Vitamin D receptor gene polymorphisms (TaqI and ApaI) in relation to 25-hydroxyvitamin D levels and coronary artery disease incidence

Abstract

Context/objective: Previous studies have illustrated the association of the ApaI and TaqI polymorphisms of the vitamin D receptor gene, located in non-coding and coding regions, respectively, with diseases such as cancer and cardiovascular disease; however, investigating such association in Egyptian patients with coronary artery disease (CAD) has never been formerly attempted. Materials and methods: Male patients (n?=?137), 35–50 years of age, with verified CAD, were recruited alongside age- and sex-matched controls (n?=?58). Genotyping and 25-hydroxyvitamin D [25(OH)D] measurement were performed by polymerase chain reaction RFLP and HPLC, respectively. Results: Comparison of the genotypic distribution of both the TaqI and ApaI polymorphisms between patients and controls yielded insignificant results (p?=?0.55 and 0.7, respectively). Comparison of the allelic distribution of both polymorphisms also yielded insignificant results. The TaqI polymorphism was not found to predict 25(OH)D levels, whereas the wild-type genotype of the ApaI polymorphism was associated with greater levels of 25(OH)D (p?=?0.02), taking all subjects into consideration. Discussion/conclusion: This study presents the ApaI and TaqI polymorphisms as non-influencing players in the pathogenesis of CAD in Egyptian males and the ability of only the ApaI polymorphism to predict 25(OH)D levels, thus warranting further investigations of the triangular relationship between the polymorphisms, 25(OH)D and CAD incidence.     

Angiotensin-converting enzyme (ACE) gene polymorphisms in patients characterised by coronary angiography

The angiotensin converting enzyme (ACE) gene is implicated as a risk factor for coronary artery disease and myocardial infarction (MI). An insertion/deletion (I/D) polymorphism is believed to be in linkage disequilibrium with a functional site elsewhere. Ten polymorphisms have recently been identified in the ACE gene. We screened patients undergoing coronary angiography (n = 258) for six of these polymorphisms (T-5491C, T-93C, A-240T, T1237C, D/I and 4656(CT)_2/3), and identified a further two rare polymorphisms. ACE levels were associated with genotype for all polymorphisms analysed individually by one way ANOVA (P < 0.0005). The polymorphisms occurring in the 5′ region were in negative linkage disequilibrium with the exonic and 3′ region polymorphisms. The A-240T polymorphism had the greatest association with ACE levels (R² = 14%); none of the others were significantly associated with levels when adjustment was made for A-240T. None of the polymorphisms were associated with the extent of coronary atheroma. Two of the promoter polymorphisms (A-240T and T-93C) were weakly related to the occurrence of MI (P = 0.03 and P = 0.05, respectively, by χ² analysis). The TT genotype of A-240T appeared to be protective against MI with an odds ratio of 0.31 (95% confidence interval, 0.12, 0.83). These findings indicate that polymorphisms in the ACE gene promoter region may have a stronger association with disease than the I/D polymorphism. Received: 16 February 1997 / Accepted: 13 May 1997     

Lack of association of glutathione-S-transferase omega 1(A140D) and omega 2 (N142D) gene polymorphisms with urinary arsenic profile and oxidative stress status in arsenic-exposed population

Individual variability in arsenic metabolism is suggested to be associated with the effects of chronic arsenic exposure on health. Glutathione-S-transferase omega (GSTO) 1 and 2 are known to have the activity of monomethyl arsenate [MMA(V)] reductase, which is the rate-limiting enzyme for the biotransformation of inorganic arsenic. This study was conducted to investigate the relationship between polymorphisms in the GSTO1 and GSTO2 genes and arsenic metabolism and oxidative stress status in Chinese populations chronically exposed to different levels of arsenic in drinking water. Two polymorphisms (GSTO1*A140D and GSTO2*N142D) with relatively higher mutation frequencies in the Chinese population were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The allele frequencies of 140D and 142D in the entire study population were 0.17 and 0.25, respectively. There were no significant differences in the urinary arsenic profile, the blood reduced glutathione (GSH) levels, the blood superoxide dismutase (SOD) activity, or the urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels between the study subjects with different genotypes of GSTO1*A140D or GSTO2*N142D. Multivariate analysis revealed that there was no association between the urinary profile or oxidative stress status and the polymorphism of GSTO1*A140D or GSTO2*N142D. Collectively, polymorphisms in GSTO1 or GSTO2 do not appear to contribute to the large individual variability in arsenic metabolism or susceptibility to arsenicosis.     

