Dopamine D1 receptor gene polymorphism is associated with myocardial infarction

Dopamine D1 receptor (DRD1) gene is associated with the pathogenesis of myocardial infarction (MI) in aspects of plaque rupture, platelet aggregation, and neutrophil-mediated injury of cardiac myocytes. Thus, the study was designed to explore whether the A-48G polymorphism of the DRD1 gene was associated with MI. The genotype of the DRD1A-48G polymorphism was determined by polymerase chain reaction in the 602 Han Chinese participants, 255 MI patients and 347 controls without MI. A significant association was found between the A-48G polymorphism of DRD1 and MI (genotype model: χ(2)=13.2, unadjusted p=0.001; χ(2)=13.9, adjusted p=0.0002; dominant model: adjusted OR 2.05, 95%CI 1.40-3.00, p=0.0002; recessive model: adjusted OR 2.34, 95%CI 1.01-5.39, p=0.047). The G allele was a risk-increased allele for MI (unadjusted OR 1.83, 95%CI 1.34-2.50, p=0.0001; adjusted OR 1.94, 95%CI 1.40-2.68, p=0.00007). Thus, the study demonstrated the significant association between A-48G polymorphism of the DRD1 gene and MI.     

A single nucleotide polymorphism at the Vrn-D1 promoter region in common wheat is associated with vernalization response

Facultative wheat varieties adapt to a particular environment. But the molecular basis for the facultative growth habit is not clear relative to winter and spring growth habit. Two sets of wheat varieties were chosen for this study. Set 1 comprised ten spring accessions and Set 2 comprised ten facultative accessions. All accessions had been tested by the previously described allele-specific markers and shown having the same allelic composition of vrn-A1 vrn-B1 Vrn-D1 and vrn-B3. Here we examined whether differences in growth habit might be associated with as yet unidentified sequence variation at Vrn-D1 locus. A region including the intron 1 deletion, the entire reading frame from a cDNA template and a part of promoter region of the dominant Vrn-D1 gene in each of the accessions was sequenced, and a single nucleotide polymorphism was found between facultative accessions and spring accessions in the CArG-box at the promoter region. The novel allele in facultative accessions was designated as Vrn-D1b. The investigation of an F₂ population segregating for Vrn-D1b and Vrn-D1a (previously, Vrn-D1) in the greenhouse under long days without vernalization showed that the plants with Vrn-D1b homozygous allele headed 32?days later and had about three more leaves than the plants with Vrn-D1a homozygous allele. As Vrn-D1b has the same deletion in intron 1 as Vrn-D1a, and, in addition, a single nucleotide mutation at promoter region, and is associated with facultative growth habit, we suggest that the promoter mutation may modify the basal activity level of an allele of VRN1 that is already active (due to the loss of segments in intron 1). Our finding further supports that both the promoter and intron 1 regulatory affect vernalization response and work independently.     

A polymorphism in the promoter region of catalase is associated with blood pressure levels

Catalase is an important antioxidant enzyme that detoxifies H2O2 into oxygen and water and thus limits the deleterious effects of reactive oxygen species (ROS). Because chronic exposure to excess ROS may contribute to vascular damage, we investigated whether genetic variation in catalase was associated with susceptibility to essential hypertension (EHYT) in 324 individuals (at least 50 years old) who were randomly sampled from an isolated population living in Xiangchang, China. They were screened for genetic variation in the promoter of catalase by direct sequencing. In total, four single nucleotide polymorphisms (SNPs) were identified. The association between the SNPs and EHYT was investigated by a linear regression model under phenotypic selection; in our analyses, we used both SBP>150 mmHg and SBP>160 mmHg as thresholds. A SNP 844 bp upstream of the start codon (SNP-844) demonstrated strong evidence of association with EHYT (SBP>150 mmHg: F=5.09, P=0.008; SBP>160 mmHg: F=7.13, P=0.002). This is the first study to implicate genetic variation in catalase in susceptibility to EHYT and suggests that polymorphisms in promoter regions may be particularly relevant to the study of complex diseases.     

Colour polymorphism is associated with lower extinction risk in birds

Colour polymorphisms have played a major role in enhancing current understanding of how selection and demography can impact phenotypes. Because different morphs often display alternative strategies and exploit alternative ecological niches, colour polymorphism can be expected to promote adaptability to environmental changes. However, whether and how it could influence populations' and species' response to global changes remains debated. To address this question, we built an up‐to‐date and complete database on avian colour polymorphism based on the examination of available data from all 10,394 extant bird species. We distinguished between true polymorphism (where different genetically determined morphs co‐occur in sympatry within the same population) and geographic variation (parapatric or allopatric colour variation), because these two patterns of variation are expected to have different consequences on populations' persistence. Using the IUCN red list, we then showed that polymorphic bird species are at lesser risk of extinction than nonpolymorphic ones, after controlling for a range of factors such as geographic range size, habitat breadth, life history, and phylogeny. This appears consistent with the idea that high genetic diversity and/or the existence of alternative strategies in polymorphic species promotes the ability to adaptively respond to changing environmental conditions. In contrast, polymorphic species were not less vulnerable than nonpolymorphic ones to specific drivers of extinction such as habitat alteration, direct exploitation, climate change, and invasive species. Thus, our results suggest that colour polymorphism acts as a buffer against environmental changes, although further studies are now needed to understand the underlying mechanisms. Developing accurate quantitative indices of sensitivity to specific threats is likely a key step towards a better understanding of species response to environmental changes.     

