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PubMed2005

Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence.

Nicotine is the primary addictive compound in tobacco smoke. In this review we summarize nicotine dependence and the genetics of smoking in brief before focusing on cytochrome P450 (CYP) 2A6. In humans nicotine is mainly inactivated to cotinine and CYP2A6 mediates approximately 90% of this conversion. Some, but not all, studies suggest that genetic variation in CYP2A6 may play a role in smoking. We review some of the recent findings on the influence of CYP2A6 genetic polymorphisms on nicotine kinetics, smoking behaviors, and how the gene appears to exert differential effects during various stages of smoking (eg, initiation, conversion to dependence, amount smoked during dependence, and quitting). These new findings will be put in the context of the discrepancies found in the literature. Implications of these recent findings on current and novel treatment approaches for smoking cessation and tobacco-related lung cancer will also be discussed.

Animals↗

PubMed2002

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Case-Control Studies↗

PubMed2003

PCR-based DNA fingerprinting indicates host-related genetic variation in the nematophagous fungus Pochonia chlamydosporia.

The mitosporic fungus Pochonia chlamydosporia is a potential biocontrol agent for cyst (Heterodera spp. and Globodera spp.) and root knot (Meloidogyne spp.) nematodes, which are important agricultural plant pests. 54 isolates from diverse geographical regions and several nematode hosts were used in this study. Genetic variation was examined using enterobacterial repetitive intergenic consensus (ERIC) primed PCR and sequences from the internal transcribed spacer (ITS) rRNA region. ERIC PCR yielded 35 scorable binary characters from all the fungi tested and cluster analysis of the data showed that isolates from cyst nematodes were more genetically variable than those from root knot nematodes. The ITS regions were highly conserved, the only significant difference being an extra thymidine in isolates from Meloidogyne spp. Assays with nematode eggs indicated that isolates differ in their ability to infect different nematode genera. The results indicate host related variation in P. chlamydosporia. This finding has significant implications for the application of P. chlamydosporia as a biocontrol agent.

Animals↗

PubMed2001

Genetic variation and obesity in Australian women: a prospective study.

OBJECTIVE: A number of candidate genes have been implicated in the pathogenesis of obesity in humans. This study examines associations between longitudinal changes in body mass and composition and the presence of polymorphisms in the beta-3 adrenergic receptor, tumor necrosis factor-alpha, leptin, and leptin receptor (Lepr) in a cohort of Australian women. RESEARCH METHODS AND PROCEDURES: Healthy white Australian women (n = 335) were randomly selected from the Barwon region of Victoria and underwent baseline anthropometry and double-energy X-ray absorptiometry for assessment of body mass and adiposity. These measurements were repeated again at 2-year follow-up. Genomic DNA was extracted and used for polymerase chain reaction-based genotyping of all polymorphisms. RESULTS: The Pro1019Pro Lepr polymorphism was associated with longitudinal increases in body weight (p = 0.02), fat mass (p = 0.05), and body mass index (p = 0.01) in this study, and individuals homozygous for the A allele at this locus had a greater propensity to gain body fat over time. The largest effects on body composition seemed to be in individuals already obese at baseline. Changes in body weight, fat mass, percent body fat, and body mass index over a 2-year period were not associated with genetic variation in the beta-3 adrenergic receptor (Trp64Arg), tumor necrosis factor-alpha promoter, or leptin genes in non-obese or obese women. DISCUSSION: These results suggest that a Lepr polymorphism is involved in the regulation of body mass and adiposity in obese Australian white women, which may have implications for the treatment of obesity in this population.

Absorptiometry, Photon↗

PubMed2003

Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects.

The orphan receptor small heterodimer partner (SHP, NR0B2) modulates the transcription activity of the MODY1 gene HNF4a. Mutations in SHP were found in 7% of Japanese obese young-onset type 2 diabetic patients and were associated with moderate obesity and increased birth weight. We investigated SHP in 1927 U.K. subjects, examining relationships with type 2 diabetes, obesity, and birth weight. Sequencing of the coding region of SHP in 122 obese, young-onset type 2 diabetic patients detected the polymorphism G171A. The polymorphism was not associated with diabetes in case control or familial association studies. The A allele (frequency 0.07) was not associated with obesity in type 2 diabetic subjects (n = 348), their parents (n = 272), or young nondiabetic adults (n = 925). However, the rare (<1%) AA homozygotes had a raised BMI in each cohort; this was significant when all cohorts were combined (Z score = 0.67 AA vs. -0.05 G/x, P = 0.02). There was no association with corrected birth weight in 382 normal babies, but the only AA baby was 4,069 g. Our study suggests that genetic variation in SHP is unlikely to be common in the predisposition to diabetes, obesity, or increased birth weight in U.K. Caucasians.

