Strong Environmental Risk Factors Research Articles

CD4 T cells restricted to DRB1*15:01 recognize two Epstein–Barr virus glycoproteins capable of intracellular antigen presentation

Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens.

Genetic ablation of Sarm1 attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injury

Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI.

DOP79 Alternative polygenic forms of Inflammatory Bowel Disease are not captured by current generations of polygenic risk scores

Abstract Background Polygenic risk scores (PRSs) have emerged as a promising tool to ascertain individuals at high risk of developing IBD. However, the sensitivity of current PRSs is limited, and will likely remain so in the immediate future. The default expectation is that patients not captured by PRSs must be enriched for rare variants with strong effects and/or environmental risk factors. We set out to investigate an alternative scenario, namely that combinations of common variants in non-GWAS genes conform population of patients that are missed by large genetic studies for the main forms of the disease. Methods MAGMA was used to identify genes from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) GWAS. We selected a sort of monogenic IBD genes1 which were significant for IBD (pval ≈ 10-4) but do not overlap with polygenic IBD genes. These genes were compared using DESeq tool on two transcriptomic databases: RISK (Crohn’s disease (CD) onset vs non-IBD) and PROTECT (ulcerative colitis (UC) onset vs 52 weeks). A second DESeq analysis was performed between patients with high against low expression of these 13 genes. We explored these genes using in-silico predicted expression based on eQTL in 9 different tissues for UK Biobank (UKBB) population, comparing UKBB individuals according to disease and polygenic risk score status. Results The starting point based on MAGMA analysis led to the detection of 13 monogenic IBD genes which may partially participate in polygenic forms of the disease. The transcriptomic analyses, based on stratification according to the levels of these 13 genes, implied that these genes participate in regulatory programmes that are particularly heterogeneous and variable among cases. The detected differentially expressed genes are associated with immune processes and receptors, inflammation transporters, and digestive problems, as well as skin development, humoral response, extracellular matrix, and mitochondrial component. The TWAS-based estimation analyses hint that low-PRS patients are indeed enriched for common variants associated with higher pathogenic levels at the 13 selected genes. Conclusion Although polygenic risk scores may play a valuable role in patient management, our study hints at the presence of patients with common polygenic forms that are not captured by current genetic risk estimators. 1. Chrissy B. et al, 2022. Gastroenterology.

High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice

BackgroundAPOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and obesity is a strong environmental risk factor for AD. These factors result in multiple central nervous system (CNS) disturbances and significantly increase chances of AD. Since over 20% of the US population carry the APOE4 allele and over 40% are obese, it is important to understand how these risk factors interact to affect neurons and glia in the CNS.MethodsWe fed male and female APOE3 and APOE4 knock-in mice a high-fat diet (HFD-45% kcal fat) or a "control" diet (CD-10% kcal fat) for 12 weeks beginning at 6 months of age. At the end of the 12 weeks, brains were collected and analyzed for gliosis, neuroinflammatory genes, and neuronal integrity.ResultsAPOE3 mice on HFD, but not APOE4 mice, experienced increases in gliosis as measured by GFAP and Iba1 immunostaining. APOE4 mice on HFD showed a stronger increase in the expression of Adora2a than APOE3 mice. Finally, APOE3 mice on HFD, but not APOE4 mice, also showed increased neuronal expression of immediate early genes cFos and Arc.ConclusionsThese findings demonstrate that APOE genotype and obesity interact in their effects on important processes particularly related to inflammation and neuronal plasticity in the CNS. During the early stages of obesity, the APOE3 genotype modulates a response to HFD while the APOE4 genotype does not. This supports a model where early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults and later result in the increased CNS damage normally associated with the APOE4 genotype.

Familial associations between autoimmune hepatitis and primary biliary cholangitis and other autoimmune diseases.

