[show abstract][hide abstract] ABSTRACT: We studied 706 participants of the San Antonio Family Diabetes Study (SAFDS) and 586 male samples from the San Antonio Center for Biomarkers of Risk of Prostate Cancer (SABOR) and used 64 ancestry informative markers to compare admixture proportions between both groups. Existence of population substructure was demonstrated by the excess association of unlinked markers. In the SAFDS sample, ancestral proportions were estimated at 50.2 ± 0.6% European, 46.4 ± 0.6% Native American, and 3.1 ± 0.2% West African. For the SABOR sample, the proportions were 58.9 ± 0.7%, 38.2 ± 0.7%, and 2.9 ± 0.2%, respectively. Additionally, in the SAFDS subjects a highly significant negative correlation was found between individual Native American ancestry and skin reflectance (R(2) = 0.07, P= 0.00006). The correlation was stronger in males than in females but clearly showed that ancestry only accounts for a small percentage of the variation in skin color and, conversely, that skin reflectance is not a robust surrogate for genetic admixture. Furthermore, a substantial difference in substructure is present in the two cohorts of Mexican American subjects from the San Antonio area in Texas, which emphasizes that genetic admixture estimates should be accounted for in association studies, even for geographically related subjects.
Annals of Human Genetics 07/2011; 75(4):529-38. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hispanic children have both a higher incidence and a poorer outcome in acute lymphoblastic leukemia (ALL). Moreover, a higher incidence for therapy-related acute myeloid leukemia with 11q23 translocations after treatment with topoisomerase II (topo II) inhibitors has been observed in Hispanic children with ALL. We sought to determine the potential role of genetic variants within the topoisomerase IIα gene (TOP2A), within the mixed lineage leukemia gene (MLL) and two of its translocation partners, cyclin AMP response element-binding protein gene (CREBBP) and E1A binding protein gene (EP300) in the increased sensitivity of Hispanic children with ALL to topo II inhibitors.
Fifty-two tagged single nucleotide polymorphisms (SNP) covering the four genes were genotyped in 241 samples (66 children with ALL and 175 age matched controls) of self-identified Hispanic origin.
Two SNPs within MLL (rs525549 and rs6589664) and three SNPs within EP300 (rs5758222, rs7286979, and rs20551) were significantly associated with ALL (P = 0.001-0.04). A significant gene-dosage effect for increasing numbers of potential high-risk genotypes (OR = 16.66; P = 2 × 10(-5)) and a major haplotype significantly associated with ALL (OR = 5.68; P = 2 × 10(-6)) were found. Replication in a sample of 137 affected White children and 239 controls showed that only rs6589664 (MLL) was significantly associated in this ethnic group.
Our findings indicate that the association between ALL and common genetic variants within MLL and EP300 is population specific.
Replication of our findings in independent Hispanic populations is warranted to elucidate the role of these variants in ALL susceptibility and define their importance in the ethnic specific differences in ALL risk.
[show abstract][hide abstract] ABSTRACT: To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.
[show abstract][hide abstract] ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The U.S. Surveillance Epidemiology and End Results (SEER) registry reports that Hispanic children have the highest incidence of ALL, however, it is unclear if this is due to genetic factors, unique environmental exposures, or both. Previous reports have shown an association between CYP1A1 variants and ALL.
To explore the contribution of CYP1A1 polymorphisms to ALL susceptibility in different ethnic groups, we conducted a case-control analysis in Caucasian, Hispanic, and African-American children.
Increased risk of developing ALL was found in the whole sample group for homozygosity of variant alleles at CYP1A1*2C (OR 2.51, 95% CI 1.18-5.33, P = 0.016) and CYP1A1*2B (OR 3.24, 95% CI 1.43-7.34, P = 0.005). Stratified analyses showed increased risks in the Hispanic group (CYP1A1*2A, OR 2.70, 95% CI 1.27-5.74, P = 0.010; CYP1A1*2C, OR 2.47, 95% CI 1.13-5.38, P = 0.023; and CYP1A1*2B, OR 3.28, 95% CI 1.40-7.69, P = 0.006) but not for the other ethnic groups. Hispanic control subjects were significantly more likely to be carriers of variant alleles as compared to Caucasians (P < 0.0001) and African Americans (P = 0.005).
