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The methylenetetrahydrofolate reductase 677C-->T polymorphism and lung cancer risk in a Chinese population.

BACKGROUND: We examined the relationship of the MTHFR C677T genotype with the risk of lung cancer in a nested case-control study conducted in a cancer screening follow-up study in Taiwan. MATERIALS AND METHODS: A total of 59 histologically confirmed lung cancer cases and 232 cancer-free controls were recruited between July 1990 and December 2000. The MTHFR C677T genotype was determined by a PCR-restriction fragment length polymorphism assay. RESULTS: The MTHFR 677T variant genotype, including 677CT and 677TT, was observed in 39% of cases and 47% of controls. The resultant adjusted odds ratio (OR) was 0.71 (95% confidence interval [CI] = 0.39-1.30). The inverse association of the MTHFR 677T variant genotype with lung cancer risk was apparent in both smokers and nonsmokers. CONCLUSION: These results suggest that the MTHFR 677T variant genotype reduces the risk of lung cancer. Larger studies incorporating dietary folate intake and the variant genotypes are needed to clarify our results.

Adult↗
PubMed2001

The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study.

Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.

Aged↗
PubMed2006

Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk.

Interactions between environment and immune system play an essential role in the aetiology of immunopathologies, including lymphomas. Toll-like receptors (TLR) belong to a group of pattern recognition receptors, with importance for innate immune response and inflammatory processes. Interleukin-10 (IL-10) is a key regulatory cytokine and has been implicated in lymphomagenesis. Functional polymorphisms in these inflammation-associated genes may affect the susceptibility towards lymphoma. To test this hypothesis, we have genotyped DNA of 710 lymphoma cases and 710 controls within the context of a population-based epidemiological study for 11 functionally important single-nucleotide polymorphisms in TLR1, -2, -4, -5, -9, IL10 and IL10 receptor (IL10RA). The IL10RA Ser138Gly variant was underrepresented among lymphoma cases (odds ratio (OR)=0.81, 95 per cent confidence interval (95% CI)=0.65-1.02), mainly owing to an inverse association with Hodgkin's lymphoma (HL). The TLR2 -16933T>A variant was associated with a 2.8-fold increased risk of follicular lymphoma (95% CI=1.43-5.59) and a decreased risk of chronic lymphocytic leukaemia (OR=0.61, 95% CI=0.38-0.95). Furthermore, the TLR4 Asp299Gly variant was positively associated with the risk of mucosa-associated lymphoid tissue lymphoma (OR=2.76, 95% CI=1.12-6.81) and HL (OR=1.80, 95% CI=0.99-3.26). In conclusion, this study suggests an effect of polymorphisms in factors of the innate immune response in the aetiology of some lymphoma subtypes.

Adult↗
PubMed2006

Association of MTHFR gene polymorphisms with breast cancer survival.

BACKGROUND: Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. METHODS: African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival. RESULTS: We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05-4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31-1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17-6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12-1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, pinteraction = 0.088; C677T, pinteraction = 0.026). CONCLUSION: We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival.

Adenine↗
PubMed2005

Gastroduodenal Crohn's disease is associated with NOD2/CARD15 gene polymorphisms, particularly L1007P homozygosity.

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15 gene polymorphisms. The aim of this study was to assess the association between NOD2 polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702W and the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007P homozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6-7.3) and to be homozygous for L1007P (11% vs. 1%; OR 5.2; 95% CI 2.5-9.4). G908R heterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1-2.9) and smoking habits (OR 2.4; 95% CI 1.2-3.8), whereas L1007P homozygosity was associated with GDCD (OR 5.8; 95% CI 2.6-10.8). L1007P variation was associated with younger age at diagnosis as well. There was no specific association between R702W homo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15 gene variants, particularly L1007P homozygosity. There is evidence of specific variant-phenotype associations. G908R heterozygosity is associated with ileal involvement and smoking, whereas L1007P homozygosity is strongly associated with GDCD and younger age at diagnosis.

Adolescent↗
PubMed2006

Cyclin D1 gene polymorphism as a risk factor for oral premalignant lesions.

