The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth muscle tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD).
A total of 66 750 individuals from two large Danish general population studies were genotyped, and 1943 Thr164Ile heterozygotes and 16 homozygotes were identified.
Thr164Ile genotype was associated with increased systolic and diastolic blood pressure in women (trend: P = 0.04 and 0.02): systolic and diastolic blood pressure increased by 5% and 2%, respectively, in female homozygotes compared with female noncarriers. All female Thr164Ile homozygotes had hypertension compared with 58% of female heterozygotes and 54% of female noncarriers (chi-square: P = 0.001). Female Thr164Ile homozygotes and heterozygotes had odds ratios for ischaemic heart disease (IHD) of 2.93 (0.56-15.5) and 1.28 (1.03-1.61), respectively, compared with female noncarriers (trend: P = 0.007). These differences were not observed in men. Furthermore, Gly16Arg (rs1042713) and Gln27Glu (rs1042714) in the ADRB2 gene were not associated with blood pressure, hypertension or CVD either in the population overall or in women and men separately.
ADRB2 Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of IHD amongst women in the general population. These findings, particularly for homozygotes, are novel.
Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR?=?0.41; 95% CI: 0.29-0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer.
Nowadays it is considered that protein kinase Akt1 could be involved in pathogenesis of affective disorders. We have examined whether AKT1 gene polymorphisms are associated with antidepressant treatment response.
The study included 106 Caucasian patients with depressive disorders from Siberia and 103 healthy control donors. The frequencies of single nucleotide polymorphisms rs1130214 and rs3730358 of AKT1 gene were examined.
A comparison of genotypic or allelic frequencies between the groups of healthy donors and depressive patients showed no statistically significant difference. No association between the polymorphisms under study and the scores according to Hamilton Depression Rating Scale 17 was found. However, an association between treatment response assessed by the Clinical Global Impression - Improvement scale and rs1130214 polymorphism was observed.
AKT1 gene polymorphism rs1130214 is associated with antidepressant treatment response in patients with depressive disorders.
We developed rheumatoid arthritis (RA) risk models based on validated environmental factors (E), genetic risk scores (GRS), and gene-environment interactions (GEI) to identify factors that can improve accuracy and reclassification.
Models including E, GRS, and GEI were developed among 317 white seropositive RA cases and 551 controls from the Nurses' Health Studies (NHS) and validated in 987 white anti-citrullinated protein antibody-positive cases and 958 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA), stratified by sex. Primary analyses included age, smoking, alcohol, parity, weighted GRS using 31 non-HLA alleles and 8 HLA-DRB1 alleles, and the HLA × smoking interaction. Expanded models included reproductive, geographic, and occupational factors and additional GEI terms. Hierarchical models were compared for discriminative accuracy using the area under the receiver operating characteristic curve (AUC) and reclassification using the integrated discrimination improvement (IDI) and the continuous net reclassification improvement.
The mean age at RA diagnosis was 56 years in the NHS and 51 years in the EIRA. Primary models produced AUCs of 0.716 in the NHS, 0.716 in women in the EIRA, and 0.756 in men in the EIRA. Expanded models produced improvements in discrimination with AUCs of 0.738 in the NHS, 0.724 in women in the EIRA, and 0.769 in men in the EIRA. Models including genetic factors (G) or G + GEI improved reclassification over E models; the full E + G + GEI model provided the optimal predictive ability by IDI analyses.
We have developed comprehensive RA risk models incorporating E, G, and GEI that have improved the discriminative accuracy for RA. Further work developing and assessing highly specific prediction models in prospective cohorts is still needed to inform primary RA prevention trials.
Cites: Ann Rheum Dis. 2010 Mar;69(3):503-919825849
Cites: Ann Rheum Dis. 2010 Jun;69(6):1077-8520233754
Cites: Nat Genet. 2010 Jun;42(6):508-1420453842
Cites: Rheum Dis Clin North Am. 2010 May;36(2):213-4120510231
Cites: Environ Health Perspect. 2010 Jul;118(7):957-6120338859
Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-binding lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.
