Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal ...microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.
Genetic Variation in the Multidrug and Toxin Extrusion 1 Transporter Protein Influences the Glucose-Lowering Effect of Metformin
in Patients With Diabetes: A Preliminary Study
Matthijs L. Becker 1 2 ...,
Loes E. Visser 1 2 ,
Ron H.N. van Schaik 3 4 ,
Albert Hofman 1 5 ,
André G. Uitterlinden 1 5 6 and
Bruno H.Ch. Stricker 1 5 6 7
1 Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
2 Hospital Pharmacy, Erasmus Medical Center, Rotterdam, the Netherlands
3 Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands
4 STAR Medical Diagnostic Center, Rotterdam, the Netherlands
5 Netherlands Consortium on Healthy Aging, Rotterdam, the Netherlands
6 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
7 Drug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands
Corresponding author: Bruno H.Ch. Stricker, b.stricker{at}erasmusmc.nl
Abstract
OBJECTIVE— Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal
epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single
nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin.
RESEARCH DESIGN AND METHODS— We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Associations between
12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed.
RESULTS— One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G>A SNP was significantly
associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669,
the A1C reduction was 0.30% (95% CI −0.51 to −0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045.
CONCLUSIONS— The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity.
These results suggest that the transporter MATE1, encoded by SLC47A1 , may have an important role in the pharmacokinetics of metformin, although replication is necessary.
Footnotes
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 8, 2008.
Received July 29, 2008.
DIABETES
Genetics of Osteoporosis Ralston, Stuart H; Uitterlinden, André G
Endocrine reviews,
2010-October, Letnik:
31, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass, defects in the microarchitecture of bone tissue, and an increased risk of fragility fractures. ...Twin and family studies have shown high heritability of bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover. Osteoporotic fractures also have a heritable component, but this reduces with age as environmental factors such as risk of falling come into play. Susceptibility to osteoporosis is governed by many different genetic variants and their interaction with environmental factors such as diet and exercise. Notable successes in identification of genes that regulate BMD have come from the study of rare Mendelian bone diseases characterized by major abnormalities of bone mass where variants of large effect size are operative. Genome-wide association studies have also identified common genetic variants of small effect size that contribute to regulation of BMD and fracture risk in the general population. In many cases, the loci and genes identified by these studies had not previously been suspected to play a role in bone metabolism. Although there has been extensive progress in identifying the genes and loci that contribute to the regulation of BMD and fracture over the past 15 yr, most of the genetic variants that regulate these phenotypes remain to be discovered.
This review addresses recent developments in understanding the genetic basis of osteoporosis. We discuss the approaches that have been used to identify predisposing genes including association studies, linkage studies, genome wide association studies and studies in model organisms. Detailed discussion of specific candidate genes and loci is also included, focusing on those where robust statistical evidence has been gained to support their role in regulating susceptibility to osteoporosis.
Objective
Cam deformity and acetabular dysplasia have been recognized as relevant risk factors for hip osteoarthritis (OA) in a few prospective studies with limited sample sizes. To date, however, no ...evidence is available from prospective studies regarding whether the magnitude of these associations differs according to sex, body mass index (BMI), and age.
Methods
Participants in the Rotterdam Study cohort including men and women ages 55 years or older without OA at baseline (n = 4,438) and a mean follow‐up of 9.2 years were included in the study. Incident radiographic OA was defined as a Kellgren/Lawrence grade of ≥2 or a total hip replacement at follow‐up. Alpha and center‐edge angles were measured to determine the presence of cam deformity and acetabular dysplasia/pincer deformity, respectively. Odds ratios (ORs) were calculated to assess the associations between both deformities and the development of OA.
Results
Subjects with cam deformity (OR 2.11, 95% confidence interval 95% CI 1.55–2.87) and those with acetabular dysplasia (OR 2.19, 95% CI 1.50–3.21) had a 2‐fold increased risk of developing OA compared with subjects without deformity, while pincer deformity did not increase the risk of OA. Stratification analyses showed that the associations of cam deformity and acetabular dysplasia with OA were driven by younger individuals, whereas BMI did not influence the associations. Female sex appears to modify the risk of hip OA related to acetabular dysplasia.
Conclusion
Individuals with cam deformity and those with acetabular dysplasia are predisposed to OA; these associations were independent of other well‐known risk factors. Interestingly, both deformities predisposed to OA only in relatively young individuals. Therefore, early identification of these conditions is important.