BACKGROUND: Deregulation of cell cycle plays an important role in tumorigenesis. Cyclin D1 gene (CCND1) is a key regulator of the G(1) phase of the cell cycle. METHODS: In this case-control study of 115 oral premalignant lesion (OPL) patients and 230 controls, we genotyped the CCND1 single nucleotide polymorphism (SNP) at the exon 4 splice site (G870A) and determined the association of this SNP with the risk of developing OPLs. RESULTS: We found significant associations between the heterozygous variant allele (GA), the homozygous variant allele (AA) and OPL risk, with adjusted odds ratios (ORs) of 1.91 [95% confidence interval (CI), 1.05-3.48] and 2.38 (95% CI, 1.16-4.87), respectively. The OR for individuals with at least one variant allele was 2.04 (95% CI, 1.15-3.60). When further stratified analyses were performed, the increased risk was more evident in younger individuals (OR = 2.82; 95% CI, 1.32-6.02), in men (OR = 2.97; 95%CI, 1.31-6.71) and in never smokers (OR = 2.92; 95% CI, 1.09-7.82). Finally, we found joint effects between the variant alleles and the smoking status. Using never smokers with the wild-type (GG) genotypes as the reference group, the ORs for never smokers with the variant genotypes (G/A + A/A), smokers with the G/G genotype and smokers with the G/A + A/A genotypes were 2.92 (1.09-7.82), 3.95 (1.36-11.5) and 7.01 (2.68-18.4), respectively. CONCLUSION: Our results suggest that the CCND1 G870A SNP may contribute to genetic susceptibility to OPLs and involve in oral cancer development.

Adult↗
PubMed2002

The XRCC1 Arg399Gln polymorphism, sunburn, and non-melanoma skin cancer: evidence of gene-environment interaction.

XRCC1, a protein directly involved in the repair of DNA base damage, contains at least three common polymorphisms. One of these, the codon 399 arg-->gln variant, has been associated with several cancer-related biomarkers, suggesting it may have functional significance in exposure-induced cancers. However, results from case-control studies have yielded conflicting results. We investigated the XRCC1 arg399gln polymorphism and its interaction with carcinogen exposure in a large, population-based case-control study of non-melanoma skin cancer. Cases were derived from an incident survey of all newly diagnosed non-melanoma skin cancer in New Hampshire, and controls were population based and frequency matched to cases on age and sex (n = 1176). Exposure information was derived from a detailed interviewer-administered questionnaire, and XRCC1 genotype was determined from blood-derived DNA using a PCR-RFLP method. Overall, the XRCC1 homozygous variant gln399gln genotype was related to a significantly reduced risk of both basal cell [BCC; odds ratio (OR) 0.7, 95% confidence interval 0.4-1.0] and squamous cell carcinoma (SCC; OR 0.6, 95% confidence interval 0.3-0.9). There was no significant gene-environment interaction of the variant XRCC1 genotype and a history of therapeutic X-ray exposure. However, there was a statistically significant multiplicative interaction of XRCC1 genotype and lifetime number of sunburns in SCC [likelihood ratio test (2 d.f.), P < 0.02]. Although the absolute risk of SCC associated with sunburns was similar across genotypes, the relative risk of SCC associated with painful sunburn history was significantly higher for homozygous variants than wild types (OR 6.8 for gln399gln and 1.5 for arg399arg). In summary, our data show that the homozygous XRCC1 variant (gln399gln) is associated with a lower risk of non-melanoma skin cancer and suggest that the etiology of sunburn-related SCC may be significantly different by XRCC1 genotype. These data, using the classic skin carcinogenesis model, provide new insight on the role of the XRCC1 399 polymorphism in neoplasia and may help explain the conflicting results relating this polymorphism to cancer risk at various sites.

Aged↗
PubMed2005

Smoky coal exposure, NBS1 polymorphisms, p53 protein accumulation, and lung cancer risk in Xuan Wei, China.

