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PubMed2005

Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma gene in first-degree relatives of subjects with polycystic ovary syndrome.

AIM: This study was designed to examine the relationship between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene and insulin resistance (IR) in first-degree relatives of subjects with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: One hundred and twenty family members of 55 patients with PCOS and 80 unrelated healthy control subjects without a family history of diabetes or PCOS were studied. IR was assessed by homeostatic model assessment (HOMA-IR) and area under the curve (AUC) for insulin during an oral glucose tolerance test in subjects with normal glucose tolerance and controls. Genetic analysis of the PPAR-gamma gene Pro12Ala polymorphism was performed by restriction fragment length polymorphism. RESULTS: Fasting insulin, HOMA-IR and AUC insulin were significantly higher in first-degree relatives of PCOS subjects than in controls. A significantly different allele distribution of the Pro12Ala polymorphism of PPAR-gamma was observed between the two groups, with the frequency of the variant Ala isoform being significantly reduced in the first-degree relatives of PCOS subjects (10.8%, 13 subjects) compared with the control group (22.5%, 18 subjects). All Pro12Ala polymorphisms of the PPAR-gamma gene were heterozygous. Compared with first-degree relatives of PCOS subjects with the Pro12Pro polymorphism of PPAR-gamma, first-degree relatives of PCOS subjects with the Pro12Ala polymorphism had low fasting insulin, HOMA-IR and AUC insulin levels. The combined prevalence rate for impaired glucose tolerance, impaired fasting glucose and diabetes was 40% (16 subjects) in mothers and 52% (20 subjects) in fathers of PCOS women. CONCLUSION: Our findings suggest that Pro12Ala PPAR-gamma gene polymorphism may be protective against IR and might prevent the development of diabetes mellitus in the first-degree relatives of subjects with PCOS.

Adolescent↗

PubMed2006

Polymorphisms within the lactoferrin gene promoter in various cattle breeds.

Lactoferrin (Lf) is an iron-binding protein and belongs to the serum transferrin family. It has broad spectrum antimicrobial action, and it is found in exocrine secretions including milk. The sequence of the bovine lactoferrin gene promoter was analyzed in five different cattle breeds (Holstein Friesian, New Zealand Holstein, Montebéliard, Normande, and Norwegian Red) to determine the extent of polymorphic variation, which exists in this region both within and across cattle breeds. Fifteen different single nucleotide polymorphisms (SNPs) were identified throughout this region. Numerous polymorphisms were found throughout the Holstein Friesian, New Zealand Holstein, Montebéliard, and Normande populations. The most frequently encountered polymorphism found in all breeds was at position -28, which is immediately proximal to the TATA box of the promoter. The most variable base position was -131, which included three types of heterozygotes including a single base deletion in one allele, and three homozygote variants. This polymorphism occurs in a putative transcription factor binding site, for the nuclear factor of activated T cells (NF-ATc). A unique polymorphism was identified in one Normande animal, and three polymorphisms were found in one Montebéliard animal. In general, Norwegian Red cattle displayed fewer SNPs than other breeds. Most nucleotide changes in these animals were within the 190 base pairs of the transcription start point, with the exception of an insertion seen in three animals at position -478. In conclusion, SNPs were found in abundance throughout this regulatory region. Whether or not these polymorphisms have an effect on the regulation of the bovine lactoferrin gene is yet to be elucidated. However, the identification of lactoferrin promoter variants may serve as a marker for healthier animals, thereby accelerating the improvement of animals through breeding.

Animals↗

PubMed2000

5569G/A polymorphism of the HFE gene: no implications for C282Y genotyping in a hemochromatosis screening study of 65,238 individuals.

In a previous hemochromatosis screening study including a total of 65,238 individuals, 566 persons were genotyped for the C282Y and the H63D mutations. Of these, a total of 433 samples (298 homozygous C282Y and 135 homozygous wild type) were reanalyzed to investigate if the potential presence of the newly described 5569G/A polymorphism had confounded the genotyping results for the C282Y mutation. Genotyping with a polymorphism-insensitive primer pair yielded no samples that altered their genotype. By utilizing the polymorphism-sensitive primer pair and elevated annealing temperatures, 133 samples previously genotyped as heterozygous C282Y were reanalyzed to verify the presence of the polymorphism in the population studied. Out of a total of 266 chromosomes, we found the polymorphism present in 9 chromosomes, yielding an allele frequency of 0.034 in this particular subpopulation. In one of the samples, the polymorphism was present on the same DNA strand as the C282Y mutation. We conclude that in the population studied, the 5569 G/A polymorphism is present, but its presence had no implications for the outcome of the previous genotyping. Nevertheless, we recommend that C282Y genotyping by restriction endonuclease digestion of PCR products in the future should utilize a primer pair that is not influenced by the 5569G/A polymorphism.

Base Sequence↗

PubMed1990

Associations between restriction site polymorphism and enzyme activity variation for esterase 6 in Drosophila melanogaster.

Thirty-five nucleotide polymorphisms were found in a 21.5-kbp region including the Est6 locus among 42 isoallelic lines extracted from a single natural population of Drosophila melanogaster. The heterozygosity per nucleotide pair was estimated to be 0.010 overall, but was lower in sequences hybridizing to transcripts than in those not hybridizing to transcripts. Eleven of 36 pairwise comparisons among the nine most common polymorphisms showed significant gametic disequilibrium. Four of these polymorphisms were also significantly associated with the major EST6-F/EST6-S allozyme polymorphism. Significant disequilibrium was generally restricted to polymorphisms less than 1-2 kbp apart. Previously reported measures of EST6 activity in virgin adult females proved not to be significantly associated with any of the six most common nucleotide polymorphisms located in the Est6 coding region or the 1.5 kbp immediately 5'. However, the 11 haplotypes for five of these polymorphisms that lie in the 1.5-kbp 5' region could explain about half of the previously reported variation among the lines for both EST6 activity and the amount of EST6 protein in virgin adult males. One particular polymorphism, for a RsaI site 530 bp 5' of the initiation codon, could explain 21% of the male activity variation among lines. This site is embedded in a large palindrome and we suggest that sequences including or close to this site may be involved in the regulation of EST6 synthesis in the ejaculatory duct of the adult male.

Animals↗

PubMed2002

The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function.

The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.

Base Sequence↗

PubMed1994

A survey of long-range DNA polymorphisms on the human Y chromosome.

The human Y chromosome is poor in conventional DNA polymorphisms, and this has hindered studies of the paternal lineage. However, three large hypervariable arrays exist, and haplotyping at these loci defines two groups in Caucasian and Asian populations, reflecting the existence of two ancestral Y chromosomes. In this study, the Y was systematically surveyed for further long-range polymorphisms, by the hybridization of 33 probes to SfiI digests of DNA from males of different ethnic origins and from the two groups. Five novel polymorphisms were identified, all showing variability consistent with a changing number of tandem repeats within an array. A search for conventional polymorphisms was also done, using 41 probes and the enzyme TaqI; three novel variants and one polymorphism with a frequency of 18% (n = 66) were found. The novel polymorphisms were typed in 66 Y chromosomes, including the set of 42 in which the two groups were originally defined. Known long-range and conventional polymorphisms were also extended to cover the whole set, yielding compound haplotypes comprising the states of twelve polymorphisms. This haplotyping distinguishes between all 66 chromosomes, and should distinguish between most in the population. The existence of the two groups is supported, and a third group can be defined; six of the eight members of this group are known to be from India. Twelve chromosomes do not fall into any of these groups, and are likely to be representatives of further groups.

Animals↗

PubMed2004

No association of estrogen receptor alpha and cytochrome P450c17alpha polymorphisms with age at menopause in a Dutch cohort.

BACKGROUND: Age at menopause is under strong genetic control. So far, genetic variations of only one gene, the PvuII polymorphism of the estrogen receptor alpha (ERalpha) gene, have been shown to be associated with age at onset of menopause. This study aims to investigate whether PvuII, XbaI and B-variant polymorphisms of the ERalpha gene, and the MspAI polymorphism of the cytochrome P450c17alpha (CYP17) gene are associated with age at menopause in a Dutch cohort. METHODS: DNA was isolated from urine samples of 385 Caucasian women with natural menopause and the genotypes of the four polymorphisms were determined. A questionnaire was used for background characteristics. The genotypes of PvuII, XbaI, MspAI were obtained by PCR restriction fragment length polymorphism analysis. The B-variant was determined with an allele-specific oligonucleotide hybridization method. Two-sided t-tests were performed to assess the association between the four polymorphisms and menopausal age. The PvuII and XbaI polymorphisms were analysed separately as well as in a combined score. RESULTS: The results show that none of the polymorphisms independently, nor the combined genotypes for PvuII and XbaI, were associated with age at natural menopause. CONCLUSION: No evidence was found for a relationship between common variants of the ERalpha gene and the CYP17 gene with age at natural menopause.

Age Factors↗

PubMed1984

Carrier detection in haemophilia B using two further intragenic restriction fragment length polymorphisms.

A normal human population has been screened for the existence of further restriction fragment length polymorphisms (RFLPs) in the clotting factor IX gene in addition to the TaqI polymorphism already characterised (1,2). Two polymorphic loci were found, both within 6 Kb of the TaqI polymorphism within the body of the factor IX gene. One of the polymorphisms has been shown to be due to either the presence or absence of a particular recognition site for the restriction enzyme XmnI. The other, visualised as a difference in fragment pattern produced by digestion with either HinfI or DdeI, has two allelic forms differing by a 50 bp element of inserted DNA. Sequence analysis has shown the inserted element to be in a region of Z type DNA sequence, the insertion representing a duplication of flanking sequence on either side. The two polymorphisms are inherited in simple Mendelian fashion and have both been used to diagnose haemophilia B carrier status. It is estimated that the combined use of these polymorphisms in the factor IX gene, despite linkage disequilibrium between the 3 polymorphic loci, should enable carrier status to be determined in approximately 66% of all haemophilia B families.

Alleles↗

PubMed1991

Segments containing alternating purine and pyrimidine dinucleotides: patterns of polymorphism in humans and prevalence throughout phylogeny.

Tandem dinucleotide repeats of GT or AC [(GT)n/(AC)n] where n greater than or equal to 14 are highly polymorphic and other simple repeats such as (CT)n/(AG)n and (A)n(T)n are also polymorphic. The uniformity of these sequences precludes a mechanistic differentiation between recombination or polymerase slippage. Since (GT)n/(AC)n or (CT)n/(AG)n segments of desired size were not available in our gene of interest, we analyzed a 187+ bp segment in the factor IX gene with multiple short dinucleotide repeats. This sequence contains a melody of short dinucleotide repeats which includes a 142+ bp segment of alternating purines and pyrimidines. Amplification of this sequence in 167 individuals of different ethnicity and direct sequencing of 106 individuals (23 kb of sequence) failed to reveal simple variation in the number of tandem dinucleotide repeats. However, polymorphism in the 142+ alternating purine and pyrimidine segment (RY)n was detected due to the insertion of two related repeat units of 24 bp (A) and 26 bp (B). Two previously described alleles (AB, A2B2) and two novel presumptive recombinants were found (A2B, A3B2) for a total of four alleles. An analysis of (RY)n segments in GenBank revealed an extraordinary enrichment in the genome of mammals, invertebrates, and yeast and a marked reduction in bacteria. Rodent (RY)n were larger and substantially more frequent than those in primates. When a second (RY)n was examined in the exon 8 of human factor IX gene, it was polymorphic at short repeats of (GT)n/(AC)n (n = 3-6) in Western Europeans and Koreans. In addition, an (RY)n in the dystrophin gene had four polymorphic alleles involving AT and GT dinucleotides. Thus (RY)n segments appear to be abundant and highly polymorphic. The asymmetric patterns of polymorphism and the absence of simple dinucleotide variation in 23 kb of sequence are compatible with recombination or sister chromatid exchange, but not polymerase slippage. By inference, recombination should underlie the polymorphisms at (GT)n/(AC)n since they are a subset of (RY)n and they commonly occur in the context of longer (RY)n.

Alleles↗

PubMed2005

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. METHODS: Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. RESULTS: Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. CONCLUSION: The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.

Angiotensinogen↗

PubMed1996

Excess amino acid polymorphism in mitochondrial DNA: contrasts among genes from Drosophila, mice, and humans.

Recent studies of mitochondrial DNA (mtDNA) variation in mammals and Drosophila have shown an excess of amino acid variation within species (replacement polymorphism) relative to the number of silent and replacement differences fixed between species. To examine further this pattern of nonneutral mtDNA evolution, we present sequence data for the ND3 and ND5 genes from 59 lines of Drosophila melanogaster and 29 lines of D. simulans. Of interest are the frequency spectra of silent and replacement polymorphisms, and potential variation among genes and taxa in the departures from neutral expectations. The Drosophila ND3 and ND5 data show no significant excess of replacement polymorphism using the McDonald-Kreitman test. These data are in contrast to significant departures from neutrality for the ND3 gene in mammals and other genes in Drosophila mtDNA (cytochrome b and ATPase 6). Pooled across genes, however, both Drosophila and human mtDNA show very significant excesses of amino acid polymorphism. Silent polymorphisms at ND5 show a significantly higher variance in frequency than replacement polymorphisms, and the latter show a significant skew toward low frequencies (Tajima's D = -1.954). These patterns are interpreted in light of the nearly neutral theory where mildly deleterious amino acid haplotypes are observed as ephemeral variants within species but do not contribute to divergence. The patterns of polymorphism and divergence at charge-altering amino acid sites are presented for the Drosophila ND5 gene to examine the evolution of functionally distinct mutations. Excess charge-altering polymorphism is observed at the carboxyl terminal and excess charge-altering divergence is detected at the amino terminal. While the mildly deleterious model fits as a net effect in the evolution of nonrecombining mitochondrial genomes, these data suggest that opposing evolutionary pressures may act on different regions of mitochondrial genes and genomes.

Amino Acid Sequence↗

PubMed2004

Chronic low-level mercury exposure, BDNF polymorphism, and associations with self-reported symptoms and mood.

Recent reports have described neurobehavioral impairments in human subjects carrying a V66M polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF). Inasmuch as ventral nervous system (CNS) deficits associated with this BDNF polymorphism are similar to those observed among subjects with chronic exposure to elemental mercury (Hg degrees ), we examined the potential effect of this BDNF polymorphism on symptoms and mood in an established cohort of dental practitioners with chronic low-level Hg degrees exposure. Self-reported symptoms and mood were obtained by computerized questionnaire from 193 male dentists (DTs) and 230 female dental assistants (DAs). Spot urine samples were analyzed for mercury concentrations to evaluate recent exposure. Detailed work histories were obtained to calculate chronic indices of Hg degrees exposure. Buccal cell samples were obtained to identify the V66M polymorphism of BDNF. Scores for 11 current and 12 recent and chronic symptom groups, along with six mood factors, were evaluated with respect to recent and chronic Hg degrees exposure and BDNF polymorphism. Multiple regression analysis controlled for age, race, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Separate evaluations were conducted for DTs and DAs. Twenty-three associations between recent or chronic Hg degrees exposure and BDNF status and self-reported symptoms were observed with p < 0.10. All but three were in the expected direction (symptom scores increasing with Hg degrees exposure or BDNF polymorphism), and all but six were among DAs. All eight correlations between chronic exposure indices and recent and chronic symptoms among DAs were in the expected direction. All seven associations between BDNF and symptoms were in the expected direction and split between DTs and DAs. All three associations with mood factors were among DAs and in the expected direction. These results indicate that among DAs very low levels of occupational Hg degrees exposure are associated with increased symptoms. The BDNF polymorphism is also associated with increased symptom and mood scores. Notably, Hg degrees and BDNF polymorphism were additive with respect to their associations with the same symptom group.

Adult↗

PubMed2003

Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients.

OBJECTIVE: To determine the functionality of identified polymorphisms in the promoter and upstream regions of the interleukin-10 gene in terms of release of interleukin-10 from lipopolysaccharide-stimulated whole blood from healthy volunteers and to evaluate the relationship of interleukin-10 polymorphisms to interleukin-10 release, development of sepsis, and mortality in critically ill patients. DESIGN: Observational study. SETTING: The academic unit of anesthesia and intensive care, university laboratories, and ten-bed general intensive care unit in a university teaching hospital. SUBJECTS: A total of 132 healthy volunteers plus 67 consecutive critically ill patients recruited within 24 hrs of admission to the intensive care unit, regardless of diagnosis. MEASUREMENTS: Plasma interleukin-10 levels were measured by enzyme-linked immunosorbent assay. Single nucleotide polymorphisms were detected by restriction fragment length polymorphism analysis. Dinucleotide repeat polymorphisms were identified after polymerase chain reaction using a DNA size analyzer. MAIN RESULTS: Stimulated interleukin-10 release in critically ill patients was significantly lower than in healthy subjects (p < .0001). In addition, in the patients who developed sepsis, interleukin-10 release at admission to the intensive care unit was significantly lower than in patients who did not subsequently develop sepsis (median [range] 1.47 [0.13-6.90] ng/mL compared with 4.93 [0.03-16.80] ng/mL, p = .001). The A allele of the single nucleotide polymorphism at -592 base pairs was associated with lower interleukin-10 release and higher mortality in critically ill patients. Other polymorphisms were not linked to interleukin-10 release, sepsis, or mortality. CONCLUSIONS: The A allele of the -592 base pair single nucleotide polymorphism in the interleukin-10 gene is associated with lower stimulated interleukin-10 release and increased mortality. Further investigations are required to determine the nature of the functionality and the potential diagnostic and therapeutic aspects of this marker.