A novel polymorphism in the 5' promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels

Interleukin (IL)-4 exerts its biological effects through binding to the IL-4 receptor (IL4R) complex, plays a central role in stimulating B-cell differentiation, and is crucial for the development of T helper 2 cells. Recently, a soluble form of the human IL4R alpha chain (sIL4R alpha), which is produced by alternate mRNA splicing of exon 8, was discovered. sIL4R is thought to play an important role in either enhancing or inhibiting IL-4 signalling. We analyzed the 5' promoter region of the human IL4R alpha-chain gene (IL4RA) of healthy volunteers by DNA sequencing and found three novel single-nucleotide polymorphisms (SNPs; T-890C, T-1914C, C-3223T) and one novel short tandem repeat [(CAAAA)(5-7)-3600]. The two common promoter region SNPs T-1914C and C-3223T as well as six known coding SNPs in the IL4RA gene were genotyped in healthy blood donors by PCR with sequence-specific primers; total sIL4R levels were measured by ELISA. Results revealed a highly significant association of the -3223T variant with lowered sIL4R levels (two-tailed t-test, P=0.0002). Results remained highly significant after Bonferroni adjustment for multiple comparisons (P=0.0017). Moreover, the C-3223T variant was found to be in strong linkage disequilibrium with the extracellular 150V variant (P<0.001), which was recently described to be associated with atopic asthma in a Japanese population. Since this novel IL4RA promoter region SNP is common (allele frequency 29.8%), we conclude that it may be of importance for the genetic regulation of the IL-4 signalling pathway.     

A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma

Several traits associated with asthma phenotypes, such as high total serum immunoglobulin E and bronchial hyperresponsiveness, have been linked by numerous genome-screen studies and linkage analyses to markers on human chromosome 5q31-q34. In the present article, we describe UGRP1 (encoding uteroglobin-related protein 1) as one of asthma-susceptibility genes that is located on chromosome 5q31-q32. UGRP1 is a homodimeric secretory protein of 17 kDa and is expressed only in lung and trachea. The G --> A polymorphism was identified at -112 bp in the human UGRP1 gene promoter. The -112A allele is responsible for a 24% reduction in the promoter activity in relation to the -112G allele, as examined by transfection analysis. Electrophoretic mobility-shift analysis revealed that an unknown nuclear factor binds to the region around -112 bp. The binding affinity with the -112A oligonucleotide was reduced by approximately one half, as compared with the -112G oligonucleotide. In a case-control study using 169 Japanese individuals (84 patients with asthma and 85 healthy control individuals), those with a -112A allele (G/A or A/A) were 4.1 times more likely to have asthma than were those with the wild-type allele (G/G).     

Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction

Lectin-like oxidized low-density lipoprotein receptor (LOX-1/OLR1) has been suggested to play a role in the progression of atherogenesis. We analyzed the OLR1 gene and found a single nucleotide polymorphism (SNP), G501C, in patients with ischemic heart disease from a single family, which resulted in the missense mutation of K167N in LOX-1 protein. We compared the group of patients with myocardial infarction (MI) (n=102) with a group of clinically healthy subjects (n=102), and found that the MI group had a significantly high frequency of 501G/C+501C/C (38.2%) compared with the healthy group (17.6%; p<0.002). The odds ratio for the risk of MI associated with the 501G/C+501C/C genotype was 2.89 (95% CI, 1.51-5.53). These findings suggest that OLR1 or a neighboring gene linked with G501C SNP is important for the incidence of MI. Manipulating LOX-1 activity might be a useful therapeutic and preventative approach for coronary artery disease, especially for individuals with the G501C genotype of OLR1.     

HindIII polymorphism of lipoprotein lipase gene and risk of myocardial infarction

The purpose of this study was to determine whether HindIII restriction polymorphism found in intron 8 of lipoprotein lipase gene is associated with the onset of myocardial infarction (MI) in Russians and Tartars living in Bashkortostan. HindIII polymorphism was investigated by the polymerase chain reaction in myocardial infarction survivors (males aged under 55 years (98 Russians and 68 Tartars) and in controls (53 Russians and 80 Tartars). The distribution of genotypes and allele frequencies in the controls were as follows: the frequencies of genotypes HindIII(-/-), HindIII(+/-), and HindIII(+/+) in Russians (3.77, 49.06, and 47.17%, respectively) did not differ from those in Tartars (7.50, 51.24, and 41.25%, respectively), while the frequency of HindIII(-) allele was 28.30% in Russians and 33.13% in Tartars. Among Tartars, the HindIII(+/+) genotype was more common in myocardial infarction survivors than in controls (OR 2.03). In the Russians this genotype was not associated with the risk of MI. The frequencies of HindIII(+/+) genotype and allele HindIII(+) were significantly higher (OR 8.96 and 6.71, respectively) and frequencies of HindIII(+/-) genotype and allele HindIII(-) were lower (OR 0.13 and 0.15) in Russian patients with repeated MI. These findings indicate that HindIII polymorphism may be a genetic risk factor for MI before 55 years of age in the Tartars and for repeated MI in Russians. This association prompts genotyping of HindIII polymorphism for predicting MI recurrence in Russian survivors after MI.     

