Single Nucleotide Polymorphisms In Block Research Articles

The 9p21.3 Locus

A series of reports in 2007 established that single nucleotide polymorphisms (SNPs) in the 9p21.3 locus are associated with coronary heart disease (CHD), both in patients with acute myocardial infarction and chronic atherosclerosis.1,–,4 Subsequently, many additional studies used a candidate locus approach to replicate the 9p21.3-CHD association. Intriguingly, other phenotypes have also been found to be associated with this genomic region, including type II diabetes, stroke, malignant melanoma, aortic aneurysms, cerebral aneurysms, and periodontitis. Unfortunately, neither the causative variants nor genes have been established. Although genetic associations may permit better disease risk stratification, without the knowledge of the genes and variants we lose opportunities to improve our basic understanding of the disease process and hence the potential for targeted therapies. Article see p 445 Many cellular pathways in multiple tissues contribute to the pathogenic processes resulting in CHD. There is value in using intermediate phenotypes as outcomes in genetic association studies because there is enhanced power to detect gene associations when the number of genes potentially responsible for the phenotype is reduced, thereby increasing the fraction of the variance explained by any single factor or gene. In addition, intermediate traits are usually easier to define (have less heterogeneity) than clinical disease. Somewhat surprisingly, 9p21.3 has not been associated with measures believed to represent the chronic process of atherosclerosis or endothelial cell reactivity,5 suggesting that this locus may contribute to CHD by an alternate pathophysiologic mechanism. There is abundant pathological and clinical evidence demonstrating the vital role played by blood platelets in acute coronary syndromes, which result from the formation of occlusive platelet thrombi in coronary arteries at the sites of ruptured atherosclerotic plaques,6,7 and antiplatelet agents have become a mainstay of therapy in patients with acute coronary syndromes. In addition to …

2052 INSULIN-LIKE GROWTH FACTOR-I (IGF-I) POLYMORPHISMS PREDICT THE SURVIVAL OF PROSTATE CANCER PATIENTS WITH BONE METASTASIS AT INITIAL PRESENTATION

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 20102052 INSULIN-LIKE GROWTH FACTOR-I (IGF-I) POLYMORPHISMS PREDICT THE SURVIVAL OF PROSTATE CANCER PATIENTS WITH BONE METASTASIS AT INITIAL PRESENTATION Norihiko Tsuchiya, Shintaro Narita, Zhiyong Ma, Yohei Horikawa, Hiroshi Tsuruta, Kazuyuki Numakura, Mitsuru Saito, Shigeru Satoh, Takamitsu Inoue, Osamu Ogawa, and Tomonori Habuchi Norihiko TsuchiyaNorihiko Tsuchiya Akita, Japan More articles by this author , Shintaro NaritaShintaro Narita Akita, Japan More articles by this author , Zhiyong MaZhiyong Ma Akita, Japan More articles by this author , Yohei HorikawaYohei Horikawa Akita, Japan More articles by this author , Hiroshi TsurutaHiroshi Tsuruta Akita, Japan More articles by this author , Kazuyuki NumakuraKazuyuki Numakura Akita, Japan More articles by this author , Mitsuru SaitoMitsuru Saito Akita, Japan More articles by this author , Shigeru SatohShigeru Satoh Akita, Japan More articles by this author , Takamitsu InoueTakamitsu Inoue Akita, Japan More articles by this author , Osamu OgawaOsamu Ogawa Kyoto, Japan More articles by this author , and Tomonori HabuchiTomonori Habuchi Akita, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2099AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The insulin-like growth factor I (IGF-I) plays an important role in androgen-independent growth of prostate cancer cells and facilitating the progression of prostate cancer particularly after hormone therapy failure. This study aimed to evaluate the predictive values of four polymorphisms in three haplotype blocks of the IGF-I gene on the survival of metastatic prostate cancer patients. METHODS A total of 213 patients with bone metastases at initial presentation were included in this study. Cytosine-adenine (CA) repeat polymorphism and rs12423791 were selected as representative polymorphisms in haplotype blocks 1 and 2, respectively. Haplotype in block 3 was analyzed using two tag single nucleotide polymorphisms (SNPs), rs7136446 and rs6220. Cancer-specific and overall survival rates were estimated from the Kaplan-Meier curve, and the survival data were compared using the log-rank test. RESULTS Cancer-specific survival was significantly associated with each polymorphism in haplotype blocks 1 and 2 of the IGF-I gene (P = 0.007 and 0.020, respectively). Although tag SNPs in block 3 alone had no significant association with survival, the expected haplotype in block 3 was significantly associated with cancer-specific survival (Fig. 1). When the patients were divided into three groups as 0 (favorable), 1–2 (intermediate), and 3 (unfavorable) based on the number of risk alleles or haplotypes, the unfavorable group showed significantly worse cancer-specific survival than the intermediate or favorable groups (P = 0.037 or 0.0002, respectively) (Fig. 2). CONCLUSIONS Polymorphisms, especially the combination of these four polymorphisms in each haplotype block of the IGF-I gene, are assumed to be novel genetic markers predicting the outcome of metastatic prostate cancer. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e797-e798 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Norihiko Tsuchiya Akita, Japan More articles by this author Shintaro Narita Akita, Japan More articles by this author Zhiyong Ma Akita, Japan More articles by this author Yohei Horikawa Akita, Japan More articles by this author Hiroshi Tsuruta Akita, Japan More articles by this author Kazuyuki Numakura Akita, Japan More articles by this author Mitsuru Saito Akita, Japan More articles by this author Shigeru Satoh Akita, Japan More articles by this author Takamitsu Inoue Akita, Japan More articles by this author Osamu Ogawa Kyoto, Japan More articles by this author Tomonori Habuchi Akita, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density