Lung cancer rates in Xuan Wei County are among the highest in China and have been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons (PAHs). The NBS1 gene product participates in DNA double-strand break repair and DNA damage-induced checkpoint activation, which are critical for maintaining genomic integrity. The p53 tumor suppressor gene is known to play key roles both in the maintenance of genomic stability in mammalian cells and in DNA damage surveillance. We examined the association between two common NBS1 polymorphisms (Leu34Leu, Gln185Glu) and lung cancer risk in a population-based case-control study in Xuan Wei, China. Individuals homozygous for the NBS1 34Leu or NBS1 185Glu variants were found to have an increased risk of lung cancer (odds ratio [OR] 2.15, 95% confidence interval [CI]: 0.91-5.10 and OR 2.53, 95% CI: 1.05-6.08, respectively). A haplotype containing the variant alleles from both NBS1 SNPs was associated with increased risk of lung cancer compared with the most common haplotype. Further, the associations were particularly pronounced among cases with over expression of p53 protein. These results suggest that NBS1 could be important in the pathogenesis of lung cancer in this population. However, additional studies in other populations with substantial environmental exposures to PAHs are needed to confirm our findings.

Adult↗
PubMed2000

Genetic variant of luteinizing hormone and risk of breast cancer in older women.

A genetic variant of luteinizing hormone (LH) characterized by two point mutations in codons 8 (TGG-->CGG) and 15 (ATC-->ACC) of the LH beta-subunit gene has been described recently. As compared with wild-type LH, the variant LH appears to have higher in vitro bioactivity but a shortened circulatory half-life, and it has been reported to affect circulating levels of sex hormones. Our purpose was to determine whether the variant form of LH is associated with an altered risk of breast cancer. This hypothesis was addressed in a case-control study nested within a prospective cohort that included 270 cases of breast cancer and twice as many matching control subjects. The study was limited to subjects diagnosed at age 50 years or older. The LH status was determined by the combination of two immunofluorometric assays of serum using monoclonal antibodies. Frequency of the variant LH was similar in breast cancer cases and controls (11.5% versus 10.7%). In conditional regression models, the presence of the variant LH was not associated with a considerable increase of breast cancer risk (odds ratio, 1.07; 95% confidence interval, 0.68-1.69). Adjustment for potential confounders did not notably change the risk estimate (odds ratio, 1.11; 95% confidence interval, 0.69-1.78). These observations do not appear to support the hypothesis that this particular variant of LH is associated with altered risk of breast cancer diagnosed at age 50 years and older.

Adult↗
PubMed2006

Lead, genetic susceptibility, and risk of adult brain tumors.

BACKGROUND: Although few etiologic factors for brain tumors have been identified, limited data suggest that lead may increase the risk of brain tumors, particularly meningioma. The ALAD G177C polymorphism affects the toxicokinetics of lead and may confer genetic susceptibility to adverse effects of lead exposure. METHODS: We examined occupational exposure to lead and risk of brain tumors in a multisite, hospital-based, case-control study of 489 patients with glioma, 197 with meningioma, and 799 non-cancer controls frequency matched on hospital, age, sex, race/ethnicity, and residential proximity to hospital. ALAD genotype was assessed by a Taqman assay for 355 glioma patients, 151 meningioma patients, and 505 controls. Exposure to lead was estimated using a rigorous questionnaire-based exposure assessment strategy incorporating lead measurement and other occupational data abstracted from published articles and reports. RESULTS: Increased risk of meningioma with occupational lead exposure (estimated by odds ratios and 95% confidence intervals) was most apparent in individuals with the ALAD2 variant allele, for whom risk increased from 1.1 (0.3-4.5) to 5.6 (0.7-45.5) and 12.8 (1.4-120.8) for estimated cumulative lead exposures of 1 to 49 microg/m3-y, 50 to 99 microg/m3-y, and >or=100 microg/m3-y, respectively, compared with unexposed individuals (two-sided P trend = 0.06). This relationship became stronger after excluding occupational lead exposures characterized by a low confidence level or occurring in the 10 years before meningioma diagnosis. Occupational lead exposure was not associated with glioma risk. CONCLUSIONS: Although our results indicate that lead may be implicated in meningioma risk in genetically susceptible individuals, these results need to be interpreted with caution given the small numbers of exposed cases with a variant genotype.