A common ABCC2 promoter polymorphism is not a determinant of the risk of spina bifida

BACKGROUND: There is compelling evidence that the risk of spina bifida, a malformation of the caudal neural tube, is associated with maternal and/or embryonic disturbances in folate/homocysteine metabolism. Hence, functional variants of genes that influence folate/homocysteine metabolism constitute a biologically plausible group of candidate risk factors for spina bifida and other neural tube defects. One such candidate is ABCC2, the gene encoding ABCC2, (a.k.a. canalicular multispecific organic anion transporter [cMOAT], multidrug resistance related protein 2 [MRP2]), a member of the ABC transporter family that effluxes natural folates and anti-folate drugs such as methotrexate. METHODS: The association between the risk of spina bifida and both the maternal and embryonic ABCC2 C(-24)T genotype was evaluated by using the transmission disequilibrium test and log-linear modeling. RESULTS: These analyses provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic ABCC2 C(-24)T genotype. CONCLUSIONS: The results of the present analyses suggest that the C(-24)T variant of the ABCC2 gene is not a major determinant of spina bifida risk.     

Functional polymorphism located in MMP-9 gene promoter is strongly associated with obesity

The adipose tissue expansion is accompanied by remodeling of extracellular matrix performed by matrix metalloproteinases (MMPs). Higher plasma and tissue MMP-9 levels are found in obese; therefore, we evaluated if the functional C(-1562)T polymorphism (rs3918242) located in promoter region of the MMP-9 gene is associated with obesity in women. We studied 112 lean and 114 obese women. Plasma MMP-9 and tissue inhibitor of MMP-9 (TIMP)-1 were measured using enzyme-linked immunosorbent assay. We found different genotype frequencies between lean and obese women (p=0.008), prevailing T-allele in obese (2.3-fold). However, although obese women present higher levels of plasma MMP-9, lack of modulation by the polymorphism was found (all p>0.05). Our findings suggest that C(-1562)T polymorphism may contribute to pathogenetic mechanisms involved in the development of obesity in women.     

A polymorphism in the cyclooxygenase 1 gene is associated with decreased inflammatory prostaglandin F2α formation and lower risk of cardiovascular disease

This study investigates the impact of genetic variation in the cyclooxygenase-1 (COX-1) gene on formation of the vasoconstrictive, pro-inflammatory prostaglandin F_2α (PGF_2α) and development of cardiovascular disease (CVD). We determined COX-1 genotypes, PGF_2α formation and CVD prevalence in a Swedish cohort of 809 men at age 77 years. Of these, 237 had a history of CVD according to the registry data. Four of nine COX-1 single nucleotide polymorphisms were associated with altered formation of PGF_2α (P<0.05). Two COX-1 gene variants (rs10306135 and rs883484) remained significantly associated with altered PGF_2α formation after adjusted significance level for multiple testing (α-level=0.0059). Furthermore, individuals homozygote for the variant allele rs10306135 had lower prevalence of CVD, compared to the common allele (0% versus 30%, P=0.0047). In conclusion, subjects homozygote for the variant allele of a COX-1 gene polymorphism represent a subpopulation of men with decreased PGF_2α formation and lower prevalence of CVD.     

A potentially functional polymorphism in the promoter region of let-7 family is associated with survival of hepatocellular carcinoma

Background: The let-7 family plays a vital role in the normal cellular activity of liver cells and the carcinogenesis of hepatocellular carcinoma (HCC). In the previous study, we have detected the association between single nucleotide polymorphisms (SNPs) in the promoter region of let-7 and susceptibility to HCC. However, it is still unknown whether these polymorphisms are associated with HCC prognosis. Methods: We investigated the effect of two potentially functional SNPs in the promoter region of let-7 family, rs10877887 (T > C) and rs13293512 (T > C), on the overall survival of 331 HCC patients. Log-rank test and Cox proportional hazard models were used for the survival analyses. Results: We found that HCC patients carrying the C allele of rs10877887 had a significantly increased death risk (adjusted HR = 1.22, 95%CI = 1.02–1.47, P = 0.03 in the additive model), compared to those with T allele. In the stratified analysis, the risk effect was evident in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B (adjusted HR = 1.24, 95%CI = 1.02–1.51, P = 0.03) and in those who received chemotherapy or intervention (adjusted HR = 1.25, 95%CI = 1.02–1.53, P = 0.04). Conclusions: Our results suggest that rs10877887 in the promoter region of let-7 may be a prognostic biomarker for HCC patients, which need the validation from other larger studies in different populations.