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deletion/insertion (Del/Ins) polymorphism of 28 base pairs (bp) in the 3′ untranslated region (UTR) of fibrinogen alpha gene ( FGA) was associated with thromboembolic diseases, but the underlying mechanisms remain unknown. Computational predication reveals that the 28 bp polymorphic fragment is complementary to the sequence of a microRNA, miR- 759. In this study, we aim to investigate the association and implicated mechanisms between FGA polymorphisms and the susceptibility to chronic thromboembolic pulmonary hypertension (CTEPH). The Del/Ins polymorphism was analyzed in 190 patients with CTEPH and 628 controls. The FGA 3′UTR and miR- 759 interaction was investigated using luciferase assay and quantitative RT-PCR method. Expression of miR- 759 and FGA in human tissues was investigated by RT-PCR. The results reveal that the allele frequency of Ins was significantly higher in the patients than in the controls (55.8 vs. 47.1%, P = 0.003, odds ratio = 1.42, 95% confidence interval: 1.13–1.79). Both miR- 759 and FGA were expressed in human liver. Co-transfection of miR- 759 decreased the expression and mRNA stability of reporter gene containing the FGA 3′UTR. The effect of miR- 759 was stronger on the Ins allele than on the Del allele. These observations suggest that the expression of FGA was regulated by miR- 759 through its interaction at the polymorphic 3′UTR sequence, which was associated with the susceptibility to CTEPH. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case–control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)=1.63, 95% confidence interval (CI); 1.41–1.89, P=5.0 × 10−11, corrected P (Pc)=4.0 × 10−10) and Korean populations (OR=1.68, 95% CI; 1.41–2.00, P=6.5 × 10−9, Pc=5.2 × 10−9), and a meta-analysis showed a significant association in the East Asian populations (OR=1.65, 95% CI; 1.48–1.85, P=1.8 × 10−18, Pc=1.4 × 10−17), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) has become a major health problem in many countries because of its increasing prevalence and high mortality. Recently, an association of a functional sequence variation, −8C>G, in the human proteasome subunit α type 6 gene (PSMA6) with the susceptibility to CAD was reported. To validate the association, we investigated a total of 1330 cases and 2554 controls from Japanese and Korean populations for PSMA6 genotypes, and no evidence of the association was obtained in both Japanese (odds ratio (OR)=1.03, 95% confidence interval (CI); 0.90–1.19, P=0.66, allele count model) and Korean populations (OR=1.00, 95% CI; 0.86–1.17, P=0.95, allele count model). However, when a meta-analysis of data from this study and previously reported six replication studies was done, OR was 1.08 for the G allele (95% CI; 1.02–1.14, P=0.0057), suggesting that the contribution of PSMA6 to CAD was not large enough to be readily replicated. Further studies are required to establish the contribution of this variant in the susceptibility to CAD.Journal of Human Genetics (2009) 54, 248–251; doi:10.1038/jhg.2009.22; published online 13 March 2009 [ABSTRACT FROM AUTHOR]

Buerger disease (BD) is an occulusive vascular disease of unknown etiology. Although cigarette smoking is a well-known risk factor of BD, genetic factors may also play a role in the etiology. Because chronic bacterial infection such as oral periodontitis is suggested to be involved in the pathogenesis of BD, gene polymorphisms involved in the infectious immunity might be associated with BD as the genetic factor(s). We have previously reported that HLA-DRB1*1501 and B54 was associated with BD in Japanese. In this study, polymorphisms in HLA-DPB1, DRB1 and B were analyzed in 131 Japanese BD patients and 227 healthy controls. In addition, we investigated a functional promoter polymorphism, −260 C > T, of CD14 that is a main receptor of bacterial lipopolysaccharide. It was found that the frequencies of CD14 TT genotype [37.4 vs. 24.2%, P = 0.008 OR = 1.87, 95% confidence interval (CI); 1.18, 2.97], DRB1*1501 (34.4 vs. 13.2%, P c = 4.4 × 10−5, OR = 3.44, 95%CI; 2.06, 5.73) and DPB1*0501 (79.4 vs. 55.1%, P c = 4.7 × 10−5, OR = 3.14, 95%CI; 1.93, 5.11) were significantly higher in the patients than in the controls, demonstrating that at least three genetic markers were associated with BD. Stratification analyses of these associated markers suggested synergistic roles of the genetic factors. Odds ratios ranged from 4.72 to 12.57 in individuals carrying any two of these three markers. These findings suggested that the susceptibility to BD was in part controlled by genes involved in the innate and adaptive immunity. [ABSTRACT FROM AUTHOR]