Adolescent↗
PubMed2004

Interleukin-1B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population.

Studies suggest that IL-1beta (encoded by IL-1B gene) is a pro-inflammatory cytokine and potent inhibitor of gastric acid secretion, which is proposed as a key determinant in gastric carcinogenesis. Two potentially functional polymorphisms (C-31T and T-511C) in the IL-1B promoter were suggested to be correlated with alteration of Helicobacter pylori infection and IL-1beta expression and therefore may be associated with risk of gastric cancer. To test the hypothesis that these two polymorphisms are associated with gastric cancer risk, we performed a case-control study of 280 histologically confirmed gastric cancer patients and 258 age, sex frequency-matched cancer-free controls in a Chinese population. Multivariate logistic regression analyses revealed that the risks (adjusted odds ratio [OR] and 95% confidence interval [CI]) associated with the IL-1B variant genotypes were 1.64 (95% CI, 1.01-2.66) for -31TT and 1.52 (95% CI, 0.91-2.54) for -511CC, respectively, compared with their wild-type homozygotes. The risks were significantly more evident in individuals with H. pylori infection (adjusted OR, 2.14; 95% CI, 1.13-4.06 for -31TT; adjusted OR, 2.00; 95% CI, 1.02-3.89 for -511CC), which was consistent with the biological effects of IL-1beta. When we used the haplotype analyses and assumed the IL-1B -31T and -511C as risk alleles, no synergistic effect was found between these two loci. These findings indicate that these two IL-1B promoter variants may contribute to the risk of developing gastric cancer in the Chinese population, especially in individuals with H. pylori infection.

Asian People↗
PubMed2006

Polymorphism of SG13S114T/A in the ALOX5AP gene and the risk for stroke in a large Chinese cohort.

The 5-lipoxygenase activating protein, an important regulator in the biosynthesis of proinflammatory leukotrienes, has been reported to confer risks for cardiovascular diseases and stroke. The purpose of this study is to assess whether genetic variants in the ALOX5AP encoding the 5-lipoxygenase activating protein will influence the risk for stroke in the Chinese population. A total of 1,773 patients with stroke and 1,713 controls were recruited from seven clinical centers. Polymorphisms of SG13S114T/A and SG13S89G/A in the ALOX5AP were genotyped by the polymerase chain reaction and the restriction enzyme analysis. The multivariate logistic regression model was used to exclude the influence of the conventional vascular risk factors on stroke. The frequency of SG13S114A allele in the ALOX5AP was significantly higher in male patients with thrombotic stroke (33.6%) than in controls (29.2%; P=0.014). The SG13S114AA genotype was significantly associated with a 1.62-fold risk for thrombotic stroke in men (95% confidence interval, 1.11 to 2.35; P=0.012). The SG13S89G/A variant was not associated with stroke or its subtypes. Haplotype analysis showed no significant differences between stroke patients and controls. The present study suggested that a common genetic variant SG13S114T/A in the ALOX5AP gene is associated with an increased risk for atherothrombotic stroke in Chinese males, and racial differences in allele and genotype frequencies may account partially for the different association findings between populations.

5-Lipoxygenase-Activating Proteins↗
PubMed2005

Single nucleotide polymorphisms in the CYP2J2 and CYP2C8 genes and the risk of hypertension.

