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.
Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated with elevated blood pressure.
We genotyped 9185 individuals from the adult Danish general population.
Allele frequencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively. Among women never treated with antihypertensive medication those heterozygous for Thr164Ile versus non-carriers had increased diastolic blood pressure (P=0.02). Women heterozygous for Thr164Ile versus non-carriers had an odds ratio for elevated blood pressure of 1.93 (95% CI: 1.30-2.86). Finally, women double heterozygous for Thr164Ile and Gln27Glu or Gly16Arg versus non-carriers at all 3 loci had an odds ratio for elevated blood pressure of 2.49 (1.28-4.85) or 3.19 (1.46-6.97). In men, blood pressure was not influenced by this genetic variation.
In women Thr164Ile heterozygosity is associated with increased diastolic blood pressure, and represent a risk factor for elevated blood pressure in women in the general population. This was most pronounced in those women also heterozygous for Gln27Glu or Gly16Arg.
The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions.
High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation.
A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated.
Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score =8.0 (prevalence = 11%) versus
Comment In: J Am Coll Cardiol. 2014 May 27;63(20):2129-3024657684
The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol.
We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), ?-glutamyl-transferase (?-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56).
In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (-4.5, 11.9) from genetic-IV analyses] and ?-GT [8.2% (7.8, 8.5) and 6.8% (-2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and ?-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [-1.5% (-1 .7, -1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (p diff
To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.
Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).
Two large, prospective cohort studies in Denmark.
We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.
Blood pressure and prospectively assessed ischaemic heart disease.
Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).
By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
Cites: Stroke. 2006 Jun;37(6):1503-716675740
Cites: JAMA. 2000 May 10;283(18):2404-1010815083
Cites: Ann Epidemiol. 2007 Jul;17(7):511-317466535
Cites: JAMA. 2007 Jul 18;298(3):299-30817635890
Cites: J Am Coll Cardiol. 2007 Nov 27;50(22):2173-9518036459
Cites: Am J Hum Genet. 2008 Jan;82(1):139-4918179892
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.
Activation of the angiotensin?II type?1 (AT1 ) receptor has been shown to mediate the structural and electrical remodelling of the atrial myocardium associated with atrial fibrillation. We hypothesized that AT1 genotypic variation is associated with atrial fibrillation or diseases predisposing to atrial fibrillation, such as hypertension, heart failure, ischaemic heart disease and myocardial infarction, in the general population.
We resequenced the AT1 gene in 760 individuals with atrial fibrillation and identified two nonsynonymous variants (I103T and A244S), which were subsequently genotyped in the prospective Copenhagen City Heart Study (n = 10?603) and the prospective Copenhagen General Population Study (n = 60?647).
Risk of atrial fibrillation for heterozygotes for AT1 genetic variants A244S and I103T/A244S vs. noncarriers was increased by 2.7-fold (95% confidence interval 1.5- to 5.1-fold) and 2.6-fold (95% confidence interval 1.6- to 4.2-fold), respectively, for men.
Heterozygosity for the nonsynonymous AT1 genetic variants A244S and I103T/A244S was associated with increased risk of atrial fibrillation in men. The AT1 recptor might be a target for the pharmaceutical industry. This finding needs to be validated in independent studies.
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
Recently, data on 2,000,000 people established that low body mass index (BMI) is associated with increased risk of dementia. Whether this observational association reflects a causal effect remains to be clarified.
We tested the hypothesis that there is a causal association between low BMI and high risk of Alzheimer's disease.
Using a Mendelian randomization approach, we studied 95,578 individuals from the Copenhagen General Population Study (CGPS) with up to 36 years of follow-up and consortia data on 303,958 individuals from the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer's Project (IGAP).
Risk of Alzheimer's disease.
The causal odds ratio for a 1-kg/m2 genetically determined lower BMI was 0.98 [95% confidence interval (CI), 0.77 to 1.23] for a weighted allele score in the CGPS. Using 32 BMI-decreasing variants from GIANT and IGAP the causal odds ratio for Alzheimer's disease for a 1-standard deviation (SD) lower genetically determined BMI was 1.02 (95% CI, 0.86 to 1.22). Corresponding observational hazard ratios from the CGPS were 1.07 (95% CI, 1.05 to 1.09) and 1.32 (95% CI, 1.20 to 1.46) for a 1-kg/m2 and a 1-SD lower BMI, respectively.
Genetic and hence lifelong low BMI is not associated with increased risk of Alzheimer's disease in the general population. These data suggest that low BMI is not a causal risk factor for Alzheimer's disease and that the corresponding observational association likely is explained by reverse causation or confounding.
Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed.
To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades.
Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n?=?13,704) and 1991-1994 (n?=?9482) and the Copenhagen General Population Study in 2003-2013 (n?=?97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first.
For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared.
Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality.
The number of deaths during follow-up was 10,624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95%CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95%CI, 9-30]), and 5580 in the 2003-2013 cohort (6%;MR, 4/1000 person-years [95%CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI associated with the lowest all-cause mortality increased by 3.3 from the 1976-1978 cohort compared with the 2003-2013 cohort. [table: see text] The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95%CI, 1.23-1.39;MR, 46/1000 person-years [95%CI, 32-66] vs 28/1000 person-years [95%CI, 18-45]) in the 1976-1978 cohort, 1.13 (95%CI, 1.04-1.22; MR, 28/1000 person-years [95%CI, 17-47] vs 15/1000 person-years [95%CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95%CI, 0.92-1.07;MR, 5/1000 person-years [95%CI, 2-12] vs 4/1000 person-years [95%CI, 1-11]) in the 2003-2013 cohort. CONCLUSIONS AND RELEVANCE Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications.