COVID-19 in Cancer Patients From New York City: A Comparative Single Center Retrospective Analysis.

In this retrospective study we analyze and compare clinical characteristics and outcomes of patients with and without cancer history who were infected with novel coronavirus disease 19 (COVID-19). Medical records were reviewed and a comparative analysis of 53 cancer and 135 non-cancer patients with COVID-19 were summarized. Results: The median age for COVID-19 patients with and without cancer was 71.5 and 61.6 years, respectively. Patients aged 60 years and above were 86.8% and 60.7% in cancer and non-cancer groups, respectively. A high proportion of cases were seen in African Americans 73.6% (with cancer) and 75.6% (without cancer) followed by Hispanic patients. Male and female patients had a high percentage of prostate (39.3%) and breast (32%) cancer respectively. Prostate cancer (18.9%) and myeloma (11.3%) were common among solid and hematological cancers respectively. Hypertension and smoking were prevalent among cancer (83% and 41.5%) compared to non-cancer (67.4% and 9.6%) patients. The common symptoms in cancer patients were dyspnea (64.2%) followed by fever and cough (50.9%) compared to fever (68.1%) and cough (66.7%) in non-cancer patients. Cancer patients had higher levels of lactic acidosis, C-reactive protein, lactate dehydrogenase, and alkaline phosphatase than non-cancer patients (p < 0.05). Conclusions: Rapid clinical deterioration was seen in cancer patients who were aged 60 years and above. Higher mortality was seen in this subgroup, especially when they had associated hypertension and elevated levels of CRP and LDH.

Quantification of IGF-1 receptor is useful in the differential diagnosis of essential thrombocytosis from reactive thrombocytosis.

BACKGROUND: To make a definite diagnosis of essential thrombocytosis (ET) from reactive thrombocytosis (RT), the most reliable criteria are the presence of driver mutations, namely JAK2, CALR, or MPL gene mutations. In the absence of these driver mutations, so-called triple-negative ET, the differential diagnosis could be difficult. Although bone marrow biopsy could be helpful, it may be difficult in some cases, to do gene sequence analysis to identify other clonal marker gene mutations than the driver mutations, as only very few were found. METHODS: IGF-1R quantification by flow cytometry in mononuclear cells (MNC) from peripheral blood was performed in 33 patients with ET (untreated or off treatment with hydroxyurea), 28 patients with RT, and 16 normal volunteer controls. RESULTS: We found IGF-1R levels were significantly elevated in ET patients compared to RT patients or controls. A cutoff value of 253 was chosen from the logistic regression to predict each patient's group, a value ≥253 meant that a patient belonged to the ET group (sensitivity 96.4% and specificity 68.6%). CONCLUSION: We suggest that adding quantification of IGF-1R in blood MNC by flow cytometry is useful in differentiating ET from RT.

Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

A genome-wide association study of alcohol dependence.

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

Recurrence of T-Cell Prolymphocytic Leukemia With a Rare Presentation as Diffuse Generalized Skin Lesion.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm that originates from mature post-thymic T-cells. Cutaneous manifestations are a common presentation in T-PLL but rarely are a presentation in the recurrent setting. Here, we describe the case of a 75-year-old female with a history of T-PLL-who at the time of initial diagnosis did not exhibit any rash-presenting with diffuse rash, facial swelling, sore throat, and dysphagia 7 months later and was found to have recurrent T-PLL. She had diffuse lymphadenopathy and diffuse skin lesions. Biopsy of the skin lesions also confirmed infiltration with T-PLL cells. After review of the literature, no previously reported cases of recurrent T-PLL presented as diffuse skin lesions. This case demonstrates that recurrent T-PLL may present with diffuse rash, respiratory distress, and anasarca. It is important to stay vigilant in patients with history of T-PLL to recognize signs of recurrent disease to allow prompt diagnosis and treatment.

Association between Prostate Carcinoma and Multiple Myeloma.

Synchronous or sequential development of multiple myeloma and prostate carcinoma is rare. It is not sure whether these two occur independently or if one influences the development of the other. We reviewed the cases published in the English literature; eight cases of myeloma developing after diagnosis and treatment for prostate carcinoma, five cases of simultaneous occurrence of myeloma and prostate carcinoma, and five cases where the patient with multiple myeloma later developed prostate carcinoma were found. This short review attempts to analyze the occurrence of these two diseases in the same patient and dissect whether there is a close association or it is just a mere coincidence.

Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature.

SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are infrequently occurring aggressive neoplasms found predominantly in young male smokers. These tumors are distinguished by the loss of expression of Brahma-related gene 1 (BRG1) due to a deactivating mutation of SMARCA4. Immunophenotype can be variable but characteristically lack the expression of BRG1. SMARCA4-dUT has a poor prognosis and generally progresses or recurs. The median survival is around 6 months. Here, we report a case of a 36-year-old male smoker who presents with multiple right-sided lung masses. The patient was found to have a loss of SMARAC4 and SMARCA2 along with the absence of markers of vascular, melanocytic, lymphoid, keratin, or myogenic origin. Tumor size was reduced significantly after 3 cycles of carboplatin and 1 cycle of pembrolizumab. From reviewing the literature and the clinical course in our case, we suggest combination chemotherapy plus immune checkpoint inhibitor (ICI) therapy to be the first choice of therapy for treating SMARCA4-dUT of lungs. Further research and studies are needed to evaluate the response to ICI therapy alone or combination therapy (chemotherapy plus ICI).