Our study suggests that polymorphisms in CYP1A1 may contribute to the increased risk of ALL in Hispanic children due to both their impact on leukemia susceptibility and the increased prevalence of the at-risk alleles in the Hispanic population.
Our study provides a novel and specific link between CYP1A1 polymorphisms and ethnic influence on ALL risk that may help explain varying susceptibilities across groups to environmental toxins.
[show abstract][hide abstract] ABSTRACT: The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.
Journal of Biological Chemistry 05/2011; 286(26):23003-11. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Three genes, namely, ELAC2 (HPC2 locus) on chromosome 17p11, 2'-5'-oligoisoadenlyate-synthetase-dependent ribonuclease L (RNASEL, HPC1 locus), and macrophage scavenger receptor 1 (MSR1) within a region of linkage on chromosome 8p, have been identified as hereditary tumor suppressor genes in prostate cancer. We genotyped 41 tagged single nucleotide polymorphisms (SNPs) covering the three genes in a case-control cohort, which included 1,436 Caucasians, 648 Hispanics, and 270 African Americans. SNPs within MSR1, ELAC2, and RNASEL were significantly associated with risk of prostate cancer albeit with differences among the three ethnic groups (P = 0.043-1.0 x 10(-5)). In Caucasians, variants within MSR1 and ELAC2 are most likely to confer prostate cancer risk, and rs11545302 (ELAC2) showed a main effect independent of other significant SNPs (P = 2.03 x 10(-5)). A major haplotype G-A-C-G-C-G combining five SNPs within MSR1 was further shown to increase prostate cancer risk significantly in this study group. Variants in RNASEL had the strongest effects on prostate cancer risk estimates in Hispanics and also showed an interaction effect of family history. In African Americans, single SNPs within MSR1 were significantly associated with prostate cancer risk. A major risk haplotype C-G-G-C-G of five SNPs within ELAC2 was found in this group. Combining high-risk genotypes of MSR1 and ELAC2 in Caucasians and of RNASEL and MSR1 in Hispanics showed synergistic effects and suggest that an interaction between both genes in each ethnicity is likely to confer prostate cancer risk. Our findings corroborate the involvement of ELAC2, MSR1, and RNASEL in the etiology of prostate cancer even in individuals without a family history.
[show abstract][hide abstract] ABSTRACT: Several viruses with known oncogenic potential infect prostate tissue, among these are the polyomaviruses BKV, JCV, and SV40; human papillomaviruses (HPVs), and human cytomegalovirus (HCMV) infections. Recently, the Xenotropic Murine Leukemia Virus-related gammaretrovirus (XMRV) was identified in prostate tissue with a high prevalence observed in prostate cancer (PC) patients homozygous for the glutamine variant of the RNASEL protein (462Q/Q). Association studies with the R462Q allele and non-XMRV viruses have not been reported. We assessed associations between prostate cancer, prostate viral infections, and the RNASEL 462Q allele in Mexican cancer patients and controls.
130 subjects (55 prostate cancer cases and 75 controls) were enrolled in the study. DNA and RNA isolated from prostate tissues were screened for the presence of viral genomes. Genotyping of the RNASEL R462Q variant was performed by Taqman method.
R/R, R/Q, and Q/Q frequencies for R462Q were 0.62, 0.38, and 0.0 for PC cases and 0.69, 0.24, and 0.07 for controls, respectively. HPV sequences were detected in 11 (20.0%) cases and 4 (5.3%) controls. XMRV and HCMV infections were detected in one and six control samples, respectively. The risk of PC was significantly increased (Odds Ratio = 3.98; 95% CI: 1.17-13.56, p = 0.027) by infection of the prostatic tissue with HPV. BKV, JCV, and SV40 sequences were not detected in any of the tissue samples examined.