Genome-wide association studies (GWAS) have identified common genetic factors influencing body mass as well as body adiposity. The functional implications of these loci are currently under investigation. Intense scrutiny of the body mass-associated FTO locus revealed age-specific effects, or a weakened effect in elderly populations. In this study, we aimed to determine the effects of single nucleotide polymorphisms (SNPs) representing 35 GWAS-identified body mass- and adiposity-associated genetic loci. In our analysis, 949 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors cohort were included. All participants were born between 1920 and 1924. Data were available for 474 male and 475 female participants at age 70 and 380 male and 390 female participants at age 75. Genetic associations with BMI and change in BMI from age 70 to 75 were analyzed. In our analysis, rs10968576, an intronic SNP within the LINGO2 (LERN3, LRRN6C) gene, was associated with body mass in a cross section of elderly Swedes at age 70. This is the first study to replicate the association of a LINGO2-related genetic variant with body mass in an independent cohort of elderly citizens.
To test whether DNA sequence variation in 11 obesity genes is associated with maximum weight loss and weight regain over 6 years of follow-up in bariatric surgery patients of the Swedish obese subjects (SOS) intervention study.
A total of 1443 subjects were available for analysis (vertical banded gastroplasty: n = 966, banding: n = 293 and gastric bypass: n = 184). Single-nucleotide polymorphisms (SNPs) from the following 11 genes were included: ADIPOQ, BDNF, FTO, GNB3, LEP, LEPR, MC4R, NR3C1, PPARG, PPARGC1A and TNF. General linear models were used to analyze associations between the SNPs and maximum weight loss and weight regain.
The average maximum weight loss was 33.7 kg (s.d. 13.3; min -95.5 kg, max +2.0 kg), which was reached 2.2 (s.d. 1.6) years after the surgery. Subjects regained approximately 12 kg (range 0.0-51.4 kg) by year 6. After correcting for multiple testing, the FTO SNP rs16945088 remained significantly associated with maximum weight loss (P = 0.0002), as minor allele carriers lost approximately 3 kg less compared with common allele homozygotes. This association was particularly evident in the banding surgery patients (P
Erratum In: Int J Obes (Lond). 2012 Jul;36(7):1016
It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding.
We applied Mendelian randomization analysis to genetic scores, comprising 26-41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26?904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR).
The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80-1.03] unadjusted, and 0.87 (95% CI: 0.78-0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01-1.18) for prostate cancer and 0.89 (95% CI: 0.82-0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder.
Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.
Recent genome-wide association studies have identified genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRSs) constructed of these variants would predict incident cardiovascular disease (CVD) events. We genotyped 32 common single nucleotide polymorphisms in several Finnish cohorts, with up to 32,669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. We created GRSs separately for systolic BP and diastolic BP by multiplying the risk allele count of each single nucleotide polymorphism by the effect size estimated in published genome-wide association studies. We performed Cox regression analyses with and without adjustment for clinical factors, including BP at baseline in each cohort. The results were combined by inverse variance-weighted fixed-effects meta-analysis. The GRSs were strongly associated with systolic BP and diastolic BP, and baseline hypertension (all P
The causal role of obesity in the development of depression remains uncertain. We applied instrumental-variables regression (Mendelian randomization) to examine the association of adolescent and adult body mass index (BMI) with adult depressive symptoms. Participants were from the Young Finns prospective cohort study (n?=?1731 persons, 2844 person-observations), with repeated measurements of BMI and depressive symptoms (modified Beck's Depression Inventory). Genetic risk score of 31 single nucleotide polymorphisms previously identified as robust genetic markers of body weight was used as a proxy for variation in BMI. In standard linear regression analysis, higher adult depressive symptoms were predicted by higher adolescent BMI (B?=?0.33, CI?=?0.06-0.60, P?=?0.017) and adult BMI (B?=?0.47, CI?=?0.32-0.63, P?