CYP2J2 and CYP2C8 metabolize arachidonic acid (AA) to cis-epoxyeicosatrienoic acids (EETs), which play a central role in regulating renal tubular fluid-electrolyte transport and vascular tone. We hypothesized that functionally relevant polymorphisms in the CYP2J2 or CYP2C8 genes influence hypertension risk. We examined associations between CYP2J2*7 (G-50 T promoter) and CYP2C8*3 (Arg139Lys and Lys399Arg, which are in 100% linkage disequilibrium) polymorphisms and hypertension in a biethnic population from Tennessee. CYP2J2*7 variant allele frequency was significantly higher in African-Americans versus Caucasians (14.1% versus 7.7%, P=0.01), irrespective of hypertension status. When analysed separately by race, the genotype distribution of the CYP2J2*7 variant allele was not significantly different among African-Americans with/without hypertension, but was significantly different among Caucasians with/without hypertension (P=0.03). Indeed, the odds ratio of having hypertension attributable to carrying the CYP2J2*7 variant allele adjusted for age, gender, body mass index and family history was 0.39 (95% confidence interval 0.17-0.89) among Caucasians, suggesting a protective effect. Additional subgroup analyses revealed a significantly lower CYP2J2*7 variant allele frequency in hypertensive versus normotensive Caucasian males (5.6% versus 12.5%, P=0.02) and in hypertensive versus normotensive Caucasians without a family history of hypertension (1.5% versus 11.0%, P=0.03). With respect to the CYP2C8*3 variant, genotype distribution and allele frequencies were similar between normotensive and hypertensive subjects. This study provides evidence for an association between CYP2J2*7 genotype and hypertension in Caucasian males and Caucasians without a family history of hypertension, but suggests no association between CYP2C8*3 genotype and hypertension. Confirmation of these findings in additional populations is warranted.

Adult↗
PubMed2004

Heterozygote AG variant of -596 A/G IL-6 gene polymorphism is a marker for cutaneous T-cell lymphoma (CTCL).

The aim of the study was to investigate possible associations of IL-6 gene polymorphisms (-596 A/G and -174 C/G) with cutaneous T-cell lymphoma (CTCL). In the case-control study, genotype distributions and allelic frequencies in two promoter IL-6 gene polymorphisms in the group of 63 Czech patients with CTCL were compared to those of 105 control non-CTCL subjects matched for age and sex. The IL-6 gene polymorphisms were determined by PCR with following restriction analysis. A significant difference of -596 A/G IL-6 genotype distribution was found between the CTCL patients and the controls (P = 0.002) with almost threefold odds ratio for the heterozygote (AG) genotype in CTCL patients (OR = 2.64, P = 0.002). No significant differences in genotype distribution and/or allelic frequency of functional -174 C/G IL-6 gene polymorphism were observed. The double heterozygote AGCG of both IL-6 promoter polymorphisms was associated with CTCL (OR = 2.24, 95% confidence interval 1.17-4.28, P = 0.01). Thus, the heterozygote variant of -596 A/G promoter IL-6 polymorphism could be considered as a genotype marker for CTCL.

Adult↗
PubMed2004

Polymorphism in the DNA repair gene XPD, polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, and breast cancer risk.

DNA repair is essential to an individual's ability to respond to damage caused by environmental carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to environmental exposures. XPD, a gene involved in nucleotide excision repair, may influence individual DNA repair capacity particularly of bulky adducts. Using a population-based breast cancer case-control study that was specifically conducted to examine markers of environmental exposures, such as polycyclic aromatic hydrocarbons (PAH), on Long Island, NY, we examined whether XPD genotype modified the associations among PAH-DNA adducts, cigarette smoking, and breast cancer risk. Specifically, we examined the XPD polymorphism at exon 23, position 751 in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele (Lys/Gln or Gln/Gln) was associated with a 20% increase in risk of breast cancer [odds ratio (OR), 1.21; 95% confidence interval (95% CI), 1.01-1.44]. The increase in risk for homozygosity of the variant allele (Gln/Gln) seemed limited to those with PAH-DNA adduct levels above the median(OR, 1.61; 95% CI, 0.99-2.63 for adducts above the median versus OR, 1.05; 95% CI, 0.64-1.74 for adductsbelow the median), although the multiplicative interaction was not statistically significant. The increasein risk for homozygosity of the variant allele (Gln/Gln) was only seen among current smokers (OR, 1.97; 95% CI, 1.02-3.81 for current smokers versus OR, 0.87; 95% CI, 0.57-1.32 for never smokers); the multiplicative interaction was statistically significant. Overall, this study suggests that those individuals with this polymorphism in the XPD gene may face an increased risk of breast cancer from PAH-DNA adducts and cigarette smoking.

Adult↗
PubMed2005

Polymorphisms in ghrelin and neuropeptide Y genes are associated with non-Hodgkin lymphoma.