Context:
Genome-wide association studies (GWAS) have revealed new susceptibility loci for Chinese patients with polycystic ovary syndrome (PCOS). Because ethnic background adds to phenotypic ...diversities in PCOS, it seems plausible that genetic variants associated with PCOS act differently in various ethnic populations.
Objective:
We studied cross-ethnic effects of Chinese PCOS loci (ie, LHCGR, THADA, DENND1A, FSHR, c9orf3, YAP1, RAB5B/SUOX, HMGA2, TOX3, INSR, SUMO1P1) in patients of Northern European descent.
Design:
This study was a genetic association study conducted at an University Medical Center.
Patients:
Association was studied in 703 Dutch PCOS patients and 2164 Dutch controls. To assess the cross-ethnic effect, we performed a meta-analysis of the Dutch data combined with results of previously published studies in PCOS patients from China (n = 2254) and the United States (n = 2618). Adjusted for multiple testing, a P value <3.1 × 10−3 was considered statistically significant.
Results:
Meta-analysis of the Chinese, US, and Dutch data resulted in 12 significant variants mapping to the YAP1 (P value = 1.0× 10−9), RAB5B/SUOX (P value = 3.8 × 10−11), LHCGR (P value = 4.1 × 10−4), THADA (P value = 2.2 × 10−4 and P value = 1.3 × 10−3), DENND1A (P value = 2.3 × 10−3 and P value = 2.5 × 10−3), FSHR (P value = 3.8 × 10−5 and P value = 3.6 × 10−4), c9orf3 (P value = 2.0 × 10−6 and P value = 9.2 × 10−6), SUMO1P1 (P value = 2.3 × 10−3) loci with odds ratios ranging from 1.19 to 1.45 and 0.79 to 0.87.
Conclusions:
Overall, we observed for 12 of 17 genetic variants mapping to the Chinese PCOS loci similar effect size and identical direction in PCOS patients from Northern European ancestry, indicating a common genetic risk profile for PCOS across populations. Therefore, it is expected that large GWAS in PCOS patients from Northern European ancestry will partly identify similar loci as the GWAS in Chinese PCOS patients.
Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 ...Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% ±0.9, men: 0.9% ±0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 × 10−27), MC1R (compound heterozygosity score, P=2.3 × 10−24), and RALY/ASIP (rs6059655, P=1.9 × 10−9). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10−8). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10−8) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.
Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut ...microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup, and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.
Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of ...supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial.
Long-term follow-up of B-PROOF trial participants (
= 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00-C97 for all cancers (except C44 for skin cancer), and C18-C20 for colorectal cancer.
Allocation to B vitamins was associated with a higher risk of overall cancer 171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53,
= 0.05. B vitamins were significantly associated with a higher risk of colorectal cancer 43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08-2.90,
= 0.02.
Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer.
Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.
The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), ...and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997-1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications.
Obesity and type 2 diabetes are associated disorders that involve a multiplicity of tissues. Both fasting and physical exercise are known to counteract dyslipidemia/hyperglycemia. Skeletal muscle ...plays a key role in the control of blood glucose levels, and the metabolic changes and related signaling pathways in skeletal muscle induced by fasting overlap with those induced by exercise. The reduction of fat disposal has been shown to extend to the liver and to white and brown adipose tissue and to involve an increase in their metabolic activities. In recent years signal transduction pathways related to exercise and fasting/food withdrawal in muscle have been intensively studied, both in animals and in humans. Combining fasting/food withdrawal with exercise in animals as well as in humans causes changes unlike those seen during fasting/food withdrawal or exercise alone, which favor repair of muscle over autophagy. In addition, compounds that mimic exercise have been studied in combination with exercise or fasting/food withdrawal. This review addresses our current knowledge of the mechanisms that underlie the individual and combined effects of fasting/food withdrawal, endurance or resistance exercise, and their mimetics, in muscle vs. other organs in rodents and humans, and highlights which combinations may improve metabolic disorders.—Jaspers, R. T., Zillikens, M. C., Friesema, E. C. H., delli Paoli, G., Bloch, W., Uitterlinden, A. G., Goglia, F., Lanni, A., de Lange, P. Exercise, fasting, and mimetics: toward beneficial combinations. FASEB J. 31, 14–28 (2017) www.fasebj.org
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