Autoimmune hepatitis (AH) and primary biliary cirrhosis (PBC) are autoimmune diseases (AIDs) targeting cellular components of the liver. Being rare diseases, limited data are available about familial risks among these AIDs (concordant) or between them and other AIDs (discordant). We aimed to carry out an unbiased study on these AIDs based on medically diagnosed patients.We collected data on patients diagnosed in Swedish hospitals with AH, PBC and other AIDs and calculated familial standardized incidence ratios (SIRs) for concordant and discordant familial relative risks. The number of AH patients was 6,269, of whom 43.0% were male; patient numbers for PBC were 4,269, with 17.8% males. AH accounted for 0.8% and 0.6% of all hospitalized AIDs in Sweden. For AH only the familial risk between siblings was significant (3.83). For PBC the risks for offspring of parents (9.05) and siblings (10.88) were high, but only risk for females was significant. Spousal risks were very high, 5.91 and 6.07 for AH. Risk for AH was 2.21 in families of PBC, and it was 2.47 for PBC in families of AH patients. Among other AIDs, 14 showed a significant association with AH, compared to 16 AIDs with PBC. The surprising finding in this nation-wide family study on medically diagnosed patients was the high risk for AH (6.0) between spouses, which exceed the risk between siblings, suggesting the existence of strong environmental risk factors. AH and PBC were associated with multiple other AIDs. The results call attention to environmental factors in AID etiology which should also be in focus in taking anamnestic data from patients.

A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers

BackgroundThe oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking.ResultsEx vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1; best p = 5.5 × 10−8) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p = 5.9 × 10−9). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p = 4.0 × 10−10. RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p = 2.2 × 10−14), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1.ConclusionThis study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.

Dissecting Brain Networks Underlying Alcohol Binge Drinking Using a Systems Genomics Approach

Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.

Neurological soft signs in Tunisian patients with first-episode psychosis and relation with cannabis use

BackgroundNeurological soft signs (NSS) are minor non-localizing neurological abnormalities that are conceptualized as neurodevelopmental markers that mediate the biological risk for psychosis. We aimed to explore the relationship between NSS and cannabis use, an environmental risk factor of psychosis.MethodsThis was a cross-sectional study in consecutively admitted patients hospitalized for first-episode psychosis. NSS were assessed by the NSS scale (23 items exploring motor coordination, motor integrative function, sensory integration, involuntary movements or posture, quality of lateralization). Presence of NSS was defined as a NSS scale total score ≥9.5. Cannabis use was ascertained with the cannabis subsection in the Composite International Diagnostic Interview.ResultsAmong 61 first-episode psychosis patients (mean age = 28.9 ± 9.4 years; male = 86.9%, antipsychotic-naïve = 75.4%), the prevalence of current cannabis use was 14.8% (heavy use = 8.2%, occasional use = 6.6%). NSS were present in 83.6% of the sample (cannabis users = 66.7% versus cannabis non-users = 85.5%, p = 0.16). The mean total NSS score was 15.3 ± 6.7, with a significant lower total NSS score in cannabis users (11.2 ± 5.6 versus 16.0 ± 6.7, p = 0.048). Differences were strongest for the “motor coordination” (p = 0.06) and “involuntary movements” (p = 0.07) sub-scores.ConclusionsThis study demonstrated a negative association between cannabis use and NSS, especially regarding motor discoordination. This finding supports the hypothesis that a strong environmental risk factor, such as cannabis, may contribute to the onset of psychosis even in the presence of lower biological and genetic vulnerability, as reflected indirectly by lower NSS scores. Nevertheless, additional studies are needed that explore this interaction further in larger samples and considering additional neurobiological and environmental risk factors.

Delay discounting and self-reported impulsivity in adolescent smokers and nonsmokers living in rural Appalachia.

Background and Objectives This study evaluated whether impulsivity (delay discounting and BIS-11-A) is associated with adolescent smoking status in a region with strong environmental risk factors for smoking. Methods Forty-two adolescent smokers and nonsmokers from rural Appalachia completed discounting and self-reported impulsivity assessments. Results The BIS-11-A, but not the measure of discounting, was associated with smoking status; however, neither assessment predicted smoking status once parent/best-friend smoking variables were statistically accounted for. Discussion and Conclusions In regions with strong environmental risk factors for smoking, delay discounting may play a more limited role in risk of initiation. Scientific Significance Helps to better define impulsivity as risk factors for smoking in relation to familial and broader cultural variables.