We previously reported a positive association among body mass index, single nucleotide polymorphisms (SNP) in the leptin and leptin receptor genes that are involved in body weight regulation, and non-Hodgkin lymphoma (NHL). Polymorphisms in the ghrelin (GHRL) and neuropeptide Y (NPY) genes were examined in the same population-based case-control study of NHL to further explore the role of genes involved in energy homeostasis and obesity in susceptibility to NHL. Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin. NPY is a potent appetite stimulator controlled by ghrelin and leptin and also acts as a mediator of immune function. DNA from 458 cases and 812 controls was genotyped. Among genotyped GHRL SNPs, the variant allele for GHRL -4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74). Another SNP, GHRL 5179A>G, decreased the risk of DLCL (homozygous variant: OR, 0.35; 95% CI, 0.10-1.2). NPY -485T>C, 1258G>A, and 5671C>T were in total linkage disequilibrium (D' = 0.99) and the homozygous variants were associated with an increased risk of NHL in NPY SNPs -485T>C (OR, 1.7; 95% CI, 1.1-2.5), 1258G>A (OR, 1.7; 95% CI, 1.1-2.5), and 5671C>T (OR, 1.9; 95% CI, 1.3-2.8). When stratified by subtype, the variant allele for NPY 1128T>C was positively associated with follicular lymphoma (OR, 2.3; 95% CI, 1.1-4.9) as were homozygous variants for NPY SNPs -485T>C (OR, 2.4; 95% CI, 1.3-4.4), 1258G>A (OR, 2.0; 95% CI, 1.1-3.5), and 5671C>T (OR, 1.8; 95% CI, 1.1-3.0). These results add further support for the hypothesis that SNPs in energy-regulating genes affect risk of NHL.

Adult↗
PubMed2005

Uncertainty due to model choice in variant Creutzfeldt-Jakob disease projections.

For some statistical applications, uncertainty due to unverifiable assumptions can be much greater than that arising from the random variability that is quantified by conventional confidence intervals. The case of projecting possible maximum numbers of eventual deaths due to variant Creutzfeldt-Jakob disease in the United Kingdom provides an extreme example of this phenomenon. The need for parametric extrapolation of the incubation distribution, along with non-identifiability of the number of infected persons, makes assumptions very influential. Several publications in leading science journals gave upper bounds that were 100-fold to 20 000-fold lower than projections from other plausible models given here that fit the data about as well. The crucial assumption for projections is how the risk of death increases with time since infection, and exponential growth is an obvious choice for pessimistic models. Parametric extrapolation from the generalized lambda, generalized F, or lognormal distributions produced upper bounds much lower than exponential extrapolation (i.e. assuming a Gompertz distribution, which fit the data up to early 2002 quite well). Had the publications considered such possibilities, they would have reached much weaker conclusions and been less suitable for leading general science journals. The scientific publication process may have inherent disincentives for thorough assessment of uncertainty.

Adolescent↗
PubMed2004

A functional polymorphism in RGS6 modulates the risk of bladder cancer.

RGS proteins negatively regulate heterotrimeric G protein signaling. Recent reports have shown that RGS proteins modulate neuronal, cardiovascular, and lymphocytic activity, yet their role in carcinogenesis has not been explored. In an epidemiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk. The risk of bladder cancer was reduced by 74% in those individuals with the variant genotype at all three SNPs (odds ratio, 0.26; 95% confidence interval, 0.09-0.71). When the SNPs were analyzed separately, the RGS6-rs2074647 (C-->T) polymorphism conferred the greatest overall reduction in risk of bladder cancer (odds ratio, 0.66; 95% confidence interval, 0.46-0.95). These reductions in risk were more pronounced in ever smokers, suggesting a gene-environment interaction. In transfection assays, the RGS6-rs2074647 (C-->T) polymorphism increased the activity of a luciferase-RGS fusion protein by 2.9-fold, suggesting that this SNP is functionally significant. Finally, we demonstrate that RGS2 transcripts and several splice variants of RGS6 are expressed in bladder cancer cells. These data provide the first evidence that RGS proteins may be important modulators of cancer risk and validate RGS6 as a target for further study.

Case-Control Studies↗