Adolescent↗

PubMed1997

Polymorphisms in the carboxy-terminus of the epithelial sodium channel in rat models for hypertension.

OBJECTIVE: To investigate whether mutations in the C-terminus of the three subunits of the rat epithelial sodium channel (alphabetagamma-rENaC) contribute to the hypertensive phenotype in five rat models for essential hypertension. DESIGN: We sequenced the C-terminal regions of alpha-, beta- and gamma-rENaC genes in five different hypertensive rat strains [spontaneously hypertensive rats (SHR), Dahl salt-sensitive (SS/Jr) rats, Milan hypertensive (MHS) rats, Sabra hypertensive (SBH) rats and Lyon hypertensive rats (LHR)] and their normotensive controls [Wistar-Kyoto (WKY) rats, Dahl salt-resistant (SR/Jr) rats, Milan normotensive (MNS) rats, Sabra normotensive (SBN) rats and Lyon normotensive rats (LNR)]. Identified polymorphisms were tested for cosegregation with blood pressure as well as for increased epithelial sodium channel (ENaC) activity. METHODS: Genomic DNA extracted from hypertensive and normotensive rat strains was amplified by the polymerase chain reaction and polymerase chain reaction fragments were sequenced. Cosegregation analysis was performed to test for correlations between blood pressure and different genotypes. The effects of a polymorphism on ENaC activity were assessed by functional expression in Xenopus laevis oocytes. The chromosomal location of the gene for gamma-ENaC was determined by linkage analysis in an F2 (MHS x MNS) population. RESULTS: We found no polymorphisms at the C-terminus of alpha- and beta-rENaC in the five rat models tested. We identified two polymorphisms at the C-terminus of the gamma-subunit, one leading to an amino acid change. Milan strains (MNS and MHS) were polymorphic for this mutation. By cosegregation analysis we could exclude the possibility that there was a correlation between blood pressure and this polymorphism. Functional expression of the polymorphism caused no increase in ENaC activity assessed by measurement of the amiloride-sensitive sodium current in Xenopus oocytes. The gene for the gamma-ENAC was located on rat chromosome 1. CONCLUSIONS: No polymorphisms at the C-terminus of the three subunits of the epithelial sodium channel cosegregating with blood pressure were detected in five different genetic rat models for hypertension. If an altered ENaC activity contributes to the pathogenesis of hypertension in these rats, it must thus arise from mutations in other parts of the protein, from mutations outside the coding region impairing the proper regulation of one of the subunits or from mutations in an ENaC-associated protein.

Animals↗

PubMed2000

beta2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians.

OBJECTIVE: The amino-terminal polymorphisms, Arg16Gly and Gln27Glu, of the beta2-adrenergic receptor (beta2AR) have been shown to affect regulation of the receptor expression by an agonist in cell culture studies. The Arg16Gly polymorphism has also been recently shown to be associated with essential hypertension. We therefore evaluated whether the amino-terminal polymorphisms of beta2AR are associated with hypertension in a Caucasian population. SUBJECTS AND METHODS: We performed an association study in 298 hypertensive patients and an equal number of age-matched normotensive controls from the East Anglian region, with blood pressure assessed categorically and quantitatively. We also examined the influence of the amino-terminal polymorphisms on blood pressure response to beta-blockade in 144 of the patients randomly assigned to this class of drug. Genotyping of the Arg16Gly polymorphism was undertaken by a newly designed mismatched polymerase chain reaction (PCR) and digestion with Nde I, whereas the Gln27Glu polymorphism was genotyped by PCR followed by Fnu4H I cleavage. RESULTS: We found no differences in the genotype or allele frequencies of the beta2AR polymorphisms between hypertensive and normotensive participants. There was also no association between the beta2AR genotypes and variations in either basal blood pressure or the blood pressure response to a beta-blocker. CONCLUSION: These findings suggest that the amino-terminal polymorphisms of the beta2AR gene are unlikely to constitute major susceptibility for essential hypertension in the East Anglian population.

Adrenergic beta-Antagonists↗

PubMed2004

A common polymorphism of uncoupling protein 2 gene is associated with hypertension.

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Adult↗

PubMed2005

Peroxisome proliferator-activated receptor-gamma2 Pro12Ala and endothelial nitric oxide synthase-4a/b gene polymorphisms are not associated with hypertension in diabetes mellitus type 2.

