Hazard ratios for risk of death by specific causes corresponding to demographic, health-related, and lifestyle variables in the Southern Community Cohort Study.

<p><b>Abbreviations:</b> CI, Confidence Interval; CHC, Community Health Center; GP, General Population; HR, Hazard Ratio; ICD, International Classification of Diseases.</p>a<p>Hazard Ratios adjusted for age (as time-scale), race, sex, enrollment source, alcohol use, depression, smoking, income, education, marital status, employment status, BMI, height, comorbidity index, faith comfort.</p>b<p>Response to question, “Has a doctor ever told you that you have depression or have you been treated for depression?”</p>c<p>Hazard ratio is undefined – no deaths from homicide in the general population enrollees.</p>d<p>Response to question, “How much is religion, faith, or God a source of strength and comfort to you?”</p><p>Hazard ratios for risk of death by specific causes corresponding to demographic, health-related, and lifestyle variables in the Southern Community Cohort Study.</p

Distribution of demographic, lifestyle, and health-related variables for Southern Community Cohort Study participants by race and sex.

<p><b>Abbreviations</b>: CHC, Community Health Center; GP, General Population; ICD, International Classification of Diseases; SD, Standard deviation.</p>a<p>Response to question, “Has a doctor ever told you that you have depression or have you been treated for depression?”</p>b<p>Response to question, “How much is religion, faith, or God a source of strength and comfort to you?”</p><p>Distribution of demographic, lifestyle, and health-related variables for Southern Community Cohort Study participants by race and sex.</p

Rate ratios for external causes of death among the population age 40 and over in the 12 SCCS states, and in the SCCS population, by race and sex.

<p><b>Abbreviations</b>: CI, Confidence Interval; ICD, International Classification of Diseases; SMR, Standardized Mortality Ratio; SCCS, Southern Community Cohort Study</p><p>Panel A: Ratio of the directly standardized rate in the 12 SCCS states (Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, and West Virginia) to the directly standardized rate in the remaining 38 states.</p><p>Panel B: Standardized mortality ratio of SCCS population relative to mortality rates in the 12 SCCS states.</p><p>Rate ratios for external causes of death among the population age 40 and over in the 12 SCCS states, and in the SCCS population, by race and sex.</p

Metabolism of COX-derived eicosanoids.

<p>Arachidonic acid is first metabolized by COX-1 or COX-2 to synthesize PGH₂. Five different types of prostaglandin synthases act on this intermediate to generate the various eicosanoids shown above. In addition, subsequent dehydration/isomerization of PGD₂ can create 15d-PGJ₂. With the exception of three eicosanoids, 15d-PGJ₂, PGD₂, and PGI₂, all of the COX-derived eicosanoids are thought to be pro-tumorigenic. COX-derived eicosanoids in green are pro-tumorigenic, while those in blue are anti-tumorigenic. Abbreviations are as followed: 15-deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂), arachidonic acid (AA), prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), prostaglandin H₂ (PGH₂), prostaglandin I₂ (PGI₂), and thromboxane A₂ (TXA₂).</p

Rare Exonic <i>ALOX15B</i> SNPs associate with a worse prognosis in female NSCLC patients.

<p>Sex-stratified survival curves calculated from the corresponding sex-specific univariate Cox proportional hazard model are shown above with the hazard ratio and p-values reported from the Cox proportional hazard model. The blue survival line is individuals without any rare <i>ALOX15B</i> variants and the red survival line is individuals with rare <i>ALOX15B</i> variants. (A) The survival curve and association of <i>ALOX15B</i> SNPs in men (N = 217), and (B) the survival curve and association in women (N = 175).</p

Genetic variation in the eicosanoid pathway is associated with non-small-cell lung cancer (NSCLC) survival

<div><p>Globally, lung cancer results in more deaths worldwide than any other cancer, indicating a need for better treatments. Members of the eicosanoid metabolism pathway represent promising therapeutic targets, as several enzymes involved in the generation of these lipids are dysregulated in many cancers and their inhibition reduces lung cancer growth in mouse models. However, genetic variation of enzymes involved in eicosanoid metabolism has not been adequately examined for association with lung cancer. The goal of this study was to determine whether germline genetic variation altering eicosanoid producing enzyme function and/or expression are associated with differences in lung cancer survival. We examined the association of genetic variation with mortality within eicosanoid metabolism genes in 395 non-small-cell lung cancer (NSCLC) cases from the Southern Community Cohort Study (SCCS). A total of 108 SNPs, both common and rare, in 19 genes, were examined for association. No common or rare variants were associated with lung cancer survival across the entire study population. However, rare variants in <i>ALOX15B</i> (arachidonate 15-lipoxygenase, type B) and the common variant rs12529 in <i>AKR1C3</i> (prostaglandin F synthase) were associated with NSCLC mortality in women and African Americans, respectively. Rare variants in <i>ALOX15B</i> were associated with greater mortality in women (HR = 2.10, 95% CI = 1.25–3.54, p-value = 0.005). The major allele of rs12529 in <i>AKCR1C3</i> associated with improved survival in African Americans (HR = 0.74, 95% CI = 0.59–0.92, p-value = 0.008). The lack of genetic associations among all NSCLC cases and the association among women only for rare variants in <i>ALOX15B</i> may, in part, explain the better NSCLC survival observed among women. These results raise the possibility that some subgroups within the NSCLC population may benefit from drugs targeting eicosanoid metabolism.</p></div

Description of combination of treatment variables.

<p>Description of combination of treatment variables.</p

Common SNPs interaction with sex in African Americans unadjusted for covariates, N = 265.

<p>Common SNPs interaction with sex in African Americans unadjusted for covariates, N = 265.</p

Metabolism of LOX-derived eicosanoids.

<p>The initial reaction in the LOX pathway can be carried out by 5-LOX, 12-LOX, or 15-LOX, with each LOX synthesizing its own corresponding HpETE. Subsequent reduction of these HpETEs generates HETEs. However, 5-HpETE and 15-HpETE can undergo other reactions as well. More specially, 5-LOX further metabolizes 5-HpETE to LTA₄ that serves a precursor for LXs, LTB₄, or cysteinyl leukotrienes. 5-LOX can also act on 15-HpETE to synthesize LXs. LOX-derived eicosanoids are color coded to indicate their effect on tumors. Blue metabolites are anti-tumorigeneic, green metabolites are pro-tumorigenic, and gray metabolites are unknown. Abbreviations are as followed: arachidonic acid (AA), hydroperoxyeicosatetraenoic acid (HpETE), hydroxyeicosatetraenoic acid (HETE), leukotriene A4 (LTA₄), leukotriene B4 (LTB₄), and lipoxins (LXs).</p

Eicosanoid metabolism.

<p>(A) Eicosanoid metabolite generation begins with the metabolism of arachidonic acid by cyclooxygenase (COX), lipooxygenase (LOX), or the cytochrome P450 monooxygenases, which includes both the cytochrome P450 epoxygenases and cytochrome p450 ω-hydroxylases. Each of these enzymes produces its own major metabolites displayed here according to the first enzyme acting on arachidonic acid. Abbreviations are as followed: prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), prostaglandin I₂ (PGI₂), thromboxane (TXA₂), hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). (B) The genes encoding the enzymes responsible for metabolism of major metabolites are shown here with the number of common and rare SNPs in blue and gray, respectively.</p