Diuretic Use and Serum Phosphate: Rotterdam Study and UK Biobank.

Purpose: Hypophosphatemia (serum phosphate < 0.80 mmol/L) leads to musculoskeletal complaints. The most common drugs linked to hypophosphatemia are thiazide and loop diuretics, but studies in the general population are lacking. Our aim was to study associations between diuretic use and serum phosphate in the Rotterdam Study (RS), a population-based cohort study, with replication in UK Biobank (UKBB). Methods: Associations between thiazide and loop diuretic use and serum phosphate and odds of hypophosphatemia were analyzed with cross-sectional multivariate linear and logistic regression in participants without chronic kidney disease in the RS and UKBB. Analyses were adjusted for age, sex, and body mass index (BMI) and pooled in 3 RS cohorts with further adjustment for cohort and serum potassium, which was not available in UKBB. Results: Thiazide diuretics were associated with lower serum phosphate in both sexes. This association lost significance in RS females after adjustment for BMI and in males after adjustment for serum potassium. Thiazide diuretics increased odds of hypophosphatemia in females in both cohorts and in males in UKBB only. Loop diuretics were associated with lower serum phosphate in females but not males. Adjustment for BMI attenuated these associations. Associations between loop diuretics and increased odds of hypophosphatemia in females lost significance after BMI adjustment. Conclusion: Thiazides, but not loop diuretics, and increased BMI and decreased serum potassium should be considered as contributing factors in subjects with hypophosphatemia. Further studies are needed to replicate the findings and elucidate the potential role of hypokalemia as a mediator of this effect.

The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density.

Osteoporosis is a highly prevalent bone disease affecting more than 37.5 million individuals in the European Union (EU) and the  United States of America (USA). It is characterized by low bone mineral density (BMD), impaired bone quality, and loss of structural and biomechanical properties, resulting in reduced bone strength. An increase in morbidity and mortality is seen in patients with osteoporosis, caused by the approximately 3.5 million new osteoporotic fractures occurring every year in the EU. Currently, different medications are available for the treatment of osteoporosis, including anti-resorptive and osteoanabolic medications. Bisphosphonates, which belong to the anti-resorptive medications, are the standard treatment for osteoporosis based on their positive effects on bone, long-term experience, and low costs. However, not only medications used for the treatment of osteoporosis can affect bone: several other medications are suggested to have an effect on bone as well, especially on fracture risk and BMD. Knowledge about the positive and negative effects of different medications on both fracture risk and BMD is important, as it can contribute to an improvement in osteoporosis prevention and treatment in general, and, even more importantly, to the individual's health. In this review, we therefore discuss the effects of both osteoporotic and non-osteoporotic medications on fracture risk and BMD. In addition, we discuss the underlying mechanisms of action.

A Large Skull Defect Due to Gorham-Stout Disease: Case Report and Literature Review on Pathogenesis, Diagnosis, and Treatment.

A 24-year old man was referred to the Erasmus MC Bone Center because of an asymptomatic increasing skull defect of the left parietal bone. The defect was first noticed at the age of six, and gradually increased over the years. His medical history was unremarkable, without any known trauma and a negative family history for bone diseases. Laboratory tests showed a low vitamin D level without other abnormalities. Particularly, there was no increase in markers of inflammation or bone turnover. CT-scans of the skull showed an osteolytic region of the parietal skull bone, with a two-centimeter increase in diameter over 9 years. Contrast enhanced MRI showed lymphangiogenic invasion, which was compatible with our suspicion of Gorham-Stout disease. The patient was referred to the neurosurgeon for treatment with a bone graft while considering additional drug treatment. Gorham-Stout or vanishing bone disease is a rare entity characterized by progressive osteolysis with lymphangiogenic bone invasion. Although already reported in 1838, currently the diagnosis and treatment of Gorham-Stout disease is still challenging. The underlying pathophysiology is not clarified yet and several theories exist. The disease usually affects persons younger than 40 years and the majority present with bone disease of the maxillofacial region, the upper extremities or the torso. The clinical presentation includes most frequently pain, swelling, and functional impairment of the affected region, but the disease can also be asymptomatic. Laboratory investigations are usually normal, and diagnosis is based upon imaging and sometimes pathology examination of affected bone tissue. Treatment is experimental and there is no general consensus about the best option due to lack of randomized controlled trials. Case reports showed patients treated with bisphosphonates, interferon-alpha, anti-VEGF therapy, mTOR inhibitors, and radiotherapy. There are some reports of surgery with prosthetic or bone grafts but no long-term follow-up data exist. This paper describes a unique case of Gorham-Stout disease of the parietal skull bone and discusses the current state of knowledge about this rare bone disease.

Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors.

OBJECTIVES: To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. METHODS: Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. RESULTS: A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5×10) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), γ-aminobutyric acid receptor subunit γ-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32-1.76), P=6.2×10]. CONCLUSION: These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.

Dietary mineral intake and lung cancer risk: the Rotterdam Study.

OBJECTIVE: Limited data are available on the role of mineral intake in the development of lung cancer (LC). We investigated whether dietary calcium, copper, iron, magnesium, selenium and zinc intake were associated with LC risk. METHODS: We analyzed data from 5435 participants of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years and older. At baseline (1990-1993), diet was measured by a validated food frequency questionnaire. LC events were diagnosed on the basis of pathology data and medical records. Hazard ratios (HRs) on LC for energy-adjusted mineral intake were calculated using Cox regression models while adjusting for potential confounders. RESULTS: During a follow-up period of 22 years, we identified 211 incident cases of LC. A higher zinc intake was associated with 42 % reduction in risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.35; 0.94, P-for trend = 0.039). Similarly, high intake of iron was associated with reduced risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.37; 0.92, P-for trend = 0.021). There was no association between dietary intake of calcium, copper, magnesium and selenium and LC risk. CONCLUSIONS: Our results suggest that dietary zinc and iron intake are associated with reduced risk of LC. No evidence was found for an association between calcium, copper, magnesium and selenium intake and LC risk.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium.

BACKGROUND: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality. METHODS: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs. RESULTS: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking. CONCLUSIONS: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.

Dietary polyunsaturated fatty acids intake modifies the positive association between serum total cholesterol and colorectal cancer risk: the Rotterdam Study.

BACKGROUND: It remains unclear whether serum total cholesterol is associated with colorectal cancer (CRC) risk. Interplay between dietary fatty acids and serum total cholesterol on CRC risk may be present as well. We aimed to investigate the association between serum total cholesterol with CRC. Furthermore, we investigated whether this association was modified by intake of dietary polyunsaturated fatty acids (PUFAs). METHODS: We analysed data from 6628 participants of the Rotterdam Study, a prospective population-based follow-up study among patients aged 55 years and older. Serum total cholesterol was measured at baseline. During a mean follow-up time of 12.9 years, we identified 248 new CRC cases based on pathology data and medical records. Multivariable HRs were calculated using Cox regression models. RESULTS: After adjustment, serum total cholesterol levels were associated with a higher risk of CRC (HR 1.49; 95% CI 1.08 to 2.06 for highest vs lowest tertile). Statistically significant effect modification was present for PUFAs intake (P-interaction=0.04). After stratification by median PUFAs intake, an increased risk with increasing tertiles of serum total cholesterol was observed among patients with low PUFAs intake (3rd tertile vs 1st tertile: HR 2.43; 95% CI 1.41 to 4.18), whereas no association was observed among patients with high PUFAs intake (3rd tertile vs 1st tertile: HR 0.93; 95% CI 0.55 to 1.58). CONCLUSIONS: Taken together, these findings suggest that high levels of serum total cholesterol increase CRC risk, but this risk may be reduced by high dietary PUFAs intake.

Antidepressants with a high serotonin reuptake transporter affinity and serum lipid levels in a population-based study in older adults.

OBJECTIVE: We aimed to investigate the association between antidepressants and serum lipid levels in a population-based study in older adults. METHODS: We included participants from the prospective Rotterdam Study with data on lipid levels (total, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, and triglycerides). We classified antidepressants based on binding affinity to the serotonin transporter (low/intermediate- and high-affinity antidepressants). We compared lipid levels in users of these groups of antidepressants with lipid levels in non-users. Furthermore, we studied effect modification by the 102 C>T polymorphism (HTR2A gene), which is associated with antidepressant drug response and metabolic outcomes. RESULTS: Compared with non-users (N = 6438), LDL cholesterol level was higher (2.9 versus 3.1 mmol/L, respectively; p = 0.05) in users of high-affinity antidepressants (N = 89). Similar levels of the other lipids were observed between the groups for the other lipids. The mean difference in serum LDL cholesterol level between non-users and users of high-affinity antidepressants was largest in participants with the CC genotype compared with the other genotypes (notably 0.47 mmol/L), indicative of effect modification (p-value for interaction = 0.03). CONCLUSION: Antidepressants with a high serotonin reuptake transporter affinity were associated with higher LDL cholesterol levels, which were modified by a common genetic variation in the HTR2A gene.