Studies on DNA markers (D4S10 and D4S43/S127) genetically linked to Huntington's disease in Japanese families

Summary This is the first full report on the genetic linkage between Japanese Huntington's disease and the DNA markers D4S10 and D4S43/S127. With use of the HindIII, BglI, and EcoRI polymorphisms detected at D4S10, and the combination of all these polymorphisms to give composite haplotypes, nine Japanese Huntington's disease families were found to be informative. Three recombinants for D4S10 were detected in these families, giving a maximum lod score of 1.662 at a of 0.10. Similarly, when we used the MspI and PvuII polymorphisms detected by D4S43/S127, five families gave informative results. No recombinant was detected in these families, giving a maximum lod score of 3.348 at a of 0.00. These results clearly support the view that the Japanese Huntington's disease gene may be identical with the Western gene, in spite of the lower prevalence rate in Japan.     

Adh Nucleotide Variation in Drosophila willistoni: High Replacement Polymorphism in an Electrophoretically Monomorphic Protein

Drosophila willistoni was the subject of intensive allozyme studies and the locus coding for alcohol dehydrogenase (Adh) was found to be virtually monomorphic. DNA sequence analysis of 18 alleles throughout the distribution of the species has revealed six replacement polymorphisms. The ratio of replacement to silent polymorphisms is higher in D. willistoni than in any other Drosophila species studied for Adh nucleotide variation. Also in contrast to other species, the variation in introns and noncoding DNA is about the same as in the coding region. We speculate that both these differences indicate D. willistoni has historically had a small population size possibly related to Pleistocene refugia in the Neotropics. Received: 5 August 1996 / Accepted: 12 April 1997     

DNA variation at the rp49 gene region in Drosophila madeirensis and D. subobscura from Madeira: inferences about the origin of an insular endemic species

An ~1.6 ‐ kb fragment spanning the rp49 gene was sequenced in 16 lines of Drosophila subobscura from Madeira and in 22 lines of the endemic species D. madeirensis. Nucleotide diversity in D. subobscura from Madeira (π=0.0081) was similar to that in lines from Spain carrying the O₃₊₄ chromosomal arrangement (π=0.0080). No significant genetic differentiation was detected between insular and continental O₃₊₄ lines of D. subobscura. These results are compatible both with a rather recent and massive colonization, and with multiple colonization events from the continent. Nucleotide diversity in D. madeirensis (π=0.0076) was similar to that in D. subobscura, which deviates from the expectation, under strict neutrality, of a lower level of variation in an insular species with a small population size. The observed numbers of shared polymorphisms and of fixed differences between D. madeirensis and D. subobscura are compatible with the isolation model of speciation, where shared polymorphisms are due to common ancestry.     

Genetic variants in the renin-angiotensin system genes are associated with cardiovascular-renal-related risk factors in Mexican Americans

The aim of this study is to examine whether the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms of the renin-angiotensin system (RAS) genes are associated with cardiovascular and renal-related risk factors in Mexican Americans. Study participants (N = 848) were genotyped by Taqman assays. Association analyses were performed by measured genotype approach. Of the phenotypes examined, the ACE-I/D, AGT-M235T, and AT1R-A1166C polymorphisms exhibited significant association with systolic blood pressure, glomerular filtration rate and body mass index, respectively. The data suggest that the polymorphisms examined in the RAS may modulate the risk factors associated with cardiovascular-renal disease.     

Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics

Association of alleles at the Taql A, Taql B, intron 6, Taql D, exon 7, exon 8, and promoter-141C sites of the D2 dopamine receptor gene with D2 dopamine receptor binding characteristics in the caudate nucleus of Caucasian alcoholic and nonalcoholic subjects was determined. For the Taql D, exon 7, exon 8, and promoter-141C sites there were no significant allelic differences in Bmax (number of binding sites) or Kd (binding affinity) of the D2 dopamine receptors. However, subjects having the minor alleles at the Taql A, Taql B, and intron 6 sites had significantly lower Bmax than subjects not having them. None of these three polymorphisms had any significant effect on Kd. Highly significant linkage disequilibria were observed among the Taql A, Taql B, and intron 6 polymorphic sites, but linkage disequilibria between these three sites and each of the Taql D, exon 7, exon 8, and promoter-141C sites were of lesser or of no significance. Taken together, these findings suggest that the Taql A, Taql B, and intron 6 polymorphisms, but not the Taql D, exon 7, exon 8, and promoter-141C polymorphisms, are in linkage disequilibrium with a functional allelic variant that affects D2 dopamine receptor expression.     

Role of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms and haplotypes in risk of papillary thyroid carcinoma,tumor stage,tumor size,and early onset of tumor: A case control study

Murine double minute clone 2 (MDM2) protein plays an important role in the regulation of p53 tumor suppressor. Genetic polymorphisms of the MDM2 gene are the candidate variants in susceptibility to various cancers. In the present study, we aimed to investigate the possible effects of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms on papillary thyroid carcinoma (PTC) susceptibility and clinical or pathological features of the disease. A case control study was carried out involving in a total of 131 patients with PTC and 144 healthy controls. Both cases and controls were genotyped for MDM2 309T>G and I/D polymorphisms. There was no significant difference regarding MDM2 309T>G and I/D genotypes between patients with PTC and controls in neither dominant nor recessive and allelic models. The frequency of G-D haplotype was higher in patients with PTC and this haplotype was associated with a 1.7-fold increased risk of PTC. The MDM2 309T>G polymorphism was associated with a higher risk of III–IV stages in patients with PTC. The MDM2 ID genotype was significantly higher in patients with PTC less than 40 years and associated with larger tumor size (≥1 cm). In conclusion, the G-D haplotype but not MDM2 309T>G and I/D polymorphisms were associated with higher risk of PTC. MDM2 309T>G polymorphism was associated with a higher incidence of III–IV stages, however, I/D polymorphism was associated with larger tumor size and a lower age of disease occurrence.     

Validation of Dwarf8 polymorphisms associated with flowering time in elite European inbred lines of maize (Zea mays L.)

The timing of transition from vegetative growth to flowering is important in nature as well as in agriculture. One of several pathways influencing this transition in plants is the gibberellin (GA) pathway. In maize (Zea mays L.), the Dwarf8 (D8) gene has been identified as an orthologue of the gibberellic acid-insensitive (GAI) gene, a negative regulator of GA response in Arabidopsis. Nine intragenic polymorphisms in D8 have been linked with variation in flowering time of maize. We tested the general applicability of these polymorphisms as functional markers in an independent set of inbred lines. Single nucleotide primer extension (SNuPe) and gel-based indel markers were developed, and a set of 71 elite European inbred lines were phenotyped for flowering time and plant height across four environments. To control for population structure, we genotyped the plant material with 55 simple sequence repeat markers evenly distributed across the genome. When population structure was ignored, six of the nine D8 polymorphisms were significantly associated with flowering time and none with plant height. However, when population structure was taken into consideration, an association with flowering time was only detected in a single environment, whereas an association across environments was identified between a 2-bp indel in the promoter region and plant height. As the number of lines with different haplotypes within subpopulations was a limiting factor in the analysis, D8 alleles would need to be compared in isogenic backgrounds for a reliable estimation of allelic effects.     