No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents

BackgroundIdentification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes.MethodsThis study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother’s history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients’ depression symptoms.ResultsBinary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression.ConclusionsTo assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

Allergies and Risk of Head and Neck Cancer: An Original Study plus Meta-Analysis

BackgroundAlthough the relationship between allergy and cancer has been investigated extensively, the role of allergy in head and neck cancer (HNC) appears less consistent. It is not clear whether allergies can independently influence the risk of HNC in the presence of known strong environmental risk factors, including consumption of alcohol, betel quid, and cigarette.MethodsThe current paper reports results from: 1) an original hospital-based case-control study, which included 252 incident cases of HNC and 236 controls frequency-matched to cases on sex and age; and 2) a meta-analysis combining the results of the current case-control study and 13 previously published studies (9 cohort studies with 727,569 subjects and 550 HNC outcomes and 5 case-control studies with 4,017 HNC cases and 10,928 controls).ResultsIn the original case-control study, we observed a strong inverse association between allergies and HNC [odds ratio = 0.41, 95% confidence interval (CI): 0.27–0.62]. The meta-analysis also indicated a statistically significant inverse association between HNC and allergies [meta-relative risk (RR) = 0.76, 95% CI: 0.63–0.91], particularly strong for allergic rhinitis (meta-RR = 0.55, 95% CI: 0.40–0.76). In addition, the inverse association between allergies and HNC was observed only among men (meta-RR = 0.67, 95% CI: 0.54–0.84) but not among women (meta-RR = 0.98, 95% CI: 0.81–1.18).ConclusionsThese findings suggest that immunity plays an influential role in the risk of HNC. Future studies investigating immune biomarkers, including cytokine profiles and genetic polymorphisms, are warranted to further delineate the relationship between allergies and HNC. Understanding the relationship between allergies and HNC may help devise effective strategies to reduce and treat HNC.

Children's Oncology Group's 2013 blueprint for research: Epidemiology

Investigators worldwide have for over 40 years conducted case-control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection. Pediatr Blood Cancer 2013; 60: 1059-1062. © 2012 Wiley Periodicals, Inc.

High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia

Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk of developing ALL. This international collaboration identified 54 sibships with two (N = 51) or more (N = 3) cases of childhood ALL (ages <18 years). The 5-year event-free survival for 61 patients diagnosed after 1 January 1990 was 0.83 ± 0.05. Ages at diagnosis (Spearman correlation coefficient, r(S) = 0.41, P = 0.002) were significantly correlated, but not WBCs (r(S) = 0.23, P = 0.11). In 18 sibships with successful karyotyping in both cases, six were concordant for high-hyperdiploidy (N = 3), t(12;21) [ETV6/RUNX1] (N = 1), MLL rearrangement (N = 1) or t(1;19)(q23/p13) (N = 1). Eleven sibships were ALL-subtype concordant, being T-cell ALL (T-ALL) (N = 5, of a total of six sibships, where the first-born had T-ALL) or B-lineage ALL belonging to the same cytogenetic subset (N = 6), a finding that differs significantly from the expected chance distribution (κ: 0.58; P < 0.0001). These data indicate strong genetic and/or environmental risk factors for childhood ALL that are restricted to specific ALL subtypes, which must be taken into account, when performing epidemiological studies to reveal etiological factors.

Clustering of concordant and discordant cancer types in Swedish couples is rare

Background Spouses are exposed to common environmental cancer risk factors during adulthood. Investigating the aggregation of cancer in couples might provide valuable insights into cancer development. Methods The 2008 update of the Swedish Family-Cancer Database includes over 2 million couples with at least one child in common with one single partner. We quantified the contribution of shared adulthood environment by standardised incidence ratios (SIRs) and population attributable fractions (PAFs). Estimated SIRs were used to build an etiological map reflecting the similarity of cancers by adult environmental exposures. Results Increased risks of concordant types amongst spouses were found for lung, upper aerodigestive tract and skin cancers (SIRs from 1.24 to 1.97),which are probably related to shared exposure to smoking and UV radiation. PAFs were low with the highest value of 1.46% for uterus cancer in wives of men affected by prostate cancer. Further analysis, based on all non-sex-specific concordant and discordant types, revealed a clustering of lung, stomach, pancreas and bladder cancers sharing smoking as a risk factor. This aggregation was used as a cut-point to identify further “novel” clusters. Conclusion Shared lifestyles including smoking and drinking habits as well as human papilloma virus infection (HPV) might be associated with an excess of cancer incidence amongst spouses. We observed significantly an increased risk for smoking-related cancers such as lung, upper aerodigestive tract and oesophageal cancers. The present population-based study confirms that the lifestyle shared by spouses plays a minor role in cancer causation. Only strong environmental risk factors such as smoking seem to influence cancer development in adulthood. The proposed etiological map based on 24 cancer types identifies novel clusters – for example, non-Hodgkin lymphoma and leukaemia, bone cancer and myeloma – that are not completely explained by established risk factors. Some of the identified clusters relied on reproduced associations between cancer risks amongst husband and wives; however, the role of chance cannot be excluded.