Change in prescription pattern as a potential marker for adverse drug reactions of angiotensin converting enzyme inhibitors.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEIs) are among the most frequently prescribed groups of medications. ACEI-induced adverse drug reactions (ADRs) are the main reason to discontinue or switch ACEI treatment. ADRs information is not available in prescription databases. OBJECTIVE :To identify a proxy for ACEI-induced ADRs in prescription databases. SETTING: The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the Netherlands and has included 14,926 subjects aged 45 years or older. METHODS: All ACEI starters from 2000 to 2011 were identified using prescription data within the Rotterdam Study. Participants were classified into 4 mutually exclusive groups: continuing, discontinuing, switching to angiotensin receptor blockers (ARBs), and switching to other antihypertensives. For categorization, the maximum time-interval between two prescription periods was set at 3 and 6 months. Subsequently, primary care physician files were searched and clinical events were classified as definite ADRs, probable ADRs, possible ADRs and definite non-ADRs. Finally the accuracy of different prescription patterns as indicators of ADRs was evaluated. Main outcome measure Positive predictive values (PPVs), negative predictive values (NPVs), sensitivity and specificity of the prescription patterns of the 4 groups were calculated. RESULTS: Totally, 1132 ACEI starters were included. The PPV for a definite ADR was 56.1 % for switchers to ARB, while the PPVs for switchers to other antihypertensives, and discontinuation were 39.5 and 19.5 %, respectively. After including probable ADRs and possible ADRs, PPVs for switchers to ARB increased to 68.3 and 90.5 %. A 6-month interval gave slightly higher PPVs compared to a 3-month interval (maximum 6.1 % higher). The differences in NPVs between 3 and 6-months interval groups were approximately 1.0 %. CONCLUSIONS: Switching ACEIs to ARBs is the best marker for ACEI-induced ADRs in prescription databases.

Use of statins is associated with lower serum total and non-sex hormone-binding globulin-bound testosterone levels in male participants of the Rotterdam Study.

OBJECTIVE: Statins, or HMG-CoA reductase inhibitors, decrease cholesterol production. Because cholesterol is a precursor of the testosterone biosynthesis pathway, there is some concern that statins might lower serum testosterone levels. The objective of the present study was to investigate the association between the use of statins and serum testosterone levels in men. DESIGN: Cross-sectional study within the prospective population-based Rotterdam Study. SUBJECTS AND METHODS: We included 4166 men with available data on total testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, and medication use. Multivariable linear regression analysis was used to compare the differences in serum testosterone levels (nmol/l) between current, past, and never statin users. We considered dose and duration of use. Analyses were adjusted for age, BMI, cardiovascular disease, diabetes mellitus, hypertension, and estradiol levels. RESULTS: We identified 577 current (mean age 64.1 years), 148 past (mean age 64.6 years), and 3441 never (mean age 64.6 years) statin users. Adjusted for all covariables, current statin use of 1-≤ 6 months or >6 months was significantly associated with lower total testosterone levels as compared to non-users (ß -1.24, 95% CI -2.17, -0.31, and ß -1.14, 95% CI -2.07, -0.20 respectively). Current use of 1-≤ 6 months was also associated with significantly lower non-SHBG-bound testosterone levels (ß -0.42, 95% CI -0.82, -0.02). There was a trend toward lower testosterone levels at higher statin doses both for total (P(trend) 2.9 × 10(-5)) and non-SHBG-bound (P(trend) 2.0 × 10(-4)) testosterone. No association between past statin use and testosterone levels was found. CONCLUSION: We showed that current use of statins was associated with significantly lower serum total and non-SHBG-bound testosterone levels. The clinical relevance of this association should be further investigated.

Dietary Fiber Intake Modifies the Positive Association between n-3 PUFA Intake and Colorectal Cancer Risk in a Caucasian Population.

BACKGROUND: The association between dietary fat intake and the risk of colorectal cancer (CRC) is still unclear. OBJECTIVES: We analyzed whether intakes of dietary polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) were associated with CRC risk and whether these associations were modified by dietary fiber (DF) intake. METHODS: This study was embedded in the Rotterdam Study, a prospective cohort study among subjects aged ≥55 y (n = 4967). At baseline, diet was measured by a food-frequency questionnaire. CRC events were diagnosed on the basis of pathology data and medical records. Multivariable adjusted HRs were calculated using Cox regression models. RESULTS: During a mean follow-up period of 14.6 y, we identified 222 incident cases of CRC. There was no association between total PUFA, n-6 (ω-6) PUFA, or SFA intake and CRC risk. n-3 PUFA intake was associated with an increased risk of CRC [tertile 3 vs. tertile 1: HR = 1.44 (95% CI: 1.02, 2.04), P-trend = 0.04]. When data were analyzed by food sources, only n-3 PUFAs from nonmarine sources were associated with an increased risk of CRC. A significant interaction between n-3 PUFA and DF intakes was found (P-interaction = 0.02). After stratification by median DF intake, an increased risk of CRC caused by n-3 PUFA intake was observed in participants with a DF intake less than the median [tertile 3 vs. tertile 1: HR = 1.96 (95% CI: 1.20, 3.19), P-trend = 0.01]. No association was observed in subjects with DF intake equal to or higher than the median. CONCLUSIONS: This study suggests that intake of n-3 PUFAs by adults is associated with an increased risk of CRC, which may be driven mainly by sources other than fish. Moreover, a complex interaction with DF intake may be present.