Adolescent↗

PubMed2004

Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis.

Hyperhomocysteinemia is an independent and graded risk factor for arterial vascular disease and venous thrombosis. It is still debated via which mechanism homocysteine (Hcy) causes vascular disease. S-adenosylhomocysteine hydrolase (AHCY) catalyses the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to Hcy. As an increase in AdoHcy, a strong inhibitor of many methyltransferases, is observed in hyperhomocysteinemic individuals, AdoHcy may play a role in the development of cardiovascular diseases by inhibiting transmethylation reactions. We sequenced the entire coding region and parts of the untranslated regions (UTRs) of the AHCY gene of 20 patients with recurrent venous thrombosis in order to identify genetic variation within this gene. We identified three sequence variants in the AHCY gene: a C > T transition in the 5' UTR (-34 bp C > T), a missense mutation in exon 2, which mandates an amino-acid conversion at codon 38 (112 C > T; Arg38Trp) and a silent mutation in exon 4 (390 C > T; Asp130Asp). We studied the effect of the first two variants on total plasma Hcy and venous thrombosis risk in a case-control study on recurrent venous thrombosis. The two polymorphisms under study seem to have no evident effect on tHcy. The adjusted relative risk of venous thrombosis associated with the 112CT genotype compared with 112CC individuals was 1.27 (95% CI 0.55-2.94), whereas the -34CT genotype confers a risk of 1.25 (95% CI 0.44-3.52) compared with the wild-type genotype at this locus. However, the wide confidence intervals do not allow firm conclusions to be drawn.

Adenosylhomocysteinase↗

PubMed1994

Genetic variation in Staphylococcus aureus coagulase genes: potential and limits for use as epidemiological marker.

To perform coagulase gene typing, the repeated units encoding hypervariable regions of the Staphylococcus aureus coagulase gene were amplified by the PCR technique; this was followed by AluI restriction enzyme digestion and analysis of restriction fragment length polymorphism (RFLP) patterns. In order to assess the discriminatory power of this typing method, 30 epidemiologically unrelated S. aureus strains which differed by their pulsed-field gel electrophoresis patterns were examined. Although 18 of the 30 strains had unique and unshared AluI RFLP patterns, there were only four observed patterns in the remaining 12 strains. This finding indicated that unrelated strains may share identical AluI RFLP patterns. To elucidate the degree of genetic variation in the C-terminus-encoding loci within the coagulase genes, the PCR products of these 12 strains were subjected to Taq polymerase-mediated sequencing. Sequence analysis confirmed the AluI recognition sites in each of the four RFLP groups and demonstrated that AluI appears to yield the highest RFLP in restriction enzyme analysis. By their DNA sequences the majority of strains sharing common AluI groups could be clearly differentiated from each other and revealed between 93.2 and 98.5% homology. When we determined the nucleotide sequences of two strains after six subcultivations no significant alterations were observed. Because the discriminatory power of the current coagulase gene typing method is not great enough to be used as the sole method to type S. aureus, additional techniques are necessary. Sequence analysis of the repeated unit-encoding region for the typing of S. aureus may be potentially useful as an alternative to other current molecular typing techniques.

Base Sequence↗

PubMed1991

Genetic variation in reproductive responses to a high-energy diet in mice.

