Biomedical subjects

Lyle J Palmer

Publications and source records attributed to Lyle J Palmer.

At least 37 records · Page 2Linked to original sources

PubMed2004

Nuclear factor kappa B activation in human cord blood mononuclear cells.

The immunologic signals participating in immune responses early in life have not been completely elucidated. Regarding the characterization of neonatal cells, little is known concerning the activity of transcription factor nuclear factor kappa B (NF-kappaB), which regulates inflammatory genes and cytokine production. The aim of this study was to characterize NF-kappaB activation in cord blood mononuclear cells (CBMC). We analyzed the potential association of NF-kappaB activity with lymphocyte proliferation and influences on cytokine secretion in the early immune system. To determine the contribution of a disease whereby inheritance may impact neonatal immunity, we assessed the influence of maternal allergic disease on NF-kappaB regulation and cytokine secretion. CBMC from healthy newborns were isolated and stimulated with mitogen (n = 28). Nuclear extracts were analyzed by electrophoretic mobility shift assay, cytokine secretion by ELISA. FISH analysis excluded relevant maternal contamination of CBMC. All samples showed a positive lymphoproliferative response, and NF-kappaB activity was both increased and decreased after mitogen stimulation. Increased NF-kappaB activation was significantly associated with decreased TNF-alpha secretion (median 6.1 versus 50.3 pg/mL) in unstimulated CBMC. Mitogen stimulation resulted in increased NF-kappaB activity with a trend to increased IL-13 production. Maternal allergic disease was associated with higher TNF-alpha (median 982 versus 173 pg/mL) and IL-13 secretion (median 1328 versus 1120 pg/mL) after mitogen stimulation. Together, NF-kappaB activity is differentially activated in cord blood and associated with a distinct cytokine pattern. Whether differential NF-kappaB activity in cord blood is related to the subsequent development of immune diseases requires further investigation.

Adult↗

PubMed2004

The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD).

Although cigarette smoking is the primary environmental risk factor, genetic risk factors likely influence the development of chronic obstructive pulmonary disease (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and COPD phenotypes was followed by association analysis of single nucleotide polymorphisms in a gene on chromosome 19q [transforming growth factor-beta1 (TGFB1)] and COPD phenotypes in a family-based sample and a case-control study (cases with severe COPD and control subjects with significant history of smoking but no COPD). Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the Boston Early-Onset COPD Study, there was significant evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV(1) (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other COPD phenotypes. In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV(1) (P<0.05). Among smokers in the COPD cases and control subjects, two SNPs in the promoter region of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073) were significantly associated with COPD (P</=0.02 in all cases). Chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking. We hypothesize that genetic variants in or near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers.

Case-Control Studies↗

PubMed2004

Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.

Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.

Administration, Inhalation↗

PubMed2004

Whole genome scan for obstructive sleep apnea and obesity in African-American families.

Obstructive sleep apnea (OSA) is a common, chronic disease associated with obesity. OSA and obesity are both prevalent in African Americans, who are also at increased risk for secondary complications. To identify susceptibility loci for OSA, we undertook a 9-centimorgans genome scan in 59 African-American pedigrees ascertained on the basis of either an affected individual with laboratory-confirmed disease or a proband who was a neighborhood control subject. Variance component linkage analysis was performed for the quantitative phenotypes apnea-hypopnea index (AHI) and body mass index. A candidate region on chromosome 8q (logarithm of odds [LOD] = 1.29, p = 0.006) gave the only evidence for linkage to the AHI. Body mass index was linked to multiple regions, most significantly to markers on chromosome 4q (LOD = 2.63, p = 0.0006) and 8q (LOD = 2.56, p = 0.0007). Evidence of linkage to the AHI was only slightly reduced after adjustment for body mass index. After adjustment for the AHI, some of the primary linkages to body mass index were greatly reduced whereas others remained suggestive. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity, and that the genetic determinants of obesity in this population may be modulated by apnea severity.

Adolescent↗

PubMed2004

Relationship between obstructive sleep apnea and diurnal leptin rhythms.

STUDY OBJECTIVES: Several studies have reported an association between obstructive sleep apnea and leptin, a hormone that influences satiety and body weight. We evaluated the relationship of leptin levels and the overnight change in levels with sleep apnea. DESIGN: Cross-sectional analysis of data from a prospective cohort study. SETTING: Case Western Reserve University General Clinical Research Center. PATIENTS OR PARTICIPANTS: A total of 138 individuals participating in the Cleveland Family Study--59% women, 45% African-American, with mean apnea-hypopnea index (AHI) of 6.9 (range 0-106)--were studied. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Serum leptin was measured at 10:00 pm to 11:00 pm and at 7:00 am to 8:00 am. Leptin levels in both the morning and evening were positively correlated with apnea-hypopnea index (AHI) in age-, sex-, and race-adjusted analyses (P < .0001) but not after additional adjustment for body mass index. The evening/morning leptin ratio, however, was associated with AHI independent of age, sex, race, body mass index, and waist-hip ratio (P = .03). Conversely, AHI was an independent predictor of the leptin ratio (P = .001) and more predictive than arousal index, oxygenation indices, time asleep, or sleep-stage distribution. An AHI > 15 was associated with a 23% increase in leptin ratio. CONCLUSIONS: These findings suggest that sleep apnea may suppress secretion of leptin in the morning. Alternatively, the relative elevation in evening leptin may influence apnea pathogenesis.

Adolescent↗

PubMed2004

The relationship between infant airway function, childhood airway responsiveness, and asthma.

The relationship between reduced pulmonary function in early life and persistent wheeze (PW) in school-aged children remains uncertain. In this study, VmaxFRC was assessed at 1 month of age, and the presence of wheeze up to 11 years of age was prospectively identified. At 11 years of age, airway responsiveness (AR) to inhaled histamine and atopy were assessed. Recent wheeze at 11 years of age was associated with a reduced mean z score for VmaxFRC at 1 month of age (-0.41 [SD 0.91], n = 31) compared with no recent wheeze (0.04 [SD 1.00], n = 153, p = 0.03). Wheeze between 4 and 6 years that persisted at 11 years (PW) was most prevalent among those with reduced VmaxFRC at 1 month and atopy aged 11 years (p = 0.002) or reduced VmaxFRC and increased AR aged 11 years (p = 0.015). When all factors were considered, reduced VmaxFRC at 1 month (p = 0.03) and increased AR aged 11 years (p < 0.001) were independently associated with PW (n = 17) compared with other outcomes (n = 129). Reduced airway function present in early infancy is associated with PW at 11 years of age, and this relationship is independent of the effect of increased AR and atopy in childhood.

Asthma↗

PubMed2004

Smoking status and occupational exposure affects oxidative DNA injury in boilermakers exposed to metal fume and residual oil fly ash.

Epidemiologic studies demonstrate increased cancer incidence among workers exposed to polycyclic aromatic hydrocarbons (PAH) and metals, probably through cumulative oxidative DNA damage in response to carcinogens. Boilermakers are exposed to particulates of residual oil fly ash (ROFA) and metal fume that contain carcinogenic PAH and metals. We conducted a repeated-measures cohort study in boilermakers during the overhaul of an oil-fired boiler to determine a possible association between the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG; an oxidative injury biomarker) and biomarkers of PAH (1-hydroxypyrene; 1-OHP) and metal exposure. Preshift and postshift urine samples were analyzed for 8-OH-dG, cotinine, 1-OHP, and metals. Generalized estimating equations were used to model the multivariate relationship of 8-OH-dG to the explanatory variables of interest. Biomarker levels were determined for 181 urine samples from 20 male subjects (mean age 45 years, 50% smokers). Metal and 1-OHP levels increased cross-week and were affected by smoking status. Levels of 8-OH-dG were higher in nonsmokers at the start of the workweek yet declined after occupational exposure to similar levels as in smokers. Multivariate analysis indicated that metal x cotinine interaction terms for nickel, vanadium, chromium, and copper were significantly associated with the 8-OH-dG level, but there were differential effects depending on the metal. This study suggests that oxidative DNA damage in boilermakers is influenced by the interaction between occupational exposures and smoking status. In addition, boilermakers may have reduced ability to repair damaged DNA after ROFA and metal fume exposure. This finding has clinical relevance because these exposures may increase the cancer susceptibility of boilermakers.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Do regular check ups and preventive drug use reduce asthma severity in school children?

OBJECTIVE: To investigate whether regular check ups and preventive drug use reduce asthma symptoms in school children. METHODS: Cross sectional retrospective questionnaire responses obtained from 2193 children aged 6-7 years in 34 primary schools, and 3650 children aged 13-14 years in nine secondary schools, selected at random by cluster sampling. MAIN OUTCOME MEASURES: Asthma severity in the past 12 months as measured by the number of attacks of wheezing, visits to a doctor, visits to a hospital emergency department, and hospital admissions, all for wheezing or asthma. ANALYSIS: Multivariate ordinal logistic regression. RESULTS: Regular general practitioner check ups were associated with reduced asthma severity. Regular use of prophylactic and bronchodilator medications was associated with reduced symptoms. Asthma action plans and peak flow meter usage were associated with reduced hospital admissions. DISCUSSION: If these associations are causal, then regular GP check ups are effective in reducing the health consequences of asthma in children.

Adolescent↗

PubMed2003

Genome-wide linkage analysis of longitudinal phenotypes using sigma2A random effects (SSARs) fitted by Gibbs sampling.

The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the familial aggregation and evidence for linkage to change in systolic blood pressure (SBP) over time. We used Gibbs sampling to derive sigma-squared-A-random-effects (SSARs) for the longitudinal phenotype, and then used these as a new phenotype in subsequent genome-wide linkage analyses. Additive genetic effects (sigma2A.time) were estimated to account for approximately 9.2% of the variance in the rate of change of SBP with age, while additive genetic effects (sigma2A) were estimated to account for approximately 43.9% of the variance in SBP at the mean age. The linkage results suggested that one or more major loci regulating change in SBP over time may localize to chromosomes 2, 3, 4, 6, 10, 11, 17, and 19. The results also suggested that one or more major loci regulating level of SBP may localize to chromosomes 3, 8, and 14. Our results support a genetic component to both SBP and change in SBP with age, and are consistent with a complex, multifactorial susceptibility to the development of hypertension. The use of SSARs derived from quantitative traits as input to a conventional linkage analysis appears to be valuable in the linkage analysis of genetically complex traits. We have now demonstrated in this paper the use of SSARs in the context of longitudinal family data.

Adult↗

PubMed2003

Lack of reproducibility of linkage results in serially measured blood pressure data.

BACKGROUND: Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points. RESULTS: The heritability of SBP was relatively stable over time, ranging from 11.6 to 23.5% (coefficient of variation = 25.7%). However, the variability in linkage results was much greater. The average correlation in LOD scores at any pair of time points was 0.46 for HTN (NPL All LOD) and 0.17 for SBP (Variance Components LOD). No evidence of reproducible linkage results was found, with a mean kappa of 0.02 for linkage to HTN and -0.03 for SBP linkage. At loci with potential evidence for linkage (LOD > 1.0 at one or more time points), the correlation was even lower. The coefficient of variation at loci with potential evidence of linkage was 126% for HTN and 135% for SBP. None of 15 chromosomal regions for HTN and only one of 28 regions for SBP with potential evidence for linkage had a LOD > 1.0 at more than two of the five time points. CONCLUSION: These data suggest that, although heritability estimates at different time points are relatively robust, the reproducibility of linkage results in serial cross-sectional samples of a geographically defined population at successive time points is poor. This may explain in part the difficulty encountered in replicating linkage studies of complex phenotypes.

Adult↗

PubMed2003

Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma.

Transforming growth factor-beta1 (TGF-beta1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C-509T) in the TGF-beta1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case-control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C-509T polymorphism alters TGF-beta1 promoter-reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.

Adult↗

PubMed2003

Genomic approaches to understanding obstructive sleep apnea.