We report a positive association between PC and HPV infection. The 462Q/Q RNASEL genotype was not represented in our PC cases; thus, its interaction with prostate viral infections and cancer could not be evaluated.
[show abstract][hide abstract] ABSTRACT: To investigate the ancestral admixture in the Mestizo population in northeastern Mexico, we genotyped 74 ancestral informative markers (AIMs) and 15 Y-single-nucleotide polymorphisms (Y-SNPs) in 100 individuals. The Native American contribution is 56% (range: 27.4-81.2%), the European contribution is 38% (range: 16.7-70.5%) and the West African contribution is 6%. The results show a higher European contribution than was reported in other similar studies in the country, albeit with a predominant Native American ancestry. No remarkable differences in the ancestry proportions were observed using subgroups of 74, 54, 34 and 24 AIMs. The paternal lineage calculated by genotyping of 15 Y-SNPs, shows a major component of European and Eurasian ancestry markers ( approximately 78%), compared with Amerindian ( approximately 12%) and African markers (10%). This information will set a reference for future determinations of admixture proportions in the Mestizo population from Mexico and for population-based association studies of complex diseases.
Journal of Human Genetics 09/2009; 54(9):504-9. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: SEMA3B and SEMA3F are 2 closely related genes lying 80 kb apart on chromosome 3 that have been shown to suppress tumor formation in vivo and in vitro. Each gene has a single nucleotide polymorphism that results in a nonsynonymous coding change, rs2071203 (SEMA3B) and rs1046956 (SEMA3F), as well as noncoding single nucleotide polymorphisms.
We performed a case-control study of 789 prostate cancer cases and 907 controls from 3 races/ethnicities to determine possible associations of 10 variants with prostate cancer risk or prognosis.
The risk of prostate cancer increased more than 2-fold in Hispanic men with TT alleles at rs2071203 in SEMA3B and with CC alleles for rs2072054 at the 5' end of SEMA3F (OR 2.13, 95% CI 1.12-4.04, p = 0.02 and OR 2.55, 95% CI 1.34-4.84, p = 0.0045, respectively). These 2 single nucleotide polymorphisms were also associated with a poor prognosis in Hispanic men (2.71 and 3.48-fold increased risk). A frequent G-C-G-G-A-T-C-C-T-G haplotype encompassing 10 SNPs was associated with an increased risk of prostate cancer and poor prognosis in Hispanic samples (OR 2.72, 95% CI 1.20-6.12, p = 0.016 and OR 3.32, 95% CI 1.21-9.10, p = 0.02). In nonHispanic white men the T-C-G-A-A-T-C-C haplotype was associated with a high Gleason score (OR 1.44, 95% CI 1.06-1.96, p = 0.021).
These data indicate that polymorphisms in SEMA3B and SEMA3F are associated with prostate cancer risk and poor prognosis in Hispanic and nonHispanic white men.
The Journal of urology 09/2009; 182(4):1614-20. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genotyping of a 615 kb region within 8q24 with 49 haplotype-tagged single-nucleotide polymorphisms (SNPs) in 2109 samples (797 cases and 1312 controls) of two ethnic/racial groups found SNPs that are significantly associated with the risk for prostate cancer (PCa). The highest significance in Caucasian men was found for rs6983267; the AA genotype reduced the risk for PCa [odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.35-0.65, P = 2.74 x 10(-6)]. This SNP also had a significant independent effect from other SNPs in the region in this group. In Hispanic men, rs7837328 and rs921146 showed independent effects (OR = 2.55, 95% CI = 1.51-4.31, P = 4.33 x 10(-4), OR = 2.09, 95% CI = 1.40-3.12, P = 3.13 x 10(-4), respectively). Significant synergist effects for increasing numbers of high-risk alleles were found in both ethnicities. Haplotype analysis revealed major haplotypes, containing the non-risk alleles, conferred protection against PCa. We found high linkage disequilibrium between significant SNPs within the region and SNPs within the CUB and Sushi Multiple Domains 1 gene (CSMD1), on the short arm of chromosome 8 in both ethnicities. These data suggest that multiple interacting SNPs within 8q24, as well as different regions on chromosome 8 far beyond this 8q24 candidate region, may confer increased risk of PCa. This is the first report to investigate the involvement of 8q24 variants in the susceptibility for PCa in Hispanic men.