Tobacco, Genetic Susceptibility and Lung cancer

Exposure to tobacco smoke is an established risk factor for lung cancer, although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analysis. Findings of familial aggregation and statistical evidence for a major susceptibility gene have led to the search for high penetrant, rare, single genes and low penetrant, high frequency susceptibility genes for lung cancer. The relatively small number of linkage studies conducted to date, have identified potential lung cancer susceptibility loci on chromosomes 6q, 12p, and 19q. A variety of studies have examined single nucleotide polymorphisms of several low penetrant, high frequency genes encoding for enzymes involved in the metabolism of carcinogens and DNA damage repair, as likely candidate susceptibility genes. These studies have produced somewhat conflicting findings and, when significant, only modest associations have been reported. Relatively few studies have looked for potential gene-environment interactions, explored associations between two or more genetic polymorphisms or evaluated interactions between genetic polymorphisms and endogenous risk factors. Few large scale genome wide association studies conducted recently have provided evidence that common variation on chromosome 15q25.1, 5p15.33 and 6p21.33 influences lung cancer risk and cancer types with strong environmental risk factors. It is hoped that newer research strategies, selecting candidate genes within pathways and genotype at multiple markers within a gene, employing new technologies, may allow complete coverage of the variation within candidate genes in multiple pathways and to unravel the genetic susceptibility to lung cancer. This knowledge could, in turn, be used to identify persons at risk, to individualize treatments such as chemoprevention, to personalize harms of smoking and to motivate cessation.

The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung

Genome-wide association studies have provided evidence that common variation at 5p15.33 [telomerase reverse transcriptase (TERT)-cleft lip and palate transmembrane 1-like (CLPTM1L)], 6p21.33 and 15q25.1 (CHRNA5-CHRNA3) influences lung cancer risk and cancer types with strong environmental risk factors. To independently validate these associations, we compared 5p15.33 (rs402710, rs401681), 6p21.33 (rs4324798) and 15q25.1 (rs1051730, rs16969968 and rs8034191) genotypes in 365 non-small cell lung cancer cases and 440 controls. Consistent with published data, variant genotypes of 5p15 (rs402710), 6p21 and 15q25 showed dose-dependent associations with lung cancer risk. To examine if variants influence the impact of environmental risk factors on lung carcinogenesis, we studied the relationship between genotype and levels of bulky aromatic/hydrophobic DNA adducts in lung tissue adjacent to tumor from 204 lung cancer cases. The risk allele of rs402710 (TERT-CLPTM1L locus) was associated with significantly higher levels of bulky aromatic/hydrophobic DNA adducts (P = 0.02). These data demonstrate a potential association between the TERT-CLPTM1L variant and levels of bulky DNA adducts measured by (32)P-postlabeling and hence a basis for susceptibility to the development of lung cancer.