Mito‐nuclear discordance with evidence of shared ancestral polymorphism and selection in cactophilic species of Drosophila

The Drosophila serido haplogroup is a monophyletic group composed of the following four cryptic and cactophilic species that are endemic to eastern Brazil: D. borborema, D. gouveai, D. seriema and D. serido. Here, we investigate the mito‐nuclear discordance in these species found among the cytochrome c oxidase subunit I (COI) mitochondrial gene, the autosomal alpha‐Esterase‐5 (α‐Est5) and the X‐linked period gene (per). Our analysis indicates that shared polymorphisms in these three molecular markers may be explained by the maintenance of ancestral polymorphisms rather than introgressive hybridization. The primary structures of COI, per and α‐Est5 genes evolve primarily under purifying selection, but we detected some sites that evolved under positive selection in α‐Est5. Considering the high variability of cacti species in eastern Brazil and the role attributed to Drosophila esterases in digestion metabolism and/or the detoxification of several compounds found in cactus tissues, we conjecture about the role of natural selection triggered by host shifts as an important factor in the intraspecific diversification of the D. serido haplogroup.     

Taxonomy and geographical distribution of Dugesia japonica and D. ryukyuensis in the Far East

Dugesia japonica Ichikawa et Kawakatsu, 1964, is a common and polymorphic species of freshwater planarian distributed widely in the Far East. In 1976 the geographic populations were separated into 2 subspecies (D.j.japonica and D.j. ryukyuensis). The taxonomy of this species is reconsidered once again from the morphological, anatomical, histological, and karyological viewpoints. From the result of these studies, D.j. ryukyuensis is elevated to the rank of species: D. ryukyuensis Kawakatsu, 1976. D. japonica (n = 8, 2x = 16, 3x = 24) differs from D. ryukyuensis (n = 7, 2x = 14, 3x = 21) in having an asymmetrical penis papilla without a well-developed valve surrounding its basal part, and a well-developed vagina (distribution: the Japanese Islands, Taiwan, the Korean Peninsula, China, and Primorskiy, Northeast Siberia, in Russia). D. ryukyuensis is characterized by an asymmetrical penis papilla with a well-developed valve surrounding its basal part, and a less-developed vagina (distribution: the Southwest Islands of Japan).     

Strain distribution pattern in AXB and BXA recombinant inbred strains for loci on murine Chromosomes 10, 13, 17, and 18

Strain distribution patterns (SDPs) of selected loci previously mapped to murine Chromosomes (Chrs) 10, 13, 17, and 18 are reported for the AXB, BXA recombinant inbred (RI) strain set derived from the progenitor strains A/J (A) and C57BL/6J (B). The loci included the simple sequence length polymorphisms (D10Nds1, D10Mit2, D10Mit10, D10Mit14, D13Mit3, D13Nds1, D13Mit10, D13Mit13, D13Mit7, D13Mit11, D17Mit18, D17Mit10, D17Mit20, D17Mit3, D17Mit2, D18Mit17, D18Mit9, and D18Mit4), the restriction fragment length polymorphisms Pdea and Csfmr, and the biochemical marker AS-1. These loci were chosen because they map to genomic regions that had few or no genetic markers in the AXB, BXA RI set. Several of these loci also were typed in backcross progeny of matings of the (AXB)F₁ to strain A or B. The strain distribution patterns for chromosomes 10, 13, 17, and 18 are reported, and the gene order and map distances determined from the backcross data. The addition of these markers to the AXB, BXA RI strain set increases the genomic region over which linkage for new markers can be detected.     

Paternal inheritance of plastids in the genus Daucus

Summary The plastid DNAs of the species Daucus carota (ssp. sativus, libanotifolia, gingidium), D. maximus and D. muricatus were compared by restriction enzyme analysis. A number of restriction fragment length polymorphisms (RFLPs) were observed. As expected from taxonomic data the degree of plastid DNA homology between D. carota and D. maximus is significantly higher (97%) than between D. carota and D. muricatus (70%). On the basis of RFLPs of plastid DNA the mode of plastid inheritance in interspecific crosses between D. muricatus and D. c. sativus was analysed. The results clearly indicate paternal plastid inheritance. Thus Daucus is the second genus among angiosperms transmitting predominantly male plastids.     

Inversion polymorphism in species of the Drosophila nasuta subgroup from Thailand

Thailand populations of three species of the D. nasuta complex have been analysed for the presence of paracentric inversions. D. albomicans and D. sulfurigaster albostrigata were collected from Phuket, Chiang Mai and the River Kwai, whilst D. kohkoa was found only in Phuket and the River Kwai. Chromosomal polymorphism was studied in respect to geographical distribution. The Phuket populations of all three species proved to be highly polymorphic by comparison with the River Kwai and Chiang Mai populations. The heterozygosity frequencies of inversions were calculated and the variations interpreted as a result of adaptation to local ecogeographical conditions. Shared polymorphisms revealed that D. kohkoa and D. s. albostrigata are more closely related to D. albomicans than they are to each other.Based on a thesis submitted for the degree of Ph.D. in the University of Queensland.     

Associations between polymorphisms in the NR1D1 gene encoding for nuclear receptor REV-ERBα and circadian typologies

Nuclear receptor REV-ERBα, a key component of an internal timekeeping system, has been considered to be related to disrupted circadian rhythms and mood disorder. In this study, we aimed to evaluate the relationship between the genotype frequencies of single gene polymorphisms (SNPs) of the NR1D1 gene encoding REV-ERBα and circadian typologies. The classification of chronotypes and genotyping of three SNPs (rs2314339, rs2071427, rs12941497) of the NR1D1 gene were conducted in 602 healthy young adults (355 males, 247 females). A significant association was found between the genotypes of rs12941497 and three chronotype categories. These findings support the role of NR1D1 polymorphisms in the regulation of circadian rhythms.     

The association between fat mass and obesity-associated (FTO) genotype and serum vitamin D level in breast cancer patients

The preventive effect of vitamin D against breast cancer can be influenced by gene polymorphisms. This study aimed to investigate the association between serum level of 25(OH) vitamin D and FTO genotype in breast cancer patients. A cross-sectional study was carried out on 180 newly diagnosed patients with breast cancer in Tehran, Iran. The blood samples were collected from the participants in order to assess the FTO gene rs9939609 polymorphism by the tetra-primer amplification refractory mutation system (Tetra-ARMS) PCR method. The serum level of 25(OH) vitamin D was measured using the direct competitive enzyme-linked immunosorbent assay (ELISA) method. The association between vitamin D and the FTO genotype in patients with breast cancer was assessed after adjustment for cofounders. The frequency of TT, AT and AA genotypes in the breast cancer patients were 43% (n = 77), 49% (n = 89) and 8% (n = 14), respectively. All patients with higher than 40 ng/dl of serum 25(OH) vitamin D had one or two copies of FTO rs9939609 risk allele (p = 0.019). No linear association was found between the number of FTO risk allele and the level of serum vitamin D. All patients with high serum level of 25(OH) vitamin D had one or two copies of FTO rs9939609 risk allele. FTO gene polymorphisms may counteract the beneficial effects of vitamin D in breast cancer prevention. Further studies can help to better understand the genetic factors predisposing to breast cancer and their effect on the association between vitamin D and breast cancer.     