[show abstract][hide abstract] ABSTRACT: To estimate the prostate cancer risk conferred by individual single nucleotide polymorphisms (SNPs), SNP-SNP interactions, and/or cumulative SNP effects, we evaluated the association between prostate cancer risk and the genetic variants of 12 key genes within the steroid hormone pathway (CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1). A total of 116 tagged SNPs covering the group of genes were analyzed in 2,452 samples (886 cases and 1,566 controls) in three ethnic/racial groups. Several SNPs within CYP19 were significantly associated with prostate cancer in all three ethnicities (P = 0.001-0.009). Genetic variants within HSD3B2 and CYP24A1 conferred increased risk of prostate cancer in non-Hispanic or Hispanic Caucasians. A significant gene-dosage effect for increasing numbers of potential high-risk genotypes was found in non-Hispanic and Hispanic Caucasians. Higher-order interactions showed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = 0.001). In African Americans, a 10-locus model, with SNPs located within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1, showed a significant interaction (P = 0.014). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < 0.001). These data are consistent with a polygenic model of prostate cancer, indicating that multiple interacting genes of the steroid hormone pathway confer increased risk of prostate cancer.
[show abstract][hide abstract] ABSTRACT: For decades, it has been well-recognized that genetics plays a critical role in the development of prostate cancer. Numerous
epidemiological and molecular biological studies have shown evidence for a significant but heterogeneous hereditary component
in prostate cancer susceptibility. Linkage analysis in twin and family-based study designs provided targeted candidate regions
for prostate cancer risk and cancer aggressiveness. Subsequent mapping efforts and mutation screening yielded several strong
candidate genes. More recent tools allow investigation of gene–gene and gene–environment interactions in population-based
designs, such as case–control or cohort studies. These analyses have identified associations between single nucleotide polymorphisms
within candidate genes and prostate cancer susceptibility. Understanding the role of these genes may help in defining heterogeneity
in prostate cancer etiology and eventually lead to better detection, treatment, and, ultimately, prevention of prostate cancer.
Key WordsCandidate gene-Prostate cancer risk-Association-Linkage-Single nucleotide polymorphism (SNP)-Disease aggressiveness
[show abstract][hide abstract] ABSTRACT: Cytochrome P450 1B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones. We compared allele, genotype and haplotype frequencies of six single-nucleotide polymorphisms (SNPs) within CYP1B1 among non-Hispanic Caucasians (496 cases and 498 controls) and Hispanic Caucasians (153 cases and 240 controls). In the Hispanic Caucasians, the GG genotype for rs1056836 decreased the risk for prostate cancer (PCa) when compared with the CC genotype [odds ratio (OR) = 0.31, P = 0.04, 95% confidence interval (CI) = 0.10-0.96]. Among non-Hispanic Caucasian men with more aggressive PCa, the prevalence of several SNPs (rs2567206, rs2551188, rs2617266, rs10012 and rs1056836) was significantly associated with the disease status. A common C-G-C-C-G-A haplotype for rs2567206-rs2551188-rs2617266-rs10012-rs1056836-rs1800440 showed an inverse association with PCa risk in Hispanic Caucasians (OR = 0.19, P = 0.04, 95% CI = 0.04-0.95) and with aggressive disease status (i.e. Gleason score >or=7) in non-Hispanic Caucasian cases (OR = 0.64, P = 0.008, 95% CI = 0.47-0.89). In the non-Hispanic Caucasian cases, a second major haplotype T-A-T-G-C-A was positively associated with the high-grade disease status (OR = 1.77, P = 0.002, 95% CI = 1.24-2.53). Our findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for PCa and support the role of CYP1B1 as a candidate gene for PCa.