The rs13064411 polymorphism in the WDR52 gene, associated with PCSK9 levels, modifies statin-induced changes in serum total and LDL cholesterol levels.

OBJECTIVE: Recently, the minor allele of the rs13064411A>G polymorphism in the WD repeat domain 52 (WDR52) gene was associated with increased statin-induced proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and with LDL cholesterol response to statins. PCSK9 promotes LDL receptor degradation, leading to increased serum LDL cholesterol. We investigated whether the polymorphism was associated with cholesterol response to statins. METHODS: We identified 1105 current, 322 past, and 4831 never statin users during follow-up in the prospective population-based Rotterdam Study. The mean delta total, LDL, and HDL cholesterol levels between current and no current statin users with the same number of minor alleles were analyzed using random-effect repeated measurements. We adjusted for age, sex, number of cholesterol measurements, and follow-up time. RESULTS: Compared with no users with the same genotype, current statin users carrying a minor allele showed a statistically significantly lower delta total and LDL cholesterol compared with reference homozygous major allele carriers [total: Δ=0.551 mmol/l (AG+GG) vs. Δ=0.732 mmol/l (AA), Pinteraction: 5.2×10(-7); LDL: Δ=0.566 mmol/l (AG+GG) vs. Δ=0.720 mmol/l (AA), Pinteraction: 1.8×10(-5)]. The effect was stronger in women (Pinteraction: 2.0×10(-5) for LDL cholesterol, 8.0×10(-6) for total cholesterol) and in high-dose users (defined daily doses>1.00) (Pinteraction: 7.0×10(-5) for LDL cholesterol, Pinteraction: 0.081 for total cholesterol). The polymorphism was not associated with HDL cholesterol in current statin users, or with total, LDL and HDL cholesterol in never statin users. CONCLUSION: The minor G allele of the rs13064411 polymorphism, associated with statin-induced PCSK9-levels, was associated with a decreased LDL-lowering and total cholesterol-lowering response to statins.

Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: the Rotterdam Study.

Some studies suggest a favorable role of antioxidants on breast cancer risk but this is still inconclusive. The aim of this study was to assess whether overall dietary antioxidant capacity, as assessed by dietary ferric reducing antioxidant potential (FRAP), and individual dietary antioxidant intake were associated with breast cancer risk. Data was used from women participating in the Rotterdam Study, a prospective cohort study among subjects aged 55 years and older (N = 3,209). FRAP scores and antioxidant intake (i.e., vitamin A, C, E, selenium, flavonoids and carotenoids) was assessed at baseline by a food frequency questionnaire. Incident cases of breast cancer were confirmed through medical reports. During a median follow-up of 17 years, 199 cases with breast cancer were identified. High dietary FRAP score was associated with a lower risk of breast cancer [hazard ratio (HR): 0.68; 95% confidence intervals (CI): 0.49, 0.96]. No overall association between individual antioxidant intake and breast cancer risk was found. However, low intake of alpha carotene and beta carotene was associated with a higher risk of breast cancer among smokers (HR: 2.48; 95% CI: 1.21, 5.12 and HR: 2.31; 95% CI: 1.12, 4.76 for alpha and beta carotene, respectively) and low intake of flavonoids was associated with breast cancer risk in women over the age of 70 (HR: 1.80; 95% CI: 1.09, 2.99). These results suggest that high overall dietary antioxidant capacity is associated with a lower risk of breast cancer. Individual effects of dietary carotenoids and dietary flavonoids may be restricted to subgroups such as smokers and elderly.

Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis.

AIMS/HYPOTHESIS: The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach. METHODS: Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression. RESULTS: Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). CONCLUSIONS/INTERPRETATION: The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

No association between CYP3A4*22 and statin effectiveness in reducing the risk for myocardial infarction.

AIM: Genetic variation has been shown to influence statin response in terms of lowering LDL cholesterol. The recently discovered CYP3A4*22 allele (defined as rs35599367) has been shown to affect statin-induced LDL cholesterol lowering. Our objective was to investigate whether this polymorphism modifies the risk reduction for myocardial infarction (MI) by statins. PATIENTS & METHODS: We analyzed the interaction between the *22 minor allele and statin use in the independent Utrecht Cardiovascular Pharmacogenetics study and Rotterdam Study, using logistic and Cox regression models. RESULTS: In total, 771 MI cases and 6131 controls were included in the analyses. There was no effect of the CYP3A4*22 allelic status in the studies separately, nor when the estimates from both studies were combined (interaction odds ratio: 1.27; 95% CI: 0.73-2.21; p = 0.40 for carriers of the minor T-allele). CONCLUSION: We found no association of the CYP3A4*22 minor allele (rs35599367) with the effectiveness of statins in reducing MI risk.

Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.