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Biomedical subjects

G A Coetzee

Publications and source records attributed to G A Coetzee.

At least 19 recordsLinked to original sources
PubMed2001

Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype.

Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometrial cancer. We examined the association between endometrial cancer risk and estrogen replacement therapy (ERT) by CYP17 genotype using 51 incident cases and 391 randomly selected controls from a multiethnic cohort in Hawaii and Los Angeles, California. The relative risk of endometrial cancer was calculated for ever use versus never use of ERT by CYP17 genotype (TT, TC, and CC). We found that women who reported ever taking ERT were more than twice as likely to develop endometrial cancer as women who never took ERT [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.19-4.23]. Among these women, the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR, 4.10; 95% CI, 1.64-10.3), but not for women with the C allele (OR, 1.31; 95% CI, 0.53-3.21). These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be potential markers of endometrial cancer susceptibility due to ERT.

Aged↗
PubMed2001

Building a multigenic model of breast cancer susceptibility: CYP17 and HSD17B1 are two important candidates.

We conducted a nested case-control study to evaluate whether polymorphisms in two genes involved in estrogen metabolism, CYP17 and HSD17B1, were useful in developing a breast cancer risk model that could help discriminate women who are at higher risk of breast cancer. If polymorphisms in these genes affect the level of circulating estrogens, they may directly influence breast cancer risk. The base population for this study is a multiethnic cohort study that includes African-American, Non-Latina White, Japanese, Latina, and Native Hawaiian women. For this analysis, 1508 randomly selected controls and 850 incident breast cancer cases of the first four ethnic groups who agreed to provide a blood specimen were included (76 and 80% response rates, respectively). The CYP17 A2 allele and the HSD17B1 A allele were considered "high-risk" alleles. Subjects were then classified according to number of high-risk alleles. After adjusting for age, weight, and ethnicity, we found that carrying one or more high-risk alleles increases the risk of advanced breast cancer in a dose-response fashion. The risk among women carrying four high-risk alleles was 2.21 [95% confidence interval (CI), 0.98-5.00; P for trend = 0.03] compared with those who carried none. This risk was largely limited to women who were not taking hormone replacement therapy (relative risk, 2.60; 95% CI, 0.95-7.14) and was most pronounced among those weighing 170 pounds or less (RR, 3.05; 95% CI, 1.29-7.25). These findings suggest that breast cancer risk has a strong genetic component and supports the theory that the underlying mechanism of "complex traits" can be understood using a multigenic model of candidate genes.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States).

OBJECTIVE: The purpose of this study was to determine whether vitamin D receptor (VDR) gene polymorphisms influence risk of colorectal adenoma. METHODS: Polymorphisms in the 5' and 3' ends of the VDR gene were genotyped for 373 colorectal adenoma cases and 394 controls. RESULTS: Overall, there was no significant association between the 5' (FokI) or the 3' (BsmI) polymorphisms and adenoma risk. However, risk of large (>1 cm) adenomas decreased with increasing copies of the FokI f allele (p = 0.04). Compared to the FF genotype, odds ratios for the Ff and ff genotypes were 0.79 (95% CI 0.44-1.41) and 0.32 (95% CI 0.11-0.91), respectively. FokI genotype was more strongly related to large adenoma risk among subjects with low dietary calcium intake (ORFf=0.48; 95% CI 0.17-1.3; ORff=0.21: 95% CI 0.04-1.3), low dietary vitamin D intake (ORFf=0.25; 95% CI 0.09-0.69; ORff= 0.22; 95% CI 0.04-1.2), or dark skin color (ORFf=0.66; 95% CI 0.27-1.6; ORff=0.10; 95% CI 0.01-1.0). CONCLUSION: These results suggest that VDR FokI genotype influences development of colorectal adenomas. and that the effect may be modified by calcium and vitamin D status.

Adenoma↗
PubMed2001

Contribution of the androgen receptor to prostate cancer predisposition and progression.