[show abstract][hide abstract] ABSTRACT: Vitamin D and dihydrotestosterone pathways interact to promote the growth of prostatic tissue. The nuclear vitamin D receptor (VDR) moderates the actions of vitamin D. 5alpha-Reductase type II (SRD5A2) codes for the enzyme that converts testosterone to dihydrotestosterone in the prostate. This study tested the interactions of VDR (CDX2, FokI) and SRD5A2 (V89L, A49T) polymorphisms, and their associations with prostate cancer.
This genetic association study included 932 non-Hispanic White (NHW) men and 414 Hispanic White (HW) men from South Texas. Cases had biopsy-confirmed cancer; controls had normal digital rectal exams and serum prostate-specific antigen levels of <2.5 ng/mL.
Using logistic regression analyses to test associations with prostate cancer, only the V89L polymorphism (VV genotype compared with LL/LV) in HW men was statistically significant [odds ratios (OR), 0.64; 95% confidence intervals (95% CI), 0.41-0.99]. The interaction terms for FokI and V89L in NHW men and CDX2 and V89L in HW men in the logistic model were significant (P = 0.02 and 0.03, respectively). When stratified by V89L genotype, the FokI polymorphism (TT/TC versus CC) was significantly associated with prostate cancer in NHW men with the V89L VV genotype (FokI OR, 1.53; 95% CI, 1.06-2.23). The CDX2 polymorphism (GG versus AG/AA) was significantly associated with prostate cancer only in HW men with the V89L VV genotype (CDX2 OR, 3.16; 95% CI, 1.39-7.19; interaction term P = 0.02).
Our results indicate that the SRD5A2 V89L VV genotype interacts with VDR FokI TT/CT genotypes in NHW men and VDR CDX2 GG genotypes in HW men to increase the risk for prostate cancer.
Clinical Cancer Research 05/2008; 14(10):3223-9. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: The dopaminergic system in the brain plays a critical role in nicotine addiction. Genetic variants in the dopaminergic system, including those in dopamine receptor genes, represent plausible candidates for the genetic study of nicotine dependence (ND). We investigated various polymorphisms in the dopamine D(2) receptor gene (DRD2) and its neighboring ankyrin repeats and kinase domain containing 1 gene (ANKK1) to determine whether they were associated with ND. We examined 16 single nucleotide polymorphisms (SNPs) at DRD2 and 7 SNPs at ANKK1 in our Mid-South Tobacco Family cohort, which consisted of 2037 participants representing two distinct American populations. Several SNPs (rs7131056, rs4274224, rs4648318, and rs6278) in DRD2, along with the Taq IA polymorphism (rs1800497) in ANKK1, revealed initial significant associations with ND in European Americans, but not after correction for multiple testing, indicating a weak association of DRD2 with ND. In contrast, associations for ANKK1 with ND in the African-American and pooled samples, specifically for SNP rs2734849, remained significant after correction. With a non-synonymous G to A transition, rs2734849 produces an amino-acid change (arginine to histidine) in C-terminal ankyrin repeat domain of ANKK1. Using the luciferase reporter assay, we further demonstrated that the variant alters expression level of NF-kappaB-regulated genes. Since DRD2 expression is regulated by transcription factor NF-kappaB, we suspect that rs2734849 may indirectly affect dopamine D(2) receptor density. We conclude that ANKK1 is associated with ND and polymorphism rs2734849 in ANKK1 represents a functional causative variant for ND in African-American smokers.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2008; 34(2):319-30. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epidemiologic studies have strongly implicated genetics in smoking behavior. Genes in the dopaminergic system, which mediates the reinforcing and dependence-producing properties of nicotine, are plausible candidates for roles in nicotine dependence (ND). In this study, we examined five single-nucleotide polymorphisms (SNPs) within or near the dopamine D(1) receptor gene (DRD1) for their association with ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). The samples were obtained from 2,037 participants representing 200 European American (EA) and 402 African American (AA) families. Although we found significant associations of SNPs rs265973, rs686, and rs4532 in the AA sample; of rs4532 in the EA sample; and of rs265975, rs686, and rs4532 in the pooled sample with various ND measures, only the association of rs686 in the AA sample and of rs686 and rs4532 in the pooled sample remained significant after correction for multiple testing. Haplotype-based association analysis revealed that haplotype C-T-A, formed by rs265973, rs265975, and rs686, was significantly associated with all three ND measures in both the AA and the pooled sample. Another haplotype, T-A-T, formed by rs265975, rs686, and rs4532, showed a significant association with FTND in the pooled sample. Furthermore, in a luciferase reporter assay, rs686, located in the 3' untranslated region, caused differential luciferase activities, indicating that rs686 is a functional polymorphism affecting expression of DRD1.