OBJECTIVE AND DESIGN: The Pro12Ala and the 4a/b polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARgamma) and the endothelial nitric oxide-synthase (eNOS) genes, respectively, have been associated with hypertension in some but not all studies. The purpose of this study was to investigate the association between these polymorphisms and hypertension in patients with diabetes mellitus type 2 (DM2). METHODS: We determined, by polymerase chain reaction (PCR), the Pro12Ala PPARgamma2 and the eNOS 4a/b gene polymorphisms in a total of 395 patients with diabetes mellitus 2 (DM2) (225 men and 170 women) from the LIANCO (Lipid-Analytic-Cologne) study. Hypertension was defined as known or newly diagnosed hypertension according to current national guidelines. Associations were determined using chi-square statistics. The influence of genotype and other parameters on blood pressure was determined by analysis of variance (ANOVA) and multivariate analyses. RESULTS: The genotype frequencies of the Pro12Ala polymorphism were 3% AlaAla, 23% ProAla and 74% ProPro and of the eNOS 4a/b polymorphism 3% a/a, 25% b/a and 72% b/b. There were 65% patients with, and 35% without hypertension. A total of 77% of the patients with hypertension were under pharmacological treatment. The mean systolic and diastolic blood pressure (SBP, DBP) was 148 +/- 22 and 84 +/- 11 mmHg in patients with, and 131 +/- 12 and 79 +/- 8 mmHg in patients without, hypertension. There was no difference in the occurrence of hypertension among ProAla and AlaAla subjects compared with ProPro subjects (P = 0.98). There was also no difference between a-allele carriers and non-carriers of the eNOS polymorphism (P = 0.42). There were no differences between men and women in the associations. Analysis of variance did neither identify an influence on systolic or diastolic blood pressure by the presence of the Ala or the a-allele of the respective genotypes nor a significant interaction of the two. CONCLUSIONS: In DM2 the Pro12Ala and 4a/b gene polymorphisms of the PPARgamma2 and eNOS genes, respectively, are not associated with systolic or diastolic blood pressure, either in men or in women. Our results in a large cohort fail to confirm reports of recent studies suggesting an association of lower blood pressure in patients with DM2 and carriers of Pro12Ala polymorphism.

Adult↗

PubMed2001

The transforming growth factor-beta1 codon 10 gene polymorphism and accelerated graft vascular disease after clinical heart transplantation.

BACKGROUND: The multifunctional cytokine transforming growth factor- (TGF) beta1 is thought to play a role in the pathogenesis of graft vascular disease (GVD). Polymorphisms at codon 10, (Leu10-->Pro) and codon 25 (Arg25-->Pro) in the signal sequence of the TGF-beta1 gene regulate the production and secretion of the protein. We investigated whether these polymorphisms are risk factors for the development of GVD after clinical heart transplantation. METHOD: TGF-beta1 polymorphisms, Leu10-->Pro and Arg25-->Pro, were determined in DNA from heart transplant recipients (n=252) and their donors (n=213), using sequence-specific oligonucleotide probing. GVD was angiographically diagnosed 1 year after transplantation. In addition other potential risk factors including underlying disease, recipient and donor age, recipient and donor gender, number of acute rejections in the first year, cold ischemia time, and HLA mismatches were analyzed by univariate and multivariate logistic regression analysis. RESULTS: Univariate analysis showed that the recipient TGF-beta1 polymorphism Leu10-->Pro, (P=0.056, chi2 test), underlying disease (P=0.01, chi2 test), number of acute rejections in the first-year (P=0.03, analysis of variance), and donor age (P<0.001, analysis of variance) were risk factors for the development of GVD. The TGF-beta1 Arg25-->Pro polymorphism was not a risk factor. Also in the multivariate analysis, the recipient TGF-beta1 codon 10 polymorphism was associated with GVD, with patients homozygous for Pro at greatest risk (odds ratio 7.7, P=0.03). Apart for the recipient TGF-beta1 Leu10-->Pro polymorphism, donor age appeared to be an independent risk factor for the development of GVD at 1 year. Patients with older donor hearts were at greater risk than patients receiving grafts from younger donors (odds ratio 1.1/year, P<0.001). CONCLUSION: Recipient TGF-beta1 Leu10-->Pro polymorphism and higher donor age are independent risk factors for the development of GVD after clinical heart transplantation.

Adult↗