Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study.

OBJECTIVE: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy. DESIGN: Case-control study. SETTING AND POPULATION: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array. METHODS: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES: Genetic predisposition to medical conditions and relationship with pre-eclampsia. RESULTS: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association. CONCLUSIONS: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACT: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.

Characterizing the influence of vitamin D levels on IVF outcomes.

BACKGROUND: Vitamin D plays a role in reproductive capacity. Recently, several investigators have demonstrated higher IVF pregnancy rates in vitamin D replete women. The objective of this study was to validate these findings and to further elucidate the role of vitamin D in reproduction among a diverse group of women. METHODS: This was a retrospective cohort study in an academic tertiary care center of 188 infertile women undergoing IVF. Serum levels of vitamin D (25OH-D) were measured in previously frozen serum samples. The main outcome measure was clinical pregnancy, defined as sonographic presence of a heartbeat following IVF. RESULTS: The relationship between vitamin D status and pregnancy rates differed by race (P < 0.01). Among non-Hispanic whites, pregnancy rates declined with progressively lower levels of vitamin D, while in Asians, the reverse was true. Adjusting for age and number and quality of embryos transferred among non-Hispanic whites, the odds of pregnancy were four times higher in vitamin D replete versus deficient patients. Live birth rates mirrored pregnancy rates. Vitamin D status was not associated with ovarian stimulation parameters or with markers of embryo quality. CONCLUSIONS: Vitamin D deficiency is associated with lower pregnancy rates in non-Hispanic whites, but not in Asians, possibly due to their lower IVF success rates. Vitamin D deficiency was not correlated with ovarian stimulation parameters or with markers of embryo quality, suggesting its effect may be mediated through the endometrium.

Genome-wide meta-analyses of smoking behaviors in African Americans.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach.

RATIONALE: Insulin-like growth factor-1 (IGF1) has been proposed to mediate the obesity-related carcinogenic effects of "Western lifestyle". While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesised to underlie the variation in cancer incidence rates remain ill-defined. METHODS: We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernising population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study. RESULTS: We identified a common (minor allele frequency = 0.36) single-nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40% decrease in risk in comparison to genotype CC (odds ratio, 0.59; 95% confidence interval, 0.45 to 0.77). This association was stronger for colon cancer than for rectal cancer (p(heterogeneity)<0.001) and for those who were physically active versus inactive (p(interaction) = 0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk. CONCLUSIONS: Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer.

IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort.

The insulin-like growth factor 1 gene (IGF1) is a strong candidate gene for a breast cancer susceptibility model. We investigated a dinucleotide repeat 969 bp upstream from the transcription start site of the IGF1 gene for possible associations with plasma IGF1 levels and breast cancer risk in a multiethnic group of postmenopausal women. Furthermore, we investigated the relation between race/ethnicity, mean plasma IGF1 levels and breast cancer rates in the Hawaii/Los Angeles Multiethnic Cohort. The mean age-adjusted IGF1 level among Latino-American women, 116 ng ml(-1), was statistically significantly lower than the mean age-adjusted IGF1 levels for each of the three other racial/ethnic groups, African-American, Japanese-American and Non-Latino White women (146, 144 and 145 ng ml(-1), respectively) (P<0.0001). Latino-American women have the lowest breast cancer rates of any racial/ethnic group in the cohort. These results support the investigation of an expansion of the hypothesis for an important role of IGF1 in breast cancer tumorigenesis to different racial/ethnic groups and to postmenopausal women. It is unlikely that any involvement of IGF1 in breast cancer aetiology is mediated by the IGF1 dinucleotide repeat polymorphism, which was not significantly associated with circulating IGF1 levels nor breast cancer risk in this study. Research into relevant determinants of IGF1 levels in the blood must continue.

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.

An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas.

Epidemiological and experimental studies have implicated bile acids (particularly secondary bile acids) as important factors in the development of colorectal cancer. The ileal sodium-dependent bile acid transporter (ISBT) is a crucial player in the enterohepatic circulation of bile acids. Genetic defects in ISBT may result in malabsorption of bile acids and a loss of bile acids into the large intestine, with a resultant increase in the cytotoxic secondary bile acids in the colon. In a case-control study, we investigated the association between two sequence variations in SLC10A2, the gene encoding ISBT, and colorectal adenomas, a precursor lesion of colorectal cancer. The frequency of the missense mutation in codon 171 of exon 3 (a nucleotide transversion from G to T resulting in an alanine to serine substitution) was not significantly different between cases and controls. However, we found a 2-fold higher risk of colorectal adenomas associated with a C-->T nucleotide transition in codon 169 of exon 3 (odds ratio = 2.06; 95% confidence interval: 1.10-3.83). Logistic regression analysis using A171S/169 C-->T haplotypes as the allelic markers showed that among AA wild-type homozygotes for A171S mutation, this C-->T nucleotide transition in codon 169 was associated with a 2.42 times increased risk (odds ratio = 2.42; 95% confidence interval: 1.26-4.63). This initial observation of an association between a polymorphism in the SLC10A2 gene and the risk of colorectal adenomatous polyps would, if confirmed by other studies, support the role of bile acids in the carcinogenesis of colorectal cancer.