Human Genetics 04/2008; 123(2):133-40. · 4.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: The RNASEL gene at 1q25 has been identified as a hereditary prostate cancer susceptibility gene, but to date, no study has investigated the role of RNASEL variants in Hispanic Caucasian men with prostate cancer.
Two RNASEL common variants, located at amino acids 462 and 541, were genotyped in non-Hispanic Caucasian, Hispanic Caucasian, and African American prostate cancer cases and controls.
The RNASEL 462 AA genotype was found to increase prostate cancer risk over 4-fold in Hispanic Caucasians [odds ratio (OR), 4.43; 95% confidence interval (95% CI), 1.68-11.68; P = 0.003] and over 10-fold in African Americans (OR, 10.41; 95% CI, 2.62-41.40; P = 0.001) when compared with the GG genotype. Analysis of the RNASEL 541 variant showed that Hispanic Caucasian patients with the GG genotype had a statistically significant increase in their risk for developing prostate cancer when compared with the TT and GT genotypes (OR, 1.91; 95% CI, 1.16-3.14; P = 0.01). A common G-T haplotype for the combination of the RNASEL 462 and 541 variants was found to occur more frequently in controls compared with cases in African Americans (P = 0.04) but not in non-Hispanic Caucasians or Hispanic Caucasians.
This is the first study that investigates the association of prostate cancer risk with RNASEL variants in Hispanic men. Our data support the role of RNASEL as a predisposition gene for prostate cancer and showed a significant association between the RNASEL 462 variant and prostate cancer risk in African Americans and Hispanic Caucasians.
Clinical Cancer Research 11/2007; 13(19):5959-64. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: The protein phosphatase 1 regulatory subunit 1B gene (PPP1R1B; also known as dopamine and cAMP-regulated phosphoprotein; DARPP32) is a target for the actions of dopamine. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, PPP1R1B is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within a region on chromosome 17 that demonstrated "suggestive linkage" to ND in our previous genome-wide scan. In the present study, we analyzed six single nucleotide polymorphisms (SNPs) within PPP1R1B for association with three ND measures: smoking quantity (SQ), the heaviness of smoking index (HSI), and the Fagerström Test for ND (FTND) score. Our sample consisted of 602 nuclear families of African-American (AA) or European-American (EA) origin. No significant associations were found for single SNPs after correction for multiple testing. However, haplotype analysis indicated that in the EA sample, the C-T-G-C haplotype formed by rs2271309-rs907094-rs3764352-rs3817160 with a frequency of 32.0% was significantly associated with SQ (Z = 2.50; P = 0.01), even after Bonferroni correction. No significant associations with haplotypes were found in the AA sample. In summary, our findings provide the first evidence for the potential involvement of PPP1R1B in the etiology of ND and further investigation is thus warranted.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):285-90. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a "suggestive" linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified.
Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND.
Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the haplotype T-T-A of rs1659400-rs1187272-rs1122530 had a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78; p = .0001, frequency 59.9%). We further identified a major haplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4075274-rs729560, which showed a significant positive association (max Z = 2.97, p = .003) with adjusted ND measures in the AA sample.
These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.