Effects of a high-energy diet on reproduction were studied in 300 mice from lines selected for litter size and(or) 6-wk BW (L+, increased litter size; W+, increased body weight; L+W-, increased litter size and decreased body weight; L-W+, decreased litter size and increased body weight; and K, randomly selected control). Mice received a high-energy diet (HED; 3.8 kcal/g of ME) or a standard diet (STD; 3.3 kcal/g of ME) from 8 to 11 wk of age and were then mated and evaluated for ovulation rate and embryo survival through 17 d of gestation. The HED increased ovulation rate in all lines (P less than .05). The line x diet interaction was significant, with increased ovulation rate due to HED ranging from 9.9% in W+ to 24.2% in L-W+. Within-line regression coefficients of ovulation rate on ME intake (kilocalories from 10 to 11 wk) varied from .08 +/- .04 (P less than .05) in L+W- to .177 +/- .05 (P less than .01) in L+. In contrast, nonsignificant increases were observed in litter size (live fetuses at 17 d of gestation) due to HED. Effects of HED on embryo survival rate were significantly negative in L+ and L+W-; the decrease in L+ was a result of preimplantation losses, and the decrease in L+W- was due to postimplantation losses. The line x diet interaction was significant for postimplantation embryo survival. The results indicate significant genetic variation in reproductive responses to a high-energy diet in mice.

Animals↗

PubMed1998

Genetic variation in a freshwater bryozoan. I: Populations in the Thames basin, UK.

In spite of increasing interest in metapopulation dynamics, the genetic consequences of a metapopulation structure remain poorly understood. Here we examine the metapopulation genetic structure of the colonial, facultatively sexual freshwater bryozoan Cristatella mucedo, in the Thames basin of southern England, UK. Populations from nine sites were sampled and colonies genetically characterized using random amplified polymorphic DNA (RAPD)-PCR. A total of 78 different clones was detected over all sites. Despite the large number of clones, genetic distances among clones both within and among sites were very small. Nonetheless, no clone was present at more than one site even though C. mucedo has an asexual dispersal propagule, and clones strongly clustered by sites. No consistent pattern of clonal structure was evident, with both the number and equitability of clones varying greatly among sites. Although sites were genetically distinct, population genetic regions were absent, and a Mantel test indicated that there was no relationship between geographical distances among sites and genetic distances among populations. Our results indicate that C. mucedo exists as a classical metapopulation in the Thames basin, with dispersal independent of distance and all sites contributing to the genetic diversity of the metapopulation.

Animals↗

PubMed1999

Genetic variation in an apomictic grass, heteropogon contortus, in the hawaiian islands

Random amplified polymorphic DNA (RAPD) markers were used to assess genetic variation within and among Hawaiian populations of an apomictic grass, Heterogopon contortus (pili grass). From among 56 individuals sampled from six populations on O'Ahu and Hawai'i, 55 unique genotypes were detected using 33 polymorphic markers. This lack of uniformity among individuals may indicate frequent sexual reproduction in these populations. Analysis of molecular variance (AMOVA) revealed significant variation among populations (30.2%), but higher levels of variation within populations (68.1%). Cluster analysis revealed a high degree of clustering for most populations, but populations from different islands did not cluster together. The presence of among-population differentiation but lack of between-island differentiation may suggest that H. contortus was an early Polynesian introduction to the Hawaiian Islands.

Journal Article↗

PubMed2005

[Genetic variation and differentiation of Abies alba Mill. populations from Ukrainian Carpathians].

Using electrophoretic analysis of 11 enzyme systems, we studied the genetic structure and differentiation of eight natural populations of silver fir Abies alba Mill. in the Ukrainian Carpathians. Of 24 isozyme loci identified, 66.8% proved to be polymorphic. The mean numbers of alleles and genotypes per locus in the populations were respectively 3.1 and 4.5. Each A. alba tree was on average heterozygous at 15.9% of genes. In six populations, the genotypic distribution for all of the loci examined corresponded to Hardy-Weinberg proportions. The populations studied had low levels of subdivision (F(ST) = 0.018; GST = 0.019) and differentiation. Nei's genetic distances between the A. alba populations in the region ranged from 0.002 to 0.009, being on average 0.006.

Abies↗

PubMed1997

A family of differentially amplified repetitive DNA sequences in the genus Beta reveals genetic variation in Beta vulgaris subspecies and cultivars.