Comparative Study of Functional Response of Common Hemipteran Bugs of East Calcutta Wetlands,India

The common and abundant hemipteran water bugs Anisops bouvieri, Diplonychus rusticus, D. annulatus, of the wetlands of East Kolkata are known predators of a wide range of aquatic insects including the mosquito larvae. In the laboratory their predation were assessed in respect to short term and long term periods using the larvae of Culex quinquefasciatus to reveal their possible role in regulating the dipteran population in nature. The attack rate (a) and handling time (T_h ) of these predators varied with respect to the prey size. For the backswimmers A. bouvieri the values for a and T_h for the small prey were 5.47 L and 18.72 min respectively, while in case of the belostomatid bugs, the values for the same were 5.37 L and 8.64 min (for D. rusticus), 5.81 L and 20.16 min (for D. annulatus). The predation rate varied with prey and predator densities for both the prey sizes. It was revealed that on an average A. bouvieri can kill and consume 10–82 and 6–44, D. rusticus 10–118 and 10–84 and D. annulatus 10–70 and 10–138 small and large sized prey per day, respectively. However the mutual interference (m) values of the three predators varied with the prey size and ranged between 0.053–0.326 for A. bouvieri, 0.0381–0.066 for D. rusticus and 0.0556–0.115 for D. annulatus, respectively. In the long term experiments A. bouvieri killed between 6–119 small preys and 3–31 large preys, D. rusticus killed 50–94 small preys and 50–96 large preys and D. annulatum were found to kill between 14–74 small prey and 50–131 large prey per day, respectively. The clearance rates were found to be proportional to the predator density as well to the prey size and density, and differed between the predator species significantly. These data are supportive of qualifying the water bugs, A. bouvieri, D. rusticus, and D. annulatus as potential biological resources in regulating the population of mosquito larvae in the wet‐lands. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Inversion polymorphism in Southeast Asian populations of the Drosophila nasuta subgroup

Heterozygosity for chromosomal arrangements was investigated in four species of the nasuta complex. D. sulfurigaster albostrigata, D. albomicans and D. kohkoa are highly polymorphic whereas D. pulaua is monomorphic. Inversions were identified with the aid of photographic chromosome maps. The geographic distribution and frequencies of inversions detected and their possible phylogenies were discussed. Most inversions in D.s. albostrigata and D. albomicans occur on chromosome IIL. In D. kohkoa there is marked preponderance of inversions on chromosome III. Non-random association of certain inversions was noted. Variation in frequencies of inversions is interpreted as a result of adaptation to local ecogeographic conditions. Shared extant polymorphisms indicate phylogenetic relationships between species.The contents of this paper were incorporated in a Ph.D. thesis accepted by the University of Queensland in 1978. The author's present address is: Unit Genetik, Universiti Kebangsaan Malaysia, Jalan Pantai Baru, Kuala Lumpur, Malaysia.     

A polymorphism in <Emphasis Type="Italic">PTPN2</Emphasis> gene is associated with an earlier onset of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) genome-wide study found association of PTPN2 with three autoimmune diseases, among them is type 1 diabetes (T1D). This result was confirmed by a follow-up study that pointed to new independent signals within the region. However, both studies were performed in patients with an early-onset T1D. We aimed at replicating the previous results and studying the influence of these polymorphisms in the age at T1D debut. We genotyped 439 T1D Spanish subjects (age at onset, 1 to 65 years) and 861 controls for two PTPN2 single nucleotide polymorphisms (SNPs), rs2542151 and rs478582, and studied the effect of both polymorphisms in age at onset through stratified and continuous analyses. The frequency of rs2542151*G carriers was significantly higher in the early-onset group compared with late-onset patients (p = 0.023) and with controls (OR = 1.61 [1.14–2.26]; p = 0.005). No significant differences were found between controls and late-onset patients. The log-rank chi-square test for the Kaplan–Meier plots (carriers of susceptibility allele vs non carriers) was statistically significant (χ _1df² = 4.485; p = 0.034), yielding an earlier disease debut for G carriers. The analysis of the SNP rs478582 did not reach statistical significance. In summary, we replicate the association detected by the WTCCC and propose that the rs2542151*G allele confers risk to an earlier onset of T1D.