Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families.

BACKGROUND: Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. OBJECTIVE: To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). METHODS: Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. RESULTS: All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (theta = 0) for markers D7S462 and D7S517. CONCLUSION: Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.

The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

BRAF polymorphisms and the risk of ovarian cancer of low malignant potential.

OBJECTIVE: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. METHODS: We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. RESULTS: Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). CONCLUSION: We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.

The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer.

Deficiencies in DNA repair have been hypothesized to increase cancer risk and excess cancer incidence is a feature of inherited diseases caused by defects in DNA damage recognition and repair. We investigated, using a case-control design, whether the double-strand break repair gene polymorphisms RAD51 5' untranslated region -135 G > C, XRCC2 R188H G > A, and XRCC3 T241M C > T were associated with risk of breast or ovarian cancer in Australian women. Sample sets included 1,456 breast cancer cases and 793 age-matched controls ages under 60 years of age, 549 incident ovarian cancer cases, and 335 controls of similar age distribution. For the total sample and the subsample of Caucasian women, there were no significant differences in genotype distribution between breast cancer cases and controls or between ovarian cancer cases and combined control groups. The crude odds ratios (OR) and 95% confidence intervals (95% CI) associated with the RAD51 GC/CC genotype frequency was OR, 1.10; 95% CI, 0.80-1.41 for breast cancer and OR, 1.22; 95% CI, 0.92-1.62 for ovarian cancer. Similarly, there were no increased risks associated with the XRCC2 GA/AA genotype (OR, 0.98; 95% CI, 0.76-1.26 for breast cancer and OR, 0.93; 95% CI, 0.69-1.25 for ovarian cancer) or the XRCC3 CT/TT genotype (OR, 0.92; 95% CI, 0.77-1.10 for breast cancer and OR, 0.87; 95% CI, 0.71-1.08 for ovarian cancer). Results were little changed after adjustment for age and other measured risk factors. Although there was little statistical power to detect modest increases in risk for the homozygote variant genotypes, particularly for the rare RAD51 and XRCC2 variants, the data suggest that none of these variants play a major role in the etiology of breast or ovarian cancer.

RAD52 Y415X truncation polymorphism and epithelial ovarian cancer risk in Australian women.

The RAD52 gene is involved in the homologous recombination repair pathway and is a plausible candidate ovarian cancer predisposition gene. We undertook a case-control comparison of 508 epithelial ovarian cancer cases (91 low malignant potential and 417 invasive) and 298 healthy controls to assess the RAD52 Y415X polymorphism as a risk factor for epithelial ovarian cancer in Australian women. Heterozygote frequencies of 2.6 and 4% were observed among cases and controls, respectively. The risk estimate was 0.55 (95%CI 0.24-1.24), suggesting that the RAD52 Y415X polymorphism is not associated with epithelial ovarian cancer in Australian women.

Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers.

OBJECTIVE: The progestagenic milieu of pregnancy and oral contraceptive use is protective against epithelial ovarian cancer. A functional single nucleotide polymorphism in the promoter of the progesterone receptor (+331A) alters the relative abundance of the A and B isoforms and has been associated with an increased risk of endometrial and breast cancer. In this study, we sought to determine whether this polymorphism affects ovarian cancer risk. METHODS: The +331G/A polymorphism was genotyped in a population-based, case-control study from North Carolina that included 942 Caucasian subjects (438 cases, 504 controls) and in a confirmatory group from Australia (535 cases, 298 controls). Logistic regression analysis was used to calculate age-adjusted odds ratios (OR). RESULTS: There was a suggestion of a protective effect of the +331A allele (AA or GA) against ovarian cancer in the North Carolina study [OR, 0.72; 95% confidence interval (95% CI), 0.47-1.10]. Examination of genotype frequencies by histologic type revealed that this was due to a decreased risk of endometrioid and clear cell cancers (OR, 0.30; 95% CI, 0.09-0.97). Similarly, in the Australian study, there was a nonsignificant decrease in the risk of ovarian cancer among those with the +331A allele (OR, 0.83; 95% CI, 0.51-1.35) that was strongest in the endometrioid/clear cell group (OR, 0.60; 95% CI, 0.24-1.44). In the combined U.S.-Australian data that included 174 endometrioid/clear cell cases (166 invasive, 8 borderline), the +331A allele was significantly associated with protection against this subset of ovarian cancers (OR, 0.46; 95% CI, 0.23-0.92). Preliminary evidence of a protective effect of the +331A allele against endometriosis was also noted in control subjects (OR, 0.19; 95% CI, 0.03-1.38). CONCLUSIONS: These findings suggest that the +331G/A progesterone receptor promoter polymorphism may modify the molecular epidemiologic pathway that encompasses both the development of endometriosis and its subsequent transformation into endometrioid/clear cell ovarian cancer.

Polymorphisms associated with circulating sex hormone levels in postmenopausal women.

BACKGROUND: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them. METHODS: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates. RESULTS: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk. CONCLUSION: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.

Association between apolipoprotein E epsilon4 and neuropsychiatric symptoms during interferon alpha treatment for chronic hepatitis C.

Neuropsychiatric complications are common in patients with chronic hepatitis C undergoing treatment with interferon alpha. These side effects include alterations of mood, cognition, and neuroendocrine function and are unpredictable. In a number of neurological disorders characterized by neuropsychiatric symptoms and cognitive dysfunction, inheritance of an apolipoprotein E (APOE) epsilon4 allele is associated with adverse neuropsychiatric outcomes. The authors present evidence that the APOE genotype may influence a patient's neuropsychiatric response to interferon alpha treatment. The inheritance of APOE genotypes was examined in 110 patients with chronic hepatitis C treated with interferon alpha. A retrospective investigation was conducted by assessing the rates of psychiatric referral and neuropsychiatric symptoms experienced during treatment along with other complaints indicating psychological distress. A highly statistically significant association was seen between APOE genotypes and interferon-induced neuropsychiatric symptoms. Patients with an epsilon4 allele were more likely to be referred to a psychiatrist and had more neuropsychiatric symptoms during antiviral treatment than those without an epsilon4 allele. Additionally, patients with an epsilon4 allele were more likely to experience irritability or anger and anxiety or other mood symptoms. These data demonstrate that an individual's APOE genotype may influence the neuropsychiatric response to antiviral therapy with interferon alpha. Prospective studies evaluating the importance of APOE in susceptibility to interferon alpha-induced neuropsychiatric complications are needed. Moreover, pathways involving APOE should be considered in understanding the pathophysiology of interferon alpha-induced neuropsychiatric complications.

COMPARATIVE PHYLOGEOGRAPHY OF A SIBLING PAIR OF RAINFOREST DROSOPHILA SPECIES (DROSOPHILA SERRATA AND D. BIRCHII).

Drosophila serrata and D. birchii are presumed sibling species; the former is a widespread generalist and the latter is restricted to rainforests. Comparison of the mtDNA sequence phylogeographies revealed two highly divergent, geographically distinct lineages of D. serrata that are as distinct from each other as either is from D. birchii. However, diversity in D. birchii is low and unstructured. The low diversity in D. birchii corresponds with a late-Pleistocene-Holocene contraction of lowland rainforests. We suggest that future studies of speciation and adaptation should compare the two lineages of D. serrata to each other as well as to D. birchii.