Multiple single nucleotide polymorphisms (SNPs) within ADAM33 have been reported to be associated with asthma and bronchial hyper-responsiveness in Caucasian populations. We examined whether these SNPs contribute to a predisposition to asthma, especially aspirin-intolerant asthma (AIA), in the Japanese population. Ten polymorphic sites (ST+4, ST+7, T1, T2, T+1, V-3, V-2, V-1, V4, V5) were genotyped in 102 AIA patients, 282 aspirin-tolerant asthma (ATA) patients and 120 control (CTR) subjects by direct sequencing. Haplotype frequencies were estimated by the expectation-maximization method. Differences in allele and haplotype frequencies among phenotypes were analyzed by the chi-square and permutation tests. ST+7, V-1 and V5 sites in the AIA group were significantly different from those in the ATA group ( P=0.034–0.004) and from those in the CTR group ( P=0.019–0.002). Haplotypes at three sites (ST+7, V-1, and V5) were significantly different in frequency between the AIA and ATA ( P=0.008) or CTR ( P=0.001) groups. Sequence variations in ADAM33 are likely to correlate with susceptibility to AIA in the Japanese population. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A( -6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A( -6) variant leads to the intriguing hypothesis that the G( -6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14,400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A( -6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A( - 6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A( - 6)G polymorphism. Further, haplotypes carrying the G( -6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G( -6) variant over the A( -6) variant in non-African populations. However, important localized effects may also be present. [ABSTRACT FROM AUTHOR]

Variation in the angiotensinogen gene, AGT, has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential h-pertension in multiple populations, making AGT a good example of a quantitative-trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4-kb genomic region spanning the entire AGT and identified 44 single-nucleotide polymorphisms (SNPs). Forty-two SNPs were observed both in 88 white and in 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations were found to share all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pairwise linkage disequilibrium (LD), measured by the D[sup'], r[sup2], and d[sup2] statistics, demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r [sup2] values >0.1, whereas this statistic was substantially higher for the white subjects (occurring in 35/39 [90%]). LD between a hypertension-associated promoter mutation, A-6G, and 39 SNPs was also measured. Similar results were obtained, with 33% of the SNPs showing r[sup2]>0.1 in the Japanese subjects and 92% of the SNPs showing r[sup2]>0.1 in the white subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the white sample. These results have important implications for the usefulness of LD... [ABSTRACT FROM AUTHOR]

Abstract We identified a new common amino acid polymorphism of isoleucine/valine at codon 796 in exon 16 of the gene for human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), a central regulator of lipid synthesis and metabolism in animal cells. It can be detected as an Ms/I restriction fragment length polymorphism. The allelic frequencies were: isoleucine (A) allele, 0.57 and valine (G) allele, 0.43. This polymorphism may be useful for genetic studies of disorders affecting intracellular lipid metabolism and hyperlipidemia. [ABSTRACT FROM AUTHOR]

Abstract Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in animal cells. A polymorphic dinucleotide (CA) repeat sequence was isolated from a genomic clone containing the SCAP gene and was mapped to chromosome 3p21.3. High heterozygosity (0.89) makes this polymorphism a useful marker in the genetic study of disorders affecting lipid metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Growth hormone receptor gene (GHR) is one of the likely candidates for determining morphological traits, because GH is a key regulator of bone growth. The genetic association of GHR in exon 10 with mandibular ramus height has been found in different populations, Japanese and Chinese. On the other hand, two common isoforms of GHR, one full-length (fl-GHR) and the other lacking the extracellular domain encoded by exon 3 (d3-GHR), are associated with differences in responsiveness to GH. The purpose of this study involving 159 Korean subjects was to study the associations between a GHR polymorphism (d3/fl-GHR) that results in genomic deletion of exon 3 and craniofacial morphology, and to study the associations between GHR genotypes in exon 10 and craniofacial morphology. Moreover, the allelic frequencies in a multi-ethnic population (24 Han Chinese, 24 African-Americans, 24 European-Americans, and 24 Hispanics) in a GHR polymorphism (d3/fl-GHR) were compared in this study. The five craniofacial linear measurements (cranial base length, maxillary length, overall mandibular length, mandibular corpus length, and mandibular ramus height) obtained from lateral cephalograms were examined as craniofacial morphology. We found that the d3/fl-GHR polymorphism had no association for any measurements, and a statistically significant association (P =0.024) between the GHR polymorphisms P561T and C422F in exon 10 and mandibular ramus height. Neither SNPs besides P561T and C422F polymorphisms in exon 10 nor the measurements besides mandibular ramus height have statistically significances. Both derived alleles at P561T and C422F SNPs were highly associated with only one haplotype, haplotype-4 in Korean population. As quantitative haplotype association, the results showed a significant difference in mandibular ramus height between individuals having one haplotype-4 and others without haplotype-4 (P =0.028). Moreover, we found that the d3/fl-GHR polymorphism showed diverse frequency in different population. Regarding GHR genotypes in exon 10, the present study mostly reflected the results obtained for a Japanese population, although our current study does not replicate the correlation between the I526L polymorphism of GHR and mandibular ramus height as was reported in a previous study of Han Chinese. The results of the present study suggest that the GHR exon 10 SNPs, not d3/fl-GHR, contribute to changes in the mandibular ramus height of Koreans. [Copyright &y& Elsevier]