Although prostate cancer is heterogeneous in its etiology and progression, androgen signaling through the androgen receptor (AR) appears to be involved in all aspects of the disease, from initiation to development of treatment resistance. Lifetime exposure to a constitutively more active AR, encoded by AR alleles as defined by two translated polymorphic microsatellites (CAG and GGC), results in a significant increase in prostate cancer risk. The AR gene is amplified or a target for somatic gain-of-function mutations in metastatic prostate cancer. Gain-of-function AR gene mutations may result in inappropriate activation of the AR, thereby contributing to the failure of conventional androgen-ablation treatments. In cases where no genetically altered receptors are observed, altered signaling through the AR, achieved by cross-talk with other signaling pathways (e.g. kinase-mediated pathways) and/or inappropriate expression of coregulatory proteins, may contribute to disease progression. Thus, the AR-signaling axis contributes to many aspects of prostate cancer, including initiation, progression and resistance to current forms of therapy. This recognition represents a paradigm shift in our understanding of the molecular mechanisms involved in progression of prostate cancer, and provides insight into novel AR-targeted therapies which ultimately may be more effective than current forms of androgen ablation.

Adenocarcinoma↗
PubMed2001

Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore.

BACKGROUND: Epidemiologic studies have identified the plasma homocysteine concentration as a risk factor for atherothrombotic vascular disease. There is little information on the distributions and determinants of homocysteine concentrations in Asian populations. OBJECTIVE: The present study was designed to examine the relations between genetic and lifestyle factors and plasma homocysteine concentrations among Chinese in Singapore. DESIGN: Plasma total homocysteine, folate, vitamin B-12, and vitamin B-6 concentrations and genetic variation at the methylenetetrahydrofolate reductase (MTHFR) locus were measured in 486 Chinese men and women aged 45-74 y in Singapore. Data on dietary and other lifestyle factors were collected in face-to-face interviews. RESULTS: Men had higher plasma concentrations of total homocysteine than women (P = 0.0001). Age was positively associated with plasma homocysteine in both sexes (P for trend = 0.0001). Plasma concentrations of folate, vitamin B-12, and vitamin B-6 were inversely associated with homocysteine concentrations. Among individuals with low plasma folate, those possessing 2 copies of MTHFR mutant alleles had significantly higher homocysteine concentrations than did those with > or = 1 copy of the wild-type allele. Cigarette smoking, daily coffee consumption, and physical inactivity were positively related to plasma homocysteine concentrations in both sexes (P < 0.05). However, these associations disappeared after adjustment for plasma folate concentrations. CONCLUSIONS: Age, sex, plasma folate, vitamin B-12 and B-6 concentrations, and MTHFR genotype are independent determinants of plasma homocysteine in middle-aged and older Chinese in Singapore. These factors combined could account for up to 40% of the total variation in homocysteine concentrations in this Asian population.

Aged↗
PubMed2001

Genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort.

We recently reported an association between prostate cancer risk and polymorphisms in the prostate-specific antigen (PSA) and androgen receptor (AR) genes. The purpose of this study is to test whether these two polymorphisms, AR CAG and PSA ARE1, influence serum PSA levels in healthy men. Serum PSA and the two genotypes were assayed for 420 healthy men from a multiethnic cohort, and regression models were fit to estimate the effects of AR CAG genotype and PSA ARE1 genotype on serum PSA levels. Predicted serum PSA decreased 3.5% with each additional AR CAG repeat decile (P = 0.01). Serum PSA was also associated with PSA ARE1 genotype, with PSA levels higher among men with the PSA AA genotype compared with men with the AG or GG genotypes (P = 0.02). The relationship between serum PSA level and AR CAG length differed according to PSA genotype (P = 0.049): for genotype GG, the slope was not significantly different from zero (P = 0.74); for genotype AG, serum PSA increased 4.5% with each decrease of one CAG repeat decile (P = 0.03); for genotype AA, serum PSA increased 7% with each decrease of one CAG repeat decile (P = 0.02). These results indicate that in healthy men, genetic variants in the PSA and AR genes contribute to variation in serum PSA levels. Men with the PSA AA genotype and short AR CAG alleles have, on average, higher serum PSA levels.

Aged↗
PubMed2000

Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor.

In the present study, the role of BRCA1 in ligand-dependent androgen receptor (AR) signaling was assessed. In transfected prostate and breast cancer cell lines, BRCA1 enhanced AR-dependent transactivation of a probasin-derived reporter gene. The effects of BRCA1 were mediated through the NH2-terminal activation function (AF-1) of the receptor. Cotransfection of p160 coactivators markedly potentiated BRCA1-mediated enhancement of AR signaling. In addition, BRCA1 was shown to interact physically with both the AR and the p160 coactivator, glucocorticoid receptor interacting protein 1. These findings suggest that BRCA1 may directly modulate AR signaling and, therefore, may have implications regarding the proliferation of normal and malignant androgen-regulated tissues.

BRCA1 Protein↗
PubMed2000

Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China.

BACKGROUND: Dietary isothiocyanates inhibit lung carcinogenesis in laboratory animals but human data are limited. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) conjugate isothiocyanates leading to more rapid elimination. Common deletion polymorphisms of GSTM1 and GSTT1 abolish enzyme activity. We hypothesised that chemopreventive effects of isothiocyanates might be heightened when enzymes that enhance their elimination are lacking. METHODS: We examined the relation between total isothiocyanate concentrations in urine, collected before diagnosis, and the subsequent risk of lung cancer among 232 incident cases of lung cancer and 710 matched controls from a cohort of 18,244 men in Shanghai, China, followed from 1986 to 1997. Homozygous deletion of the GSTM1 and GSTT1 genes were determined by PCR. FINDINGS: Individuals with detectable isothiocyanates in the urine were at decreased risk of lung cancer (smoking-adjusted relative risk for lung cancer=0.65 [95% CI 0.43-0.97]). This protective effect of isothiocyanates was seen primarily among individuals with homozygous deletion of GSTM1 (0.36 [0.20-0.63]) and particularly with deletion of both GSTM1 and GSTT1 (0.28 [0.13-0.57]). INTERPRETATION: Isothiocyanates appeared to reduce lung-cancer risk in this cohort of Chinese men. Reduction in risk was strongest among persons genetically deficient in enzymes that rapidly eliminate these chemopreventive compounds.

Case-Control Studies↗
PubMed2000

Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle. Dissociation of cyclin A-cyclin-dependent kinase 2 from E2F4-p130 complexes.

Unique cell cycle control is instituted in confluent osteoblast cultures, driving growth to high density. The postconfluent dividing cells share features with cells that normally exit the cell cycle; p27(kip1) is increased, p21(waf1/cip1) is decreased, free E2F DNA binding activity is reduced, and E2F4 is primarily nuclear. E2F4-p130 becomes the predominant E2F-pocket complex formed on E2F sites, but, unlike the complex that typifies resting cells, cyclin A and CDK2 are also present. Administration of dexamethasone at this, but not earlier stages, results in reduction of cyclin A and CDK2 levels with a parallel decrease in the associated kinase activity, dissociation of cyclin A-CDK2 from the E2F4-p130 complexes, and inhibition of G(1)/S transition. The glucocorticoid-mediated cell cycle attenuation is also accompanied by, but not attributable to, increased p27(kip1) and decreased p21(waf1/cip1) levels. The attenuation of osteoblast growth to high density by dexamethasone is associated with severe impairment of mineralized extracellular matrix formation, unless treatment commences in cultures that have already grown to high density. Both the antimitotic and the antiphenotypic effects are reversible, and both are antagonized by RU486. Thus, glucocorticoids induce premature attenuation of the osteoblast cell cycle, possibly contributing to the osteoporosis induced by these drugs in vivo.

