The ß(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes.
We tested the hypothesis that the ADRB2rs1800888(Thr164Ile) polymorphism associates with risk of obesity and diabetes and compared effect sizes with those of FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238).
We conducted a population-based cohort study in Copenhagen, Denmark.
We genotyped more than 64,000 individuals from the Danish general population.
We evaluated body mass index (BMI), obesity (BMI =30 kg/m(2)), and diabetes.
Rare allele frequencies were 0.02 for T for ADRB2rs1800888(Thr164Ile), 0.40 for A for FTOrs9939609, 0.25 for C for MC4Rrs17782313, and 0.20 for T for TMEM18rs6548238. For rare vs. common homozygotes, odds ratio for obesity was 3.32 (95% confidence interval = 1.08-10.19) for ADRB2rs1800888(Thr164Ile), 1.42 (1.35-1.52) for FTOrs9939609, 1.18 (1.06-1.30) for MC4Rrs17782313, and 1.28 (1.10-1.50) for TMEM18rs6548238 (common vs. rare). Corresponding odds ratios for diabetes were 1.85 (0.24-14.29), 1.22 (1.07-1.39), 0.96 (0.80-1.16), and 1.61 (1.17-2.22), respectively. After adjustment for BMI, only TMEM18rs6548238 remained associated with diabetes. BMI was increased in rare vs. common homozygotes in FTOrs9939609, MC4Rrs17782313, and TMEM18rs6548238 (common vs. rare) but not in ADRB2rs1800888(Thr164Ile).
Our results suggest that ADRB2rs1800888(Thr164Ile) rare vs. common homozygotes are not significantly associated with an increase in BMI measured continuously but may be associated with an increased risk of obesity. Also, TMEM18rs6548238 associated with risk of diabetes after adjustment for BMI. These findings need confirmation in other studies.
BACKGROUND: Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD). METHODS: We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV1 decline and risk of asthma or COPD. RESULTS: 5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV1 decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV1 decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV1 of 19 ml compared with 21 ml in 7T homozygous controls (t-test: P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (chi2: P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank: P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI: 1.5-78) and 6.3 (0.84-47) in 7T homozygotes with vs. without an F508del allele. CONCLUSION: Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.
BACKGROUND: Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we tested whether alpha(1)-antitrypsin deficiency is associated with reduced blood pressure, risk of ischemic cerebrovascular (ICVD) and ischemic heart disease (IHD), and longevity. METHODS AND RESULTS: We genotyped 7963 control subjects from the adult general population of Denmark, 1131 Danish patients with ICVD, and 2221 Danish patients with IHD. Compared with MM/MS individuals, systolic blood pressure was lower by 15 mm Hg in ZZ homozygotes (n=6, P=0.03) and 9 mm Hg in MZ heterozygotes with IHD (n=39, P=0.02). Odds ratios for ICVD and IHD in MZ versus MM/MS individuals were 0.70 (0.51 to 0.96) and 0.77 (0.61 to 0.98). Finally, mean ages of MZ and MM/MS control subjects were 58 and 56 years (Mann-Whitney: P=0.008), and relative alpha(1)-antitrypsin MZ genotype frequencies increased from 20 to 93 years among control subjects (chi(2), P=0.002). CONCLUSIONS: ZZ alpha(1)-antitrypsin deficiency and MZ intermediate deficiency in the context of IHD are associated with reduced blood pressure, and MZ is associated with reduced risk of ICVD and IHD. Because MZ heterozygosity was associated with increased age, MZ heterozygosity could be a beneficial condition.
Comment In: Circulation. 2003 Aug 26;108(8):e62-3; author reply e62-312939251
RATIONALE: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight(2)). OBJECTIVES: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD. METHODS: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account. MAIN RESULTS: The mean FFMI was 16.0 kg/m(2) for women and 18.7 kg/m(2) for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI. CONCLUSIONS: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.
Comment In: Am J Respir Crit Care Med. 2006 Jan 1;173(1):4-516368791
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of ß = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF
Cites: Am J Respir Crit Care Med. 2012 Feb 15;185(4):373-8122161163
BACKGROUND: A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain. OBJECTIVE: To test the hypothesis that MZ intermediate alpha(1)-antitrypsin deficiency affects pulmonary function and disease. DESIGN: Population-based cohort study with 21-year follow-up. SETTING: Copenhagen, Denmark. PARTICIPANTS: 9187 adults randomly selected from the Danish general population. MEASUREMENTS: Plasma alpha(1)-antitrypsin levels, annual decrease in FEV(1), airway obstruction, and hospitalization and mortality from chronic obstructive pulmonary disease (COPD). RESULTS: 451 participants (4.9%) carried the MZ genotype. Plasma alpha(1)-antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype (Student t -test, P
SummaryForPatientsIn: Ann Intern Med. 2002 Feb 19;136(4):I3511848738
Among 5,812 individuals with COPD defined by FEV1/FVC < 0.7 participating in the Copenhagen General Population Study, we identified 920 individuals with FEV1 < 60% predicted. Prescriptions were identified in an all-inclusive nationwide registry. For each individual, we examined treatment with medication in the year before the day of the baseline examination, as well as treatment in the first year after the examination. Multivariable logistic regression analyses were applied in individuals with FEV1 < 60% predicted to identify predictors of treatment in the first year after baseline.
Only 30% of individuals with COPD and FEV1 < 60% predicted were treated with medication in the year before the examination, whereas 42.2% were treated with medication in the first year after. Reporting six to 10 previous respiratory infections during the preceding 10 years that required consulting a doctor and/or staying home from work was the strongest predictor of treatment with medication (OR, 7.9; 95% CI, 3.5-19.8; P < .001). Breathlessness, low FEV1, previous admissions with a discharge diagnosis of COPD, and former smoking were also predictors of treatment with medication, whereas comorbidity predicted lack of treatment. In subgroup analysis, among individuals with FEV1 < 50% predicted, visits to the general practitioner and age were additional predictors of treatment, whereas male sex and being a widow/widower predicted lack of treatment.
In this study, we observed important characteristics of a major undertreatment in individuals with COPD in the general population. Previous reported respiratory infections were the strongest predictors of treatment with medications, which indicates that most COPD treatment is initiated because of acute exacerbations.
It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design.
The authors measured high-sensitivity CRP in plasma, genotyped for four single nucleotide polymorphisms in the CRP gene, and screened for spirometry-defined COPD and hospitalisation due to COPD in 7974 individuals from the Copenhagen City Heart Study and in 32,652 individuals from the Copenhagen General Population Study.
The angiotensin-converting enzyme (ACE) gene is a potential candidate gene for risk of asthma, COPD, and COPD co-morbidity. In 9034 Danish adults, we determined whether individuals homozygous or heterozygous for the ACE D allele are at greater risk of asthma, COPD, or COPD co-morbidity compared with ACE II homozygous individuals. In the general population, serum ACE activity increased with the number of D alleles (Kruskal-Wallis ANOVA: II vs. ID, p
Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population.
We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers.
Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P(trend) = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P(trend) = 0.003), whereas HRs among never-smokers did not differ from 1.0.
Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings.
To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population.