominant alleles (HP(1) and HP(2)) that account for 3 phenotypes. HP(2) is generated by a 1.7-kb intragenic duplication of HP(1)., Methods: We used the real-time TaqMan PCR system to develop an effective method for HP genotyping that allows us to evaluate the relative number of copies of the HP(2) allele-specific junctional region of the 1.7-kb gene duplication (HP2) by comparing the intensity of the amplification signals to those of the HP promoter region (HP5'), which was used as the internal control. The difference in threshold cycles (DeltaCt) between HP2 and HP5' was used to assess HP(2) copy number. In addition, the assay detects the HP deletion (HP(del)) at the same time., Results: The mean 2(-DeltaDeltaCt) values (the HP2/HP5' ratio) obtained from 123 samples of known HP genotypes clearly differentiated 2 nonoverlapping intervals that correspond to the HP genotypes. Ratios for HP(2)/HP(1) samples ranged from 0.34-0.50, HP(2)/HP(2) samples ranged from 0.79-0.98, and the absence of an HP(2) allele signal was defined as HP(1)/HP(1). We simultaneously detected HP(del). The assay produces results in <1 h., Conclusions: The TaqMan-based real-time PCR method was successfully applied to HP genotyping. The method is easy to use in a molecular diagnosis laboratory, and its robustness and rapidity make it suitable for high-throughput analysis of large populations.

Groundwater pollution by arsenic is a serious worldwide problem, especially in Asian countries. Inter-individual variation in arsenic metabolism has been reported and recent studies demonstrate that 287T allele in human arsenic (+3 oxidation state) methyltransferase (AS3MT) increase the percentage of monomethylated arsenic in urine. The objectives of the present study was to evaluate the ethnic difference in M287T (T/C) polymorphism in AS3MT among Japanese (n=1074), Koreans (n=435), Chinese (n=154), Mongolians (n=246), Uygurs (n=56), Tibetans (n=180), Tamangs (n=53), Tamils (n=58), Sinhalese (n=54), Turks (n=243), Ovambos (n=185), Ghanaians (n=121), Xhosas (n=101), and other four populations from previous studies. Of 17 populations, Xhosas had the highest 287T frequency (0.233). Other African and Caucasian populations had similar287T frequencies above 0.100 with the exception of the Ghanaians (0.071). On the other hand, the Asian populations had relatively lower 287T allele frequencies ranging from 0.000 to 0.041 than the Africans and Caucasians. Our findings indicate that genetic susceptibility to arsenic toxicity in Asian is different from Africans and Caucasians.

Objectives: To investigate the association between single-nucleotide polymorphisms (SNPs) in the pulmonary surfactant protein (SP) genes and the presence or absence of interstitial lung disease (ILD) in SSc patients., Methods: We studied 127 Japanese patients with SSc and 206 normal subjects. Investigated SNPs were C/T within amino acid (aa) 219, Arg219Trp in the SP-A1 gene (rs4253527), C/T within aa 131 (at nucleotide 1580) and Thr131Ile of the SP-B gene (rs1130866). Genotypes were determined by the TaqMan method., Results: Genotype frequencies were not different between the SSc patients and normal controls for both loci. The patients were subsequently divided into two groups based on presence or absence of ILD. In the SNP in the SP-B gene, the frequency of the T/T genotype was significantly lower in the patients with ILD than in those without ILD. Limited in the patients who were positive for anti-Scl-70 antibody, the difference in the frequency of the T/T genotype between the ILD-positive and ILD-negative groups became more apparent. On the other hand, in the SNP in the SP-A1 gene, there was no significant skewing for a certain genotype., Conclusion: In SSc, where massive fibrosis occurs, possession of the T/T genotype in the SP-B gene would reduce the risk of ILD in Japanese.

The sixth complement component (C6) has a common charge polymorphism, C6A and C6B, with similar gene frequencies in all major populations. In addition, C6B2 is also found in Japanese populations at a frequency of about 6%. Sequence analyses of the coding region of three human and ape C6 alleles indicated four nonsynonymous and three synonymous changes in C6*B2 relative to C6*A, suggesting that a recombination event occurred between C6*B2 and C6*A to give rise to C6*B. Sequence variation in a 3.86 kb region encompassing exon 3, where the causal base change of the common C6 polymorphism is found, indicated that several single nucleotide polymorphisms (SNPs) were in extensive linkage disequilibrium (LD), with little differentiation among populations. Sliding window estimates of two test statistics for neutrality revealed significant values in a subregion where the replacement coding polymorphism resides, in all three human populations. These results raise the possibility that the two common C6 alleles in human populations are maintained by balancing selection.

We found a novel polymorphic short tandem repeat (FUT2/01), 3.8 kb downstream of the coding region of FUT2. Seventeen length and 33 sequence variants were identified in 300 individuals representing three major human populations. Africans (Xhosa) and Europeans were characterized by high microvariation, and Japanese were characterized by a simple repeat structure. All exhibited high haplotype diversity.

Polymorphisms of the promoter region (-108C/T) and the coding region (192Q/R) of the paraoxonase 1 gene (PON1) showed differences in association with cardiovascular disease risk in various populations. To characterize the genetic variation underlying these important polymorphisms, we examined DNA sequence variation both in a 1.3-kb promoter region 16.5 kb from codon 192, and in a 1.7-kb region centered on the 192Q/R polymorphic site of the coding region of PON1, in 30 Africans, 30 Europeans and 64 Japanese. We found 10 polymorphic sites and 11 haplotypes in the 1.3-kb promoter region and 10 biallelic polymorphic sites and 10 haplotypes in the 1.7-kb region. From the PON1 sequences of chimpanzees and an orangutan, the ancestral type of codon 192 was found to be R. The number of pairs of polymorphic sites between the promoter and 1.7-kb regions that were in significant linkage disequilibrium was much higher in a Japanese population than in African and European populations. In addition, the pairs of polymorphic sites in linkage disequilibrium differed among the three populations. These results suggest that some of the population differences in association with risk for coronary heart disease can be explained by population differences in haplotype frequency of PON1 haplotypes.