3T3 Cells↗
PubMed2000

Susceptibility to prostate cancer: interaction between genotypes at the androgen receptor and prostate-specific antigen loci.

The androgen receptor (AR) regulates gene transcription by binding to androgen response elements in target gene promoters. The prostate-specific antigen (PSA) gene has a polymorphic androgen response element sequence with two alleles, A and G. We hypothesize that allelic differences in AR-driven PSA expression may influence prostate cancer risk. To test this hypothesis, we assayed PSA genotype for 57 prostate cancer cases and 156 controls from our previous pilot study in which prostate cancer risk was associated with the AR "CAG-short" genotype. Odds ratios (ORs) were estimated relating prostate cancer risk to AR and PSA genotypes, singly and in combination. Subjects with the PSA GG genotype were at significantly increased risk for advanced, but not for localized, prostate cancer (OR, 2.90; 95% confidence interval, 1.24-6.78). When cross-classifying subjects by AR and PSA genotypes, subjects with either a CAG-short allele (and not PSA GG) or with the PSA GG genotype (and not CAG-short) had a modest, statistically insignificant increase in prostate cancer risk overall. However, subjects with both a short CAG allele and PSA genotype GG had a more than 5-fold increase in prostate cancer risk (OR, 5.08; 95% confidence interval, 1.59-16.25). All of the ORs were substantially greater for advanced prostate cancer. Studies with larger numbers of advanced cases will be needed to confirm these results. These results indicate that polymorphism in the PSA gene promoter influences prostate cancer risk, and that the allelic variation in promoter activity may be androgen-dependent. Furthermore, these results support a multigenic etiology for prostate cancer.

Aged↗
PubMed2000

Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length.

Normal polymorphic size variation of the exon 1 CAG microsatellite of the androgen receptor (AR) is associated with prostate cancer, benign prostatic hyperplasia and male infertility. Furthermore, abnormal expansion of the satellite leads to Kennedy's disease. We have shown recently that the AR N-terminal domain (NTD), which contains the polyglutamine (polyQ) stretch (encoded by the CAG repeat), functionally interacts with the C-termini of p160 coactivators. In the present study we explored possible AR CAG size effects on the p160 coactivator-mediated transactivation activity of the receptor. First, we mapped the p160 coactivator interaction on the AR NTD and found an interaction surface between amino acids 351 and 537. Although this region is 'downstream' from the polyQ stretch, it is still within the AR NTD, is implicated in constitutive transactivation activity of the receptor, and thus might be subject to polyQ size modulation. Indeed, cotrans- fection experiments in cultured prostate epithelial cells, using AR constructs of varying CAG sizes and p160 coactivator expression vectors, revealed that increased polyQ length, up to a size of 42 repeats, inhibited both basal and coactivator-mediated AR transactivation activity. AR expression in these cells, on the other hand, was unaffected by the same increased CAG repeat size range. We conclude that the AR NTD contributes to AR transactivation activity via functional interactions with p160 coactivators and that increasing polyQ length negatively affects p160-mediated coactivation of the AR. This molecular mechanism thus might explain, at least in part, the observed phenotypic effects of the AR CAG size polymorphism.

Androgen Receptor Antagonists↗
PubMed2000

Vitamin D receptor genotype and breast cancer in Latinas (United States).

OBJECTIVE: Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk. METHODS: Polymorphisms in the 5' and 3' ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls. RESULTS: Both the BsmI and poly-A polymorphisms in the 3' end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0 2.3) and 3.2 (1.5-6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1-2.5) and 2.2 (1.0-4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk. CONCLUSION: These results suggest that polymorphic variation in or near the 3' end of the VDR gene influences breast cancer risk in Latina women.

Aged↗
PubMed2000

Elevated mortality rates from circulatory disease in African American men and women of Los Angeles County, California--a possible genetic susceptibility?