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.

Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy.

Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.

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.

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.

Linkage analysis and loss of heterozygosity for chromosome arm 1p in familial breast cancer.

We conducted linkage analysis of 64 multiple-case families with early-onset bilateral breast cancer using DNA markers on chromosome band 1p36. Evidence against tight linkage was obtained using a dominant model for transmission (summary LOD scores at recombination fraction theta = 0.000001 were -4.71 for D1S160 and -2.70 for D1S170). Similar results were obtained after excluding 20 families that were potentially attributable to BRCA1 or BRCA2. We also investigated loss of heterozygosity for a panel of markers on chromosome arm 1p using breast tumors from affected family members. The most common regions of allele loss were 1p36 (32% for D1S160, 35% for D1S243) and 1p32 (51% for MYCL). The frequency and location of 1p allele loss did not differ substantially from previous studies of sporadic breast cancer. We conclude that 1p36 probably does not contain a locus of susceptibility for a large proportion of breast cancer families, but a variety of loci on 1p may contribute to progression of familial and sporadic disease. Genes Chromosomes Cancer 25:354-361, 1999.

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.

Aromatase and breast cancer susceptibility.

Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-Latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA)n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.

Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas.

Cruciferous vegetables, especially broccoli, may prevent cancer through anticarcinogenic compounds. For example, broccoli contains isothiocyanates that induce carcinogen-detoxifying enzymes. Glutathione transferase enzymes conjugate isothiocyanates, leading to excretion. We hypothesized that broccoli consumption in combination with the glutathione transferase M1 (GSTM1) null genotype would be associated with a lower prevalence of colorectal adenomas because of higher isothiocyanate levels. We used a case-control study of mainly asymptomatic subjects aged 50-74 years who underwent a screening sigmoidoscopy at either of two Southern California Kaiser Permanente Medical Centers during 1991-1993. Cases (n = 459) had a first-time diagnosis of histologically confirmed adenomas detected by flexible sigmoidoscopy. Controls (n = 507) had no polyp detected. Subjects had a 45-min in-person interview for information on various risk factors and basic demographic data and completed a 126-item, semiquantitative food frequency questionnaire. Blood samples were used for GSTM1 genotyping. Subjects with the highest quartile of broccoli intake (an average of 3.7 servings per week) had an odds ratio of 0.47 (95% confidence interval, 0.30-0.73) for colorectal adenomas, compared with subjects who reportedly never ate broccoli. When stratified by GSTM1 genotype, a protective effect of broccoli was observed only among subjects with the GSTM1 null genotype (P for trend, 0.001; P for interaction, 0.01). The observed broccoli-GSTM1 interaction is compatible with an isothiocyanate mechanism.

Association of prostate cancer with vitamin D receptor haplotypes in African-Americans.

In previous studies, allelic variation in the 3' end of the vitamin D receptor gene was associated with increased risk of prostate cancer in white men. Several polymorphisms, including a BsmI restriction site and a poly(A) microsatellite, can be used interchangeably to mark the unidentified locus in whites. In African-Americans, however, these markers are not interchangeable, due to weaker linkage disequilibrium in this genomic region in this population. Here, we genotyped both the BsmI and poly(A) markers for 151 African-American prostate cancer cases (102 localized and 49 advanced) and 174 African-American male controls from a large epidemiological cohort. A direct haplotyping procedure was devised to determine BsmI/poly(A) haplotypes for double heterozygotes so that haplotypes could be used as allelic markers in standard logistic regression analyses. Using BsmI alone, b alleles were associated with a 2-fold decrease in risk of advanced prostate cancer. The association was, however, confined to haplotypes carrying a long (L) allele of the poly(A) microsatellite. BL and bL haplotypes were associated with increased and decreased risk, respectively, whereas neither BS nor bS haplotypes were associated with prostate cancer risk. An allelic variant that confers increased risk of advanced prostate cancer appears to be associated with the BsmI/poly(A) BL haplotype in African-Americans.

Plasma tocopherol and prevalence of colorectal adenomas in a multiethnic population.