Dissection of the phenotypic and genotypic associations with nicotinic dependence.

INTRODUCTION: Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968, rs6474412, rs3733829, and rs1329650 in large-scale Genome-Wide Association Studies. We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures. METHODS: Four genetic variants were analyzed in 2,047 subjects of European descent (1,062 cases and 985 controls). Nicotine dependence was assessed with multiple smoking measures, including the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual for Mental Disorders-IV (DSM-IV) nicotine dependence, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives. Single-item measures of cigarettes per day (CPD) and time to first cigarette (TTF) in the morning were also examined. RESULTS: Among the variants, association effect sizes were largest for rs16969968, with measures of craving and heavy smoking, especially cigarettes smoked per day, showing the largest effects. Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650. None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did CPD. CONCLUSIONS: CPD is an important simple measure that captures in part the genetic associations of CHRNA5 and nicotine dependence, even when other more comprehensive measures of smoking behaviors are examined. The CHRNA5 gene is associated with heavy compulsive smoking and craving; this should inform the mission to improve the diagnostic validity of DSM-V.

Axillary Lymphadenopathy as an Initial Presentation of Systemic Amyloidosis: A Case Report and Literature Review.

Amyloidosis rarely presents as localized lymphadenopathy. Various studies have elucidated the varied presentation and manifestations of this interesting disease. We reviewed the literature and found 36 cases of primary amyloidosis with lymph node enlargement as a presentation, and 17 of the 36 cases (47%) had systemic involvement on further work up. We describe a patient who presented with an isolated right axillary mass. Clinical examination and radiology were indicative of a lymph node enlargement with no evidence of malignancy in the breasts or lungs. Histopathological examination was indicative of amyloidosis. A further work up including serum, urine biochemistry, cardiac work up, bone marrow examination, and a kidney biopsy revealed systemic amyloidosis. Patient was treated with daratumumab and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) followed by a stem cell transplantation. Patient is in remission for 1 year, at the time of submission of this report. Therefore, we conclude (1) systemic amyloidosis presenting as an isolated lymph node enlargement is rare, (2) a structured systemic work up is imperative for early diagnosis and proper management of amyloidosis, when there is an index of suspicion, and (3) use of novel therapeutic options such as CD38 + antibody (daratumumab) and stem cell transplant have positive impact on disease outcomes.

Review of Checkpoint Inhibitor Immunotherapy in Neuroendocrine Tumor of Prostate and Our Experience in 2 Cases.

Neuroendocrine prostate cancer (NEPC) is a rare entity. De novo NEPC is extremely rare; other cases are usually adenocarcinoma previously treated with hormonal therapies transforming to NEPC. Most of the cases are metastatic at diagnosis and regardless of the histology types, the prognosis is poor. In this report, we reviewed the checkpoint inhibitor (CPI) immunotherapies used for neuroendocrine tumors of the prostate. Very limited data with only a few cases were published which showed a limited activity by immunotherapy; therefore, we present our experience of 2 cases: (1) adenocarcinoma with foci of NEPC and (2) adenocarcinoma transforming to NEPC after treatment with androgen deprivation therapy (ADT); both of which were initially managed with ADT, chemotherapy followed by immunotherapy with durvalumab, a programmed death ligand 1 inhibitor. In these 2 cases, CPI therapy showed limited efficacy, suggesting that neuroendocrine histology is not very responsive to CPI treatment, regardless if onset is early or late. Other therapies need to be explored for the treatment of NEPC.

SMARCA4-Deficient Undifferentiated Tumor of Lung Mass-A Rare Tumor With the Rarer Occurrence of Brain Metastasis: A Case Report and Review of the Literature.

Among thoracic tumors, these include subsets of a relatively newly described and yet to be fully characterized tumor entity: SMARCA4-deficient Undifferentiated Tumor (SMARCA4-dUT). Mutations of SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and loss of BRG1 (Brahma-related gene-1) is the underlying molecular hallmark of SMARCA4-dUT. They mostly involved the mediastinum, lung, and/or pleura showing undifferentiated round cell or rhabdoid morphology associated with aggressive clinical behavior. The pathogenesis of these tumors is still not clear. Morphologically, SMARAC4-dUT is differentiated from SMARCA4-dNSCLC by the presence of squamous and solid components in the latter. Immunohistochemically SMARC4-dUT has characteristic loss of SMARCA4 and SMARCA2 and strong expression of SOX2, CD34, and SALL4. Common sites of metastasis include lymph nodes, bones, and adrenal glands but rarely brain metastasis. We present a unique and rare case of a 76-year-old male with a right lung mass with documented pathology of SMARCA4-dUT and was found to have multiple brain metastases.