OBJECTIVE: Reports of higher mortality in African Americans have often focused on socioeconomic differences. Such differences do not explain the excess mortality in African Americans compared with Hispanics in Los Angeles County. We suggest the existence of genetic factors to explain at least some of the differences in mortality risk. METHODS: We compared the mortality rates from circulatory diseases in African American and Hispanic adults of Los Angeles County for 1988 to 1992 with the frequency of the angiotensin-converting enzyme (ACE) genotype. RESULTS: African American adults 45 to 74 years old had a 2-fold higher overall mortality rate than Hispanics. The largest differences were seen for hypertensive disease and cardiomyopathy in men; the most striking differences were seen in the youngest age group. Rates were lower in women than in men, but African American women also showed substantial excess compared with Hispanics. ACE genotype also showed a significant difference between the Hispanic and African American population; the latter had a significantly higher prevalence of the DD genotype, which is associated with a higher level of circulating enzyme, and lower prevalence of the II genotype, which is associated with a lower enzyme level. CONCLUSION: African American adults aged 45 to 74 years in Los Angeles County have a substantial excess mortality from hypertensive diseases compared with a similar Hispanic population. The frequency of the ACE DD genotype was higher in African Americans than in Hispanics. These studies may indirectly support the possibility of a genetic contribution to the excess hypertensive disease mortality in African Americans.

Aged↗
PubMed2000

CYP1A1 I462V genetic polymorphism and lung cancer risk in a cohort of men in Shanghai, China.

Cytochrome P450 (CYP) CYP1A1 activates tobacco-related carcinogens. A point mutation at codon 462 in exon 7 of CYP1A1 results in a substitution of isoleucine by valine near the heme binding site. This mutation is rare in Caucasians but common in Japanese populations, in which association with increased risk of lung cancer has been reported. There are few data in other Asian populations. We investigated this I462V polymorphism using DNA from 214 incident cases of lung cancer and 669 controls in a prospective cohort study of 18,244 middle-aged and older men in Shanghai, China. The valine allele frequency was 0.138 among the control population. The I462V genotype was not appreciably associated with lung cancer risk overall. There was some suggestion that having at least one valine allele might be related to increased risk of lung cancer among smokers of <20 cigarettes/day (odds ratio, 1.72; 95% confidence interval, 0.82-3.62), particularly among those with homozygous deletion of GSTM1 (odds ratio, 2.80; 95% confidence interval, 1.07-7.33), which is involved in the detoxification of activated tobacco carcinogens. In this Chinese cohort, with CYP1A1 valine allele frequency intermediate between Japanese and Caucasian populations, the I462V polymorphism is not related to lung cancer overall, but it might play a role at lower levels of cigarette smoking among subjects with impaired carcinogen detoxification as assessed by the GSTM1-null genotype.

Benzo(a)pyrene↗
PubMed1999

Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy.

We investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with higher endogenous hormone levels, influences the use of hormone replacement therapy (HRT). The study included 749 postmenopausal women ages 44-75 years at baseline randomly selected from a larger multiethnic cohort. African-American, Japanese, Latina, and white women were included in the study. Women who carry the CYP17 A2/A2 genotype were about half as likely as women with the A1/A1 genotype to be current HRT users (odds ratio = 0.52; 95% confidence interval, 0.31-0.86). This association was present in all four racial/ethnic groups and for women above and below the median weight of 150 pounds. These findings suggest that the actual risk of breast cancer associated with HRT use may be higher than previously reported.

Adult↗
PubMed1999

Vitamin D receptor 3'-untranslated region polymorphisms: lack of effect on mRNA stability.

Allelic variation at the 3'-end of the vitamin D receptor (VDR) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization. This genetic diversity does not alter the VDR protein structurally, but instead may be a marker(s) of other, nearby polymorphisms that influence message stability or translation. The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability. Initially, four novel, frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously. These common sequence variants were not found within three message-destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA. Furthermore, the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene, in an in vitro assay. We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability.

3' Untranslated Regions↗