Although vitamin E can block mutagenesis and cell transformation in vitro and can reduce the number of chemically induced colonic adenomas in mice, previous clinical trials have found no protective effect of vitamin E supplements against colorectal adenomas, and epidemiological studies have found only weak protective effects of dietary or plasma alpha-tocopherol against colorectal cancer. We previously examined first diagnosis of colorectal adenomas in a sigmoidoscopy screening population and failed to find a protective effect of dietary vitamin E. Because measurements of dietary intake may not be a good proxy of vitamin E status, we assayed plasma alpha- and gamma-tocopherol concentration for 332 subjects with colorectal adenomas and 363 control subjects from this previous sigmoidoscopy-based study. Increasing alpha-tocopherol and decreasing gamma-tocopherol levels were associated with decreased occurrence of large (> or = 1 cm) but not of small (<1 cm) adenomas; however, after adjustment for potential confounding variables, these trends were not statistically significant. A strong trend (P = 0.02) was observed by using the alpha-tocopherol:gamma-tocopherol ratio, which may be a more sensitive indicator of alpha-tocopherol intake. Subjects in the highest versus lowest quintile of alpha-tocopherol: gamma-tocopherol ratio had an odds ratio of 0.36 (95% confidence interval, 0.14-0.95) for large adenomas. The finding that a high alpha-tocopherol:gamma-tocopherol ratio is associated with decreased occurrence of large, but not of small, colorectal adenomas is consistent with previous findings that alpha-tocopherol may be protective against colon cancer. A high plasma alpha-tocopherol:gamma-tocopherol ratio may be a better predictor of decreased cancer risk than high plasma alpha-tocopherol alone.

Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States).

The often observed association between red meat and colorectal cancer could be due in part to mutagens, such as heterocyclic amines (HCA), that are present in cooked meat. HCAs are highly mutagenic and cause intestinal tumors in animals. The hypothesis that HCAs are also carcinogenic to humans remains to be substantiated in epidemiologic studies. We determined the associations of meat preparation and frequency of intake (proxy variables for HCA exposure, since HCA concentration depends on the type of meat and the way it is cooked) with the prevalence of distal colorectal adenomas in a sigmoidoscopy-based case-control study of 488 matched pairs of subjects from two California (United States) Kaiser Permanente Medical Centers. A more than twofold difference in adenoma prevalence between subjects at extreme ends of estimated HCA intake was observed. For subjects who ate red meat more than once per week, fried it more than 10 percent of the time, and ate it with a darkly browned surface, compared with subjects who ate red meat one time or less per week, fried it 10 or less percent of the time, and ate it with a lightly browned surface, the odds ratio was 2.2 (95 percent confidence interval = 1.1-4.3). Adenoma prevalence also increased with frequency of frying red meat (P trend = 0.004). These results are consistent with a carcinogenic effect of HCA.

Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies.

Markers in the 3' end of the vitamin D receptor gene have recently been associated with prostate cancer risk. To evaluate the adequacy of the commonly used BsmI restriction fragment length polymorphism as a marker of this locus, we genotyped 627 individuals from five ethnic groups for this marker, as well as for a polymorphic site in the 3' untranslated region of this gene. At the latter site, we identified 12 alleles, A13 to A24, of a poly(A) microsatellite. Allele size followed a bimodal distribution with distinct short (A13-A17) and long (A18-A24) allele populations. Poly(A) allele frequency differed by ethnicity, with the frequency of short alleles being highest in non-Hispanic whites (41%), intermediate in Hispanics and African-Americans (31 and 29%, respectively), and lowest in Japanese-Americans and Chinese (8 and 9%, respectively). In each of the ethnic groups, some degree of coupling was observed between BsmI B and short poly(A) alleles and between BsmI b and long poly(A) alleles. However, the strength of the linkage disequilibrium varied by ethnicity, with departures from complete disequilibrium producing disagreement between the BsmI and poly(A) genotypes. Genotypic disagreement was lowest in Japanese-Americans and non-Hispanic whites (6 and 7%, respectively), intermediate in Chinese and Hispanics (11 and 19%, respectively), and highest among African-Americans (37%), indicating that BsmI is not a good marker for the vitamin D receptor 3' untranslated region genotype in all populations. This finding may explain contradictory results from recent association studies using the BsmI marker.

Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor.

BACKGROUND: Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility. PURPOSE: We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer. METHODS: Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatellite (CAG repeats) in the AR gene and for a newly discovered poly-A microsatellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests. RESULTS: Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A18 to A22) VDR poly-A allele versus two short (A14 to A17) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. CONCLUSIONS: In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer. IMPLICATIONS: These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.