The polyol pathway consists of two enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH); the former is the first enzyme in the polyol pathway, that catalyzes the reduction of glucose to sorbitol, the latter is the second one, that converts sorbitol to fructose using by NAD(+) as a cofactor. We along with others have recently found that SDH activity, the second step in the polyol pathway, might make a greater contribution to the etiology of diabetic retinopathy than does the first step involving AR. In this paper, we propose a novel hypothesis that polymorphisms of SDH gene may be correlated with SDH gene expression levels in diabetic retinas, thus being a valuable genetic marker for diabetic retinopathy., (Copyright 2003 Elsevier Science Ltd.)

Allele frequencies for eight short tandem repeal loci (D16S539, D7S820, D13S317, D5S818, CSF1PO, TPOX, TH01 and vWA) were obtained from samples of 100 Chinese and 96 African (Xhosa) unrelated individuals.

Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye. We, along with others, have very recently found that loss of PEDF is involved in the development and progression of diabetic retinopathy. However, there are no studies on the allelic effects of PEDF gene polymorphism in diabetic retinopathy. In this study, we investigated whether a functional amino acid change, a methionine to threonine polymorphism (Met72Thr polymorphism) of the PEDF gene, is associated with microangiopathy in 143 patients with diabetes. We found that there were no significant associations between PEDF Met72Thr gene polymorphism and diabetic microangiopathy. These observations suggest that these genetic variants might not be involved in the mechanism of diabetic microangiopathy in patients with diabetes.

The polymorphic alleles of the human ABO-Secretor locus (FUT2 or Se) show high heterogeneity and overt ethnic specificity. To provide additional data for analysis to elucidate the origins of populations, we have investigated the allelic polymorphism of FUT2 in 40 unrelated Tibetan and 53 Tamang individuals from Nepal, 42 Indonesian individuals from Surabaya, and 55 Uygur individuals from Urumqi, using DNA sequencing. In Tibetan, Tamang and Indonesian populations, the frequency of a nonfunctional allele, se 357,385, which is found only in Asian populations, was 0.638, 0.509 and 0.631, respectively. In Uygur, the se 428, which is common in Caucasian populations, and the se 357,385 consisting of two common nonfunctional FUT2 alleles, had frequencies of 0.3 and 0.145, respectively. The fixation index (F ST) based on genetic differentiation was obtained pairwise among the four populations in this study and six populations in our previous studies. The results suggested that genetic differentiation among Tibetan, Tamang, Indonesian and East Asian populations is very low, while the distribution feature of the FUT2 alleles in the Uygur population implied an admixture of European with Asian. The distribution of nonfunctional alleles at the FUT2 locus provided further evidence of human migration among the Asian populations.

The coding sequences ( approximately 1 kb) of FUT2 [ABO-Secretor type alpha(1,2)fucosyltransferase] and of FUT6 [plasma alpha(1,3)fucosyltransferase] were analyzed for allelic polymorphism by direct sequencing in five populations. The nucleotide diversities of FUT2 estimated from pairwise sequence differences were 0.0045, 0.0042, 0.0042, 0.0009, and 0.0008 in Africans, European-Africans, Iranians, Chinese, and Japanese, respectively. The nucleotide diversities of FUT6 were 0.0024, 0.0016, 0.0015, 0.0017, and 0.0020 in Africans, European-Africans, Iranians, Chinese, and Japanese, respectively. At FUT2, excesses in pairwise sequence differences compared to the number of polymorphic sites as indicated by a significantly positive Tajima's D were observed in European-Africans and in Iranians. The data do not fit expectations of the equilibrium neutral model with an infinite number of sites. On the other hand, Tajima's D's at FUT6 in each of the five populations and at FUT2 in Africans, Chinese, and Japanese were not significantly different from zero. F(ST) between the Asians and the others measured at FUT2 was higher than at FUT6. These results suggest that natural selection was responsible for the generation of the FUT2 polymorphism in European-Africans and in Iranians.

The human secretor type alpha(1,2)fucosyltransferase gene (FUT2) polymorphism was investigated in Xhosa and Caucasian populations of South Africa by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. Six new base substitutions were found in the coding region of FUT2. A single base (C) deletion at nucleotide 778, which led to a frame shift and produced a stop codon at codon 275, was responsible for the enzyme inactivation. Three nonsynonymous base substitutions, A40G (lle14Val), C379T (Arg127Cys), and G481A (Asp161Asn), and two synonymous base substitutions, A375G (Glu125) and C480T (His160), were also identified in functional alleles. As a result, seven new alleles, Se40, Se481, Se40,481, Se357,480, Se357,379,480, Se375, and se357,480,778 were identified. Population studies revealed that an allele containing a nonsense mutation G428A (Trp143stop) (se428) was the common null allele in both Xhosa and Caucasian populations, whereas an allele containing a missense A385T (Ile129Phe) mutation (se357,385), which is the common null allele in Orientals, was found to be absent from both populations. The heterozygosity rates of FUT2 genotypes were as high as 0.75 in the Xhosa population and 0.65 in the Caucasian population. Therefore, the extensive polymorphism and race specificity of the FUT2 gene make it suitable for application as a new tool in genetic studies of modern human evolutionary history.