High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast. We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density. Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n=656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method. The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01-0.04). The same SNPs were related with modestly higher percent breast density before menopause and-in the subgroup of women that became postmenopausal during follow-up-with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP<0.5 assuming prior probabilities of 0.01 and higher. Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.

Genetic Polymorphisms of the CYP19A1 Gene and Breast Cancer Survival

The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus may be related to the progression of breast cancer. We examined the association between CYP19A1 genetic polymorphisms and breast cancer survival in a cohort of 1,136 patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and who has donated a DNA sample to the study. Patients were followed for cancer recurrence and mortality through July 2005. Nineteen haplotype tagging single-nucleotide polymorphisms (SNP) in the CYP19A1 gene were evaluated. For each of the five SNPs located in haplotype block 2, patients homozygous for the minor alleles had a reduced 5-year disease-free survival rate compared with those carrying the major allele. The age-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were 1.5 (1.1-2.1), 2.1 (1.2-3.6), 1.5 (1.1-2.0), 1.4 (1.0-2.0), and 1.4 (1.0-2.0) for hCV1664178, rs12900137, rs730154, rs936306, and rs1902586, respectively. Haplotype analyses showed that the haplotype CCCTA (all minor alleles of the five SNPs in block 2) was associated with decreased disease-free survival (HR, 1.9; 95% CI, 1.1-3.3). The nonsynonymous SNP, rs700519 (Arg264Cys), located in haplotype block 4, was also associated with breast cancer survival. The age-adjusted HR for the Cys/Cys (T/T) genotype was 2.2 (95% CI, 1.2-4.1) for overall survival and 2.1 (95% CI, 1.1-3.9) for disease-free survival, compared with those carrying the Arg (C) allele. These results suggest that polymorphisms in the CYP19A1 gene may have effects on breast cancer prognosis.

Association between two µ-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence

We examined 13 single nucleotide polymorphisms (SNPs) spanning the coding region of the mu-opioid receptor gene (OPRM1), among 382 European Americans (EAs) affected with substance dependence [alcohol dependence (AD) and/or drug dependence (DD)] and 338 EA healthy controls. These SNPs delineated two haplotype blocks. Genotype distributions for all SNPs were in Hardy-Weinberg equilibrium (HWE) in controls, but in cases, four SNPs in Block I and three SNPs in Block II showed deviation from HWE. Significant differences were found between cases and controls in allele and/or genotype frequencies for six SNPs in Block I and two SNPs in Block II. Association of SNP4 in Block I with DD (allele: P=0.004), SNP5 in Block I with AD and DD (allele: P< or =0.005 for both) and two SNPs in Block II with AD (SNP11 genotype: P=0.002; SNP12 genotype: P=0.001) were significant after correction for multiple testing. Frequency distributions of haplotypes (constructed by five tag SNPs) differed significantly for cases and controls (P<0.001 for both AD and DD). Logistic regression analyses confirmed the association between OPRM1 variants and substance dependence, when sex and age of subjects and alleles, genotypes, haplotypes or diplotypes of five tag SNPs were considered. Population structure analyses excluded population stratification artifact. Additional supporting evidence for association between OPRM1 and AD was obtained in a smaller Russian sample (247 cases and 100 controls). These findings suggest that OPRM1 intronic variants play a role in susceptibility to AD and DD in populations of European ancestry.

Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer Risk: A Haplotype-Based Analysis

The PROGINS allele of the progesterone receptor (PGR) gene has been associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. We set out to refine the association between common variation at the PGR gene locus and these two diseases. We characterized the haplotype structure of the PGR gene by genotyping 54 single-nucleotide polymorphisms (SNPs) in 349 women. We then selected a subset of 17 haplotype-tagging SNPs that captured variation across the locus and typed them in 267 ovarian cancer case patients and 397 control subjects from two case-control studies and in 1715 breast cancer case patients and 2505 control subjects from a cohort study. The PGR locus was characterized by four blocks of strong linkage disequilibrium. Two SNPs in block 4 were associated with an increased risk of ovarian cancer among homozygous carriers as compared with noncarriers: rs1042838 (PROGINS allele; odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.19 to 8.75, P = .022) and rs608995 (minor allele; OR = 3.10, 95% CI = 1.63 to 5.89, P<.001). The PROGINS allele was observed on a subset of chromosomes carrying the minor allele at rs608995, and its association with ovarian cancer was fully explained by its association with rs608995. In addition, rs608995 fell on two common haplotypes (4-D and 4-E), whose association with ovarian cancer was the same as that of rs608995. These same two haplotypes were associated with a non-statistically significantly reduced risk of breast cancer. Variation in PGR was associated with ovarian cancer risk, although the strongest result was not with the PROGINS allele. Instead, any causal allele(s) are likely in or downstream of block 4 and carried on haplotypes 4-D and 4-E. There was some evidence that the same variation was associated with a reduced risk of breast cancer, but the association was not statistically significant.

RACIAL VARIABILITY IN HAPLOTYPE FREQUENCIES OF UGT1A1 AND GLUCURONIDATION ACTIVITY OF A NOVEL SINGLE NUCLEOTIDE POLYMORPHISM 686C&gt; T (P229L) FOUND IN AN AFRICAN-AMERICAN

Ethnic differences in genetic polymorphisms in UDP-glucuronosyltransferase 1A1 (UGT1A1) were investigated among African-Americans, Caucasians, and Japanese using samples obtained from 150 individuals for each population. Genotyping of -3279T>G in the phenobarbital-responsive enhancer module, TA repeats in the TATA box, 211G>A (G71R) and 686C>A (P229Q) in exon 1, and three single nucleotide polymorphisms (SNPs) (1813C> T, 1941C>G, and 2042C>G) in the 3'-untranslated region in exon 5 was performed. Eight haplotypes of block 1 (exon 1 and its 5'-flanking region) harboring the first four variations were assigned to each individual. The dominant haplotype for African-Americans was *28b (-3279G;TA(7); 211G;686C) (0.446), whereas that for the Japanese was *1a (-3279T; TA(6);211G;686C) (0.610). Frequencies of the two haplotypes *1a and *28b were comparable in Caucasians. Haplotype *6a (-3279T;TA(6); 211A;686C) was characteristic of the Japanese, whereas haplotypes *36b and *37b (-3279T;TA(5) and TA(8);211G;686C) were found mostly in African-Americans. Although the three SNPs in block 2 (exons 2-5) were in complete linkage in the Japanese, they were not completely linked in African-Americans or Caucasians. These differences in haplotype distribution patterns among the three populations suggest the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C>T (P229L), was found in an African-American. The intrinsic clearance of 7-ethyl-10-hydroxycamptothecin (SN-38) by P229L UGT1A1 expressed in COS-1 cells was about 3% of the wild type. The results of Western blotting and real-time reverse transcription-polymerase chain reaction suggest that the low glucuronidation activity of the variant was partly due to its low stability. The variation 686C>T may cause high toxicity during 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) therapy or hyperbilirubinemia in patients.