Members of a highly abundant restriction satellite family have been isolated from the wild beet species Beta nana. The satellite DNA sequence is characterized by a conserved RsaI restriction site and is present in three of four sections of the genus Beta, namely Nanae, Corollinae, and Beta. It was not detected in species of the evolutionary old section Procumbentes, suggesting its amplification after separation of this section. Sequences of eight monomers were aligned revealing a size variation from 209 to 233 bp and an AT content ranging from 56.5% to 60.5%. The similarity between monomers in B. nana varied from 77.7% to 92.2%. Diverged subfamilies were identified by sequence analysis and Southern hybridization. A comparative study of this repetitive DNA element by fluorescent in situ hybridization and Southern analyses in three representative species was performed showing a variable genomic organization and heterogeneous localizations along metaphase chromosomes both within and between species. In B. nana the copy number of this satellite, with some 30,000 per haploid genome, is more than tenfold higher than in Beta lomatogona and up to 200 times higher than in Beta vulgaris, indicating different levels of sequence amplification during evolution in the genus Beta. In sugar beet (B. vulgaris), the large-scale organization of this tandem repeat was examined by pulsed-field gel electrophoresis. Southern hybridization to genomic DNA digested with DraI demonstrated that satellite arrays are located in AT-rich regions and the tandem repeat is a useful probe for the detection of genetic variation in closely related B. vulgaris cultivars, accessions, and subspecies.

DNA, Plant↗

PubMed2003

Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease.

BACKGROUND: We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. METHODS AND RESULTS: The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and >or=50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G-->A, intron 5/T-->G, and 3' UTR/T-->C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3'UTR/T allele was significantly higher in whites than blacks (49% versus 19%; P<0.0001). Among white women, the frequency of the 3'UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and >or=50% stenosis groups, respectively (chi2 trend=6.23; P=0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; P=0.007) and LOX1 (odds ratio, 1.67; P=0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3'UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94+/-0.20 versus 0.86+/-0.16; P=0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3'UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. CONCLUSIONS: Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women.

3' Untranslated Regions↗

PubMed2006

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T(H)2 inflammation. OBJECTIVE: We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. METHODS: A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. RESULTS: The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). CONCLUSIONS: The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.

Adolescent↗

PubMed2004

Genetic variation in the multifunctional transcription factor Yy1 and type 1 diabetes mellitus in the BB rat.

Spontaneous diabetes in B(io)B(reeding) rats is complex, polygenic, and recessively inherited. Several crossing studies have demonstrated that beside the class II genes of the major histocompatibility complex (MHC, Iddm1) additional non-MHC genes are involved in diabetes development. One of them, Iddm4, was initially mapped on chromosome 6q32. To study the physiologic importance of Iddm4 a congenic BB.SHR rat strain (BB.6S) was established. The BB.6S is characterised by a drastic reduction of diabetes frequency (86 vs. 14%) indicating existence of diabetes protective genes of SHR on the exchanged chromosomal segment. One of the possible diabetes susceptibility candidate genes located within this exchanged region is the multifunctional transcription factor Yin yang 1 (Yy1). Yy1 was therefore sequenced in BB/OK and SHR rats. No genetic variation in exons between BB/OK and SHR was found. However, three single nucleotide polymorphisms (SNPs) were detected in intron 4. To determine the "wild type" allele, intron 4 of several diabetes-resistant inbred rat strains (DA, LEW, BN, and WOKW) and wild rats was sequenced. In addition, a congenic BB/OK strain was established by introgressing the same segment of chromosome 6 (D6Rat184-D6Rat3) of wild rats onto BB/OK background (BB.6W). The sequence analysis showed the SNP pattern of SHR (A/C/C) in all inbred rat strains studied whereas both unrelated wild rats showed the pattern of BB/OK rats (T/G/A). The congenic BB.6W rats developed diabetes in the same extent than BB/OK rats. This finding may support the assumption that the SNP pattern of BB/OK and wild rats favours and that of SHR suppresses diabetes development. Because of strong synteny between rat chromosome 6q32 and human 14q32, Yy1 may be also of interest in human type 1 diabetics showing significant linkage to markers on chromosome 14q32.

Animals↗

PubMed1990

Genetic variation on chromosome 16 is associated with abdominal aortic aneurysm.