Hemorrhagic Brain Metastasis as an Initial Presentation of Hepatocellular Carcinoma in a Patient With Alcohol-Related Liver Cirrhosis: A Case Report and Review of Literature.

Hepatocellular carcinoma (HCC) is the most common primary hepatic cancer. Although it usually presents as a liver mass, rarely HCC can have an initial presentation at an extrahepatic site before the diagnosis of the primary lesion in the liver. Even rarely was that brain metastasis as initial extrahepatic presentations. Furthermore, the initial presentation of HCC as brain metastases has been with most cases being secondary to hepatitis-related hepatoma. In this case report, we are presenting a rare and unusual case of hemorrhagic cerebral metastasis as an initial extrahepatic presentation of an alcohol-related hepatoma. Our case is the second case in the English literature that has been presented in such a way. Due to the uncommonness of presentation, there can be diagnostic dilemmas and delay in treatment. Therefore, a high level of suspicion is needed in the high-risk patients of HCC who present with unexplained or new neurological signs and symptoms. More exploration is warranted for clinical research and treatment guidelines for brain metastases of HCC to help improve survival and quality of life.

Plasmablastic Lymphoma Presenting as Extensive Peritoneal and Retroperitoneal Nodules in an HIV-Positive Patient.

Plasmablastic lymphoma (PBL) is a rare but aggressive subtype of diffuse large B-cell lymphoma (DLBCL). The diagnosis of PBL is challenging as its features overlap with lymphoma and myeloma. The most common presentation involves the oral cavity/jaw in human immunodeficiency virus (HIV)-positive patients. It has also been reported in the gastrointestinal (GI) tract, lymph nodes, and soft tissues. Usually, if PBL involves the GI tract, it presents as a gut tumor mass. In this report, we present an HIV-positive patient with PBL presenting with multiple peritoneal nodules. To our knowledge, this is the first case of PBL presenting as multiple peritoneal and retroperitoneal nodules in an HIV-positive patient. This case emphasizes the rare presentation of a rare malignancy, difficulties in establishing a diagnosis, and the importance of proper and timely management.

Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5.

Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.

The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.

OBJECTIVE: To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism. METHODS: The conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European-Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, (i) single time point measures of D2-cotinine/(D2-cotinine+D2-nicotine) after oral administration were used as a metric of CYP2A6 activity; (ii) the impact of CYP2A6 haplotype was treated as acting multiplicatively; (iii) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and (iv) a minimum number of predictive polymorphisms were justified to be included in the model based on statistical evidence of differences between haplotypes. RESULTS: The final model includes seven polymorphisms and fits the phenotype, 30-min after D2-nicotine oral administration, with R=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R=0.758 and vice versa with R=0.617; estimates calculated in current smokers (n=102) predict the phenotype in former-smokers (n=86) with R=0.690 and vice versa with R=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5'-untranslated region conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype, modest associations were found between increased metabolism and both female sex (P=4.8×10) and current smoking (P=0.02). CONCLUSION: Among European-Americans, seven polymorphisms in the CYP2A6 gene explain the majority of variability in the metabolism of nicotine to cotinine after oral administration. Parameters determined from this in-vivo experiment can be used to predict nicotine metabolism based on CYP2A6 genotype.

Common polymorphisms in FMO1 are associated with nicotine dependence.

BACKGROUND: Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking. METHODS: To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases. RESULTS: Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue. CONCLUSION: These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.

Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence.

Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case-control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects.

H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence.

Animal research supports a central role for corticotropin-releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype x environment (G x E) interaction involving rs1876831, a corticotropin-releasing hormone receptor 1 (CRHR1) polymorphism, and negative events. CRHR1 and at least four other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here, we examine whether G x E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (n = 1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from four indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G x E interaction was found for ACFS involving the H2 haplotype and CSA (P < 0.017). A similar G x E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95% confidence interval 0.20-0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence.

Association of CHRN genes with "dizziness" to tobacco.

The neuronal nicotinic receptor genes (CHRN) have been implicated in a variety of smoking-related behaviors. Here we tested for association between an early subjective response phenotype, "dizziness," and 226 single nucleotide polymorphisms (SNPs) in CHRN genes. The sample included 789 nicotine-dependent cases and 811 controls, where early "dizziness" reports were significantly associated with case/control status (P < 0.0001). Multiple SNPs in the putative promoter region of the CHRNB3 gene were nominally associated with "dizziness" experience from the first few cigarettes (P < 0.01). Cell culture studies were conducted to examine the ability of different haplotypes in the CHRNB3 promoter to drive luciferase expression. Data from these experiments support the hypothesis that different alleles in the CHRNB3 upstream promoter region may lead to different levels of RNA expression. In addition, a novel finding of association between SNPs in the CHRNA10 gene reached experiment-wide empirical significance (P = 0.048), which implicates another CHRN gene as being involved in early subjective response to tobacco.