Obstructive sleep apnea (OSA) is an increasingly recognized, common chronic disease in the developed nations and is a complex disease that has high social and economic costs. OSA and its associated 'intermediate' phenotypes-craniofacial structure, body fat distribution and metabolism, and neurological control of the upper airway muscles and of sleep and circadian rhythm-are under a substantial degree of genetic control. Investigating the genetic aetiology of OSA offers a means of better understanding its pathogenesis, with the goal of improving preventive strategies, diagnostic tools and therapies. Molecular studies of OSA itself are in their infancy, but considerable effort and expense has already been expended in attempts to detect genetic loci contributing to OSA-associated intermediate phenotypes, such as obesity. However, many of the fundamental questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This chapter reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep disorders.

Animals↗

PubMed2003

Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with significant and increasing morbidity and mortality. The cardinal feature of COPD is persistent airflow obstruction, measured by reductions in quantitative spirometric indices including forced expiratory volume at one second (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC). However, many patients have substantial improvement in spirometric measures with inhaled bronchodilator medications, and bronchodilator responsiveness (BDR) has been associated with disease severity and progression. To identify susceptibility loci for BDR phenotypes, we performed a 9 cM genome scan in 72 pedigrees (n=560 members) ascertained through probands with severe, early-onset COPD. Multipoint variance component linkage analysis was performed for quantitative phenotypes including BDR measures and post-bronchodilator FEV(1) and FEV(1)/FVC. Post-bronchodilator FEV(1) was linked to multiple regions, most significantly to markers on chromosome 8p (LOD=3.30) and 1q (LOD=2.24). Post-bronchodilator FEV(1)/FVC was also linked to multiple regions, most significantly to markers on chromosome 2q (LOD=4.42) and 1q (LOD=2.52). When compared with pre-bronchodilator spirometric indices, the post-bronchodilator values demonstrated increased evidence of linkage in multiple genomic regions. In particular, the LOD score for the 8p linkage to FEV(1) roughly doubled from 1.58 to 3.30. Candidate regions on chromosomes 4p (LOD=1.28), 4q (LOD=1.56), and 3q (LOD=1.50) gave the strongest evidence for linkage to BDR measures. Our results provide evidence for significant linkage to airflow obstruction susceptibility loci on chromosomes 2q and 8p, and further suggest that post-bronchodilator spirometric measures are optimal phenotypes for COPD genetic studies. This study has also identified several genomic regions that could contain loci regulating BDR in early-onset COPD families.

Bronchodilator Agents↗

PubMed2003

Association of a missense mutation in the NOS3 gene with exhaled nitric oxide levels.

There is evidence that genetic factors affect nitric oxide formation and that sequence variants in the nitric oxide synthase genes contribute to the observed variance of nitric oxide levels in exhaled air (fraction of expired nitric oxide, FENO) in subjects with asthma. We identified a strong association between a known functional NOS3 missense sequence variant in the endothelial nitric oxide gene (G894T) and FENO level in a cohort of subjects with asthma. Age- and sex-adjusted FENO levels were lowest in asthmatic subjects with the TT genotype (geometric mean FENO [95% CI] = 7.17 [4.48 to 11.48] ppb) and were significantly higher in those with either the GT genotype (geometric mean FENO [95% CI] = 17.11 [13.80 to 21.23] ppb) or the GG genotype (geometric mean FENO [95% CI] = 12.06 [9.91 to 14.67] ppb) (F2,59 = 5.97, p = 0.004). The G894T DNA variant explained 16.3% of the residual variance in FENO levels. Our results demonstrate that the endothelial nitric oxide synthase, a nitric oxide synthase constitutively expressed in epithelial cells, plays an important role in determining measured levels of exhaled nitric oxide, a marker of the asthmatic condition.

Adult↗

PubMed2003

Apolipoprotein E gene polymorphisms are associated with carotid plaque formation but not with intima-media wall thickening: results from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS).