Abstract A121: The association of menstrual and reproductive factors with the risk of upper gastrointestinal tract cancers in the NIH-AARP cohort

Abstract A121 Upper gastrointestinal tract cancers (UGI), including cancers of the esophagus, head and neck, and stomach have high worldwide incidence and mortality. Incidence rates are consistently higher among men than women; the male/female ratios are 2:1 for cancers of the stomach and 7:1 for cancers of the larynx. Strong environmental risk factors have been identified for these cancer sites, but do not appear to explain differences in incidence rates between men and women. Differences in sex hormones in men vs. women and among women of different ages might affect UGI risk. In nearly 10 studies of menstrual and reproductive factors with stomach cancer risk in women, significant inverse associations with older age at menopause or use of menopausal hormone therapy (MHT) were observed in some, but not all studies. Only a few studies have investigated the association of these factors with squamous cancers of the esophagus and head and neck. We prospectively investigated the association of menstrual and reproductive factors with UGI cancer risk in 201,506 women of the NIH-AARP Diet and Health cohort study. We used Cox proportional hazard models adjusted for age, alcohol intake, cigarette smoking, body mass index, physical activity, education, and total energy intake and report hazard ratios (HRs) and 95% confidence intervals. During 1,463,551 person years of follow-up from 1995/1996-2003, 162 women were diagnosed with adenocarcinomas (ACs; esophagus and stomach) and 353 women were diagnosed with squamous cell carcinomas (SCCs; oral cavity, pharynx, larynx, and esophagus). We found no significant associations between age at menopause, age at menarche, parity, or age at first birth and AC risk. Ever- versus never-use of MHT showed a borderline non-significant inverse association with adenocarcinoma (HR=0.74, 95% CI 0.54-1.02) in age adjusted models. After multivariate adjustment, the association was attenuated (HR=0.81, 95% CI, 0.59-1.12). For SCCs, we found a significant inverse association with older age at menopause but not with age at menarche, parity, or age at first birth. The HR for age at menopause of &amp;gt;55 years (vs. &amp;lt;45 years) was 0.53 (95% CI 0.28-1.01; p-value for trend=0.019). We also observed an inverse association with ever- versus never-use of MHT (HR=0.77, 95% CI 0.62-0.96). We further examined relations with the type of MHT stratified by hysterectomy status, using data from a subsequent questionnaire (1996-1997) completed by 127,385 women. In 51,515 women with a reported hysterectomy at baseline, the HRs and 95% CIs for &amp;lt;5 years of estrogen-plus-progestin MHT, relative to never MHT users, were 0.74 (0.43-1.27) for ACs (N=38) and 0.51 (0.18-1.46) for SCCs (N=80), respectively; for ≥5 years of use, the HRs and 95% CIs were 0.47 (0.19-1.16) and 0.28 (0.13-0.58), respectively. In 74,372 women with intact uteri, we found no associations between estrogen MHT and ACs (N=49) or SCCs (N=130). Our results suggest that estrogen-plus-progestin therapy is associated with reduced risk of UGI tract cancers, supporting the involvement of sex hormones in the etiology of these cancers. Future studies are needed to replicate these results. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A121.

Family‐based association study between NOS‐I and ‐IIA polymorphisms and autism spectrum disorders in Korean trios

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component and environmental risk factors. Nitric oxide (NO), which is produced by nitric oxide synthase (NOS), may play a role in the development of ASD. We genotyped nine single nucleotide polymorphisms (SNPs) in the NOS-I gene and nine SNPs in the NOS-IIA gene and carried out the transmission disequilibrium test (TDT) and haplotype analysis in 151 Korean ASD trios. We found preferential transmission of the A allele of rs8068149 (P = 0.039) and G allele of rs1060826 (P = 0.035) of NOS-IIA in ASD and the haplotype analysis revealed that the two haplotypes had significant associations (P = 0.014 and 0.031, respectively). The behavioral subdomain score of failure to use nonverbal behaviors to regulate social interaction in Autism Diagnostic Interview-Revised (ADI-R) was significantly higher in subjects with the GG or AG allele in rs1060826 of NOS-IIA compared to those who had the AA allele (P = 0.027). These results provide significant but weak evidence for an association between NOS-IIA and ASD in the Korean population.

Assessing the Influence of a Genetic Characteristic on Disease in the Presence of a Strong Environmental Etiology

An inference as to the possible causal role of a genetic characteristic in the development of a disease is strengthened when there is a large disparity in disease incidence between persons with and without that characteristic. If the disparity is particularly great when, based on the presence or absence of a strong environmental risk factor, we would predict it to be so, then a causal inference is further strengthened. Only analyses that focus on the gene-disease association, conditional on the environmental factor, directly bear on the etiologic role of the genetic characteristic.