1. There is a familial tendency to abdominal aortic aneurysms. We have followed up a previous report of a weak association between the haptoglobin 2-1 phenotype and aortic aneurysm and investigated polymorphisms of the haptoglobin gene and neighbouring cholesterol ester transfer protein gene on the long arm of chromosome 16 in patients with atherosclerotic abdominal aortic aneurysm, patients with stenosing aortic atherosclerosis and healthy control subjects. The protein polymorphism of haptoglobin results from variant alpha-chains, alpha 1 and alpha 2, the phenotype nomenclature describing the two alpha-chains. We have also investigated whether the different haptoglobin phenotypes influence the degradation of aortic connective tissue. 2. The frequency of the haptoglobin alpha 1 allele was increased in patients with aneurysms compared with healthy control subjects (0.51 versus 0.35, P less than 0.05). Patients homozygous for the alpha 2 allele had the highest mean age at aneurysm resection. The frequency of a rare polymorphism at the cholesterol ester transfer protein locus was also increased in aneurysm patients (0.15 versus 0.05 in control subjects, P less than 0.01). These two genetic markers appear to act independently. Haptoglobins containing an alpha 1-chain accelerated two- to four-fold the degradation by elastases of aortic elastin in vitro. 3. Genetic variation in the haptoglobin and cholesterol ester transfer protein genes appears to influence dilatation of the abdominal aorta. Variation at the haptoglobin locus could have a direct effect on the degradation of elastin in atherosclerotic aorta, whereas variation at the cholesterol ester transfer protein locus could affect lipid metabolism and promote atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMedDate not supplied

Genetic variation in susceptibility to Marek's disease in a commercial broiler population.

Two commercial broiler pure lines that were previously identified to differ in their susceptibility to Marek's disease (MD) were line-crossed to generate an F1 population. Eight F1 males were randomly mated to four or five F1 females to produce an F2 test population that would be segregating for genes affecting MD. All F2 progeny (four hatches) were pedigreed at hatch and placed in colony houses as nonvaccinated. At 5 days of age, they were challenged intraabdominally with MD virus RB1B. Clinical signs, mortality, and gross and microscopic lesions were recorded during the MD challenge. At 8 wk postchallenge, all remaining birds were euthanatized and necropsied. During the MD challenge of the first two hatches, we observed that several severely stunted broilers originated from certain families and the differences in body weight among birds appeared as early as 3 wk postchallenge. To confirm this observation, body weight at 6 wk postchallenge was determined for all surviving birds in hatches 3 and 4 (n = 242). Genetic variation in body weight among broiler sire families was apparent; the average body weight for males at this time was 2.07 kg, whereas with females, it was 1.87 kg. At least 12.2% of the broilers, including both sexes, weighed less than 1 kg ("severely stunted") at this time. The incidence of these growth-stunted birds within each broiler sire family ranged from 0 to 26% and for dam families, 0 to 60%. Correlation analyses between stunting and other MD-associated traits revealed that the incidence of stunting had a significant and positive association with paralysis (r = 0.50). Therefore, the data suggest that there may be a genetic component affecting body weight loss during MD infection. The genetic component is speculated to affect susceptibility to MD paralysis with an indirect effect on the body weight of birds. The significance of this finding is best exemplified by the identification of a broiler sire family with over 26% of its progeny affected by this MD-associated trait.

Animals↗

PubMed1995

Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis.

Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identified a common polymorphism in the stromelysin gene promoter located 1171 bp upstream from the start of transcription in which one allele has a run of six adenosines (6A) and another has five adenosines (5A). 72 men with coronary heart disease, were genotyped. They were participants in the St Thomas' Atherosclerosis Regression Study who were randomised to receive usual care (UC), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 months. In these patients the frequency of the 5A allele was 0.49 (95% CI from 0.41 to 0.57) and was not significantly different from that in a sample of 354 healthy UK men. In the UC group, patients who were homozygous for the 6A allele showed greater progression of angiographic disease than those with other genotypes: the minimum absolute width of coronary segments decreased by 0.04 (SEM 0.10) mm for 5A5A, 0.20 (0.07) mm for 5A6A, and 0.67 (0.19) mm for 6A6A (P < 0.01). The findings were similar but slightly less significant for the change in mean absolute width of coronary segments (P < 0.05). No significant associations were seen in patients in the D or DC groups. In data pooled from the three treatment groups, the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percentage diameter stenosis greater than or equal to 20%. These results provide the first evidence of a link between genetic variation in stromelysin and progression of coronary atherosclerosis and support the hypothesis that connective tissue remodeling mediated by metalloproteinases contribute to the pathogenesis of atherosclerosis.

Base Sequence↗