BACKGROUND AND PURPOSE: Several studies have investigated the role of apolipoprotein E (apoE) polymorphisms on carotid intima-media thickness (IMT) with conflicting results. The objective of this study was to use a large, community-based population to investigate associations between apoE gene polymorphisms and cardiovascular disease-associated phenotypes: IMT, carotid artery plaque, and low- (LDL-C) and high-density lipoprotein cholesterol (HDL-C). METHODS: ApoE genotypes were determined in 1109 randomly selected community subjects with an equal man-to-woman ratio and equal numbers in each age decile who were 27 to 77 years of age and had bilateral carotid B-mode ultrasound and cardiovascular risk factor measurements. RESULTS: Multivariate analyses, stratified by sex, demonstrated an association between apoE genotypes and LDL-C levels in men (P=0.03) and women (P<0.001). A significant linear trend in increasing LDL-C (beta=0.33 per unit change in genotype; SE=0.07; P<0.001) levels with increasing number of epsilon4 alleles across the epsilon3/epsilon3, epsilon3/epsilon4, or epsilon4/epsilon4 genotypes was observed in women but not in men. The associations were independent of age, diastolic blood pressure, and history of diabetes mellitus. Multivariate analyses found a log-additive trend in risk of developing carotid plaque with increasing numbers of epsilon4 alleles across the epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes (odds ratio [OR], 1.72 per unit change in genotype; 95% CI, 1.05 to 2.80; P=0.03) in men. There was no association between plaque frequency and the epsilon4 allele in women. However, the epsilon2/epsilon3 genotype was shown to be associated with a lower OR (OR, 0.40; 95% CI, 0.17 to 0.91; P=0.03) for carotid plaques relative to the epsilon3/epsilon3 genotype in women. The associations were independent of age and standard vascular risk factors. There were no significant independent associations between apoE genotypes and IMT in either men or women. CONCLUSIONS: Our data suggest that polymorphisms in the apoE gene are significantly associated with LDL-C levels and increased risk of carotid plaque formation in men but not IMT in either men or women.

Adult↗

PubMed2003

Population stratification and spurious allelic association.

Great efforts and expense have been expended in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, technology for detection and scoring of single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a means for investigation of the genetic causes of complex human diseases. For many diseases, population-based studies of unrelated individuals--in which case-control and cohort studies serve as standard designs for genetic association analysis--can be the most practical and powerful approach. However, extensive debate has arisen about optimum study design, and considerable concern has been expressed that these approaches are prone to population stratification, which can lead to biased or spurious results. Over the past decade, a great shift has been noted, away from case-control and cohort studies, towards family-based association designs. These designs have fewer problems with population stratification but have greater genotyping and sampling requirements, and data can be difficult or impossible to gather. We discuss past evidence for population stratification on genotype-phenotype association studies, review methods to detect and account for it, and present suggestions for future study design and analysis.

Alleles↗

PubMed2003

Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population.

AIMS: Atherosclerosis can be viewed as a low grade inflammatory process, and genetic polymorphisms within cytokines are candidate risk factors for the development of atherosclerosis. We examined the association of a common functional variant in the IL-6 gene with carotid intimal-medial wall thickness (IMT) and the presence of plaques in a randomly selected, cross-sectional Australian population. METHODS: B-mode carotid ultrasound was performed on 1109 subjects aged 27-77 years, who were genotyped for the IL-6 polymorphism (-174G>C) and assessed for conventional cardiovascular risk factors. RESULTS: The frequency of the IL-6 -174C allele was 0.41. Initial univariate analysis showed no association of the IL-6 -174G>C polymorphism with carotid IMT. Multivariate analysis however showed an association of the IL-6 -174C allele with increased IMT in subjects older than the median age of 53 years (P=0.005). Initial univariate analysis of the IL-6 -174G>C polymorphism and carotid plaque showed no association in the whole sample. In multivariate analysis the -174C allele was independently associated with an increased risk of carotid plaque in the whole sample (CC vs GG, OR=2.22, 95% CI=1.32 to 3.73, P=0.003). CONCLUSIONS: This study shows that the IL-6 -174G>C variant is independently associated with carotid plaque formation in the whole population and an increased carotid IMT in older subjects within a randomly selected, cross-sectional Australian population.

Adult↗

PubMed2003

Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies.

TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (-1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at -1237 (odds ratio 1.85, 95%CI 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity.

Black People↗