***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Raised C-reactive protein ( CRP ) is a risk factor for type 2 diabetes . According to the Mendelian r and omization method , the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes . Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables . Methods and Findings We genotyped three tagging SNPs ( CRP + 2302 G > A ; CRP + 1444 T > C ; CRP + 4899 T > G ) in the CRP gene and measured  serum CRP  in 5,274 men and women at mean ages 49 and 61 y ( Whitehall II Study ) .  Homeostasis model assessment -insulin resistance ( HOMA-IR ) and hemoglobin A1c ( HbA1c ) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report . Common major haplotypes were strongly associated with serum CRP levels , but unrelated to obesity , blood pressure , and socioeconomic position , which may confound the association between CRP and diabetes risk . Serum CRP was associated with these potential confounding factors . After adjustment for age and sex , baseline serum CRP was associated with incident diabetes ( hazard ratio = 1.39 [ 95 % confidence interval 1.29–1.51 ] , HOMA-IR , and HbA1c , but the associations were considerably attenuated on adjustment for potential confounding factors . In contrast , CRP haplotypes were not associated with HOMA-IR or HbA1c ( p = 0.52–0.92 ) . The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis , with genetic variants as the instrument for serum CRP . Instrumental variables estimates differed from the directly observed associations ( p = 0.007–0.11 ) . Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings ( p = 0.25–0.88 ) . Analyses based on the Wellcome Trust Case Control Consortium ( 1,923 diabetes cases , 2,932 controls ) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations . Conclusions Observed associations between serum CRP and insulin resistance , glycemia , and diabetes are likely to be noncausal . Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP Background C-reactive protein ( CRP ) is associated with immune , cardiometabolic , and psychiatric traits and diseases . Yet it is inconclusive whether these associations are causal . Methods and Findings We performed Mendelian r and omization ( MR ) analyses using two genetic risk scores ( GRSs ) as instrumental variables ( IVs ) . The first GRS consisted of four single nucleotide polymorphisms ( SNPs ) in the CRP gene ( GRSCRP ) , and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest  genome-wide association study ( GWAS ) to date ( GRSGWAS ) . To optimize power , we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes , with up to 123,865 participants per outcome from population s of European ancestry . We performed heterogeneity tests to disentangle the pleiotropic effect of IVs . A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant . An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association , yet to be confirmed . The strengths ( F-statistics ) of the IVs were 31.92–3,761.29 and 82.32–9,403.21 for GRSCRP and GRSGWAS , respectively . CRP GRSGWAS showed a statistically significant protective relationship of a 10 % genetically elevated CRP level with the risk of schizophrenia ( odds ratio [ OR ] 0.86 [ 95 % CI 0.79–0.94 ] ; p < 0.001 ) . We vali date d this finding with individual-level genotype data from the schizophrenia GWAS ( OR 0.96 [ 95 % CI 0.94–0.98 ] ; p < 1.72 × 10−6 ) . Further , we found that a st and ardized CRP polygenic risk score ( CRPPRS ) at p-value thresholds of 1 × 10−4 , 0.001 , 0.01 , 0.05 , and 0.1 using individual-level data also showed a protective effect ( OR < 1.00 ) against schizophrenia ; the first CRPPRS ( built of SNPs with p < 1 × 10−4 ) showed a statistically significant ( p < 2.45 × 10−4 ) protective effect with an OR of 0.97 ( 95 % CI 0.95–0.99 ) . The CRP GRSGWAS showed that a 10 % increase in genetically determined CRP level was significantly associated with coronary artery disease ( OR 0.88 [ 95 % CI 0.84–0.94 ] ; p < 2.4 × 10−5 ) and was nominally associated with the risk of inflammatory bowel disease ( OR 0.85 [ 95 % CI 0.74–0.98 ] ; p < 0.03 ) , Crohn disease ( OR 0.81 [ 95 % CI 0.70–0.94 ] ; p < 0.005 ) , psoriatic arthritis ( OR 1.36 [ 95 % CI 1.00–1.84 ] ; p < 0.049 ) , knee osteoarthritis ( OR 1.17 [ 95 % CI 1.01–1.36 ] ; p < 0.04 ) , and bipolar disorder ( OR 1.21 [ 95 % CI 1.05–1.40 ] ; p < 0.007 ) and with an increase of 0.72 ( 95 % CI 0.11–1.34 ; p < 0.02 ) mm Hg in systolic blood pressure , 0.45 ( 95 % CI 0.06–0.84 ; p < 0.02 ) mm Hg in diastolic blood pressure , 0.01 ml/min/1.73 m2 ( 95 % CI 0.003–0.02 ; p < 0.005 ) in estimated glomerular filtration rate from serum creatinine , 0.01 g/dl ( 95 % CI 0.0004–0.02 ; p < 0.04 ) in serum albumin level , and 0.03 g/dl ( 95 % CI 0.008–0.05 ; p < 0.009 ) in serum protein level . However , after adjustment for heterogeneity , neither GRS showed a significant effect of CRP level ( at p < 0.0016 ) on any of these outcomes , including coronary artery disease , nor on the other 20 complex outcomes studied . Our study has two potential limitations : the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses . Conclusions Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia . We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS — with persistence after correction for heterogeneity — for a causal relationship of elevated CRP levels with psoriatic osteoarthritis , rheumatoid arthritis , knee osteoarthritis , systolic blood pressure , diastolic blood pressure , serum albumin , and bipolar disorder . These associations remain yet to be confirmed . We can not verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study . This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes Summary Background Low circulating concentrations of 25-hydroxyvitamin D ( 25[OH]D ) , a marker of vitamin D status , are associated with an increased risk of type 2 diabetes  , but whether this association is causal remains unclear . We aim ed to estimate the unconfounded , causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian r and omisation approach . Methods Using several data sources from population s of European descent , including type 2 diabetes cases and non-cases , we did a mendelian r and omisation analysis using single nucleotide polymorphisms ( SNPs ) within or near four genes related to 25(OH)D synthesis and metabolism : DHCR7 ( related to vitamin D synthesis ) , CYP2R1 ( hepatic 25-hydroxylation ) , DBP ( also known as GC ; transport ) , and CYP24A1 ( catabolism ) . We assessed each SNP for an association  with circulating 25(OH)D concentration ( 5449 non-cases ; two studies ) , risk of type 2 diabetes ( 28 144 cases , 76 344 non-cases ; five studies ) , and glycaemic traits ( concentrations of fasting glucose , 2-h glucose , fasting insulin , and HbA1c  ; 46 368 non-cases ; study consortium ) . We combined these associations in a likelihood-based mendelian r and omisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits , and compared them with that from a meta- analysis of data from observational studies ( 8492 cases , 89 698 non-cases ; 22 studies ) that assessed the association between 25(OH)D concentration and type 2 diabetes . Findings All four SNPs were associated with 25(OH)D concentrations ( p<10−6 ) . The mendelian r and omisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 ( 95 % CI 0·75–1·36 ; p=0·94 ) per 25·0 nmol/L ( 1 SD ) lower 25(OH)D concentration . The corresponding ( potentially confounded ) relative risk from the meta- analysis of data from observational studies was 1·21 ( 1·16–1·27 ; p=7·3 × 10−19 ) . The mendelian r and omisation-derived estimates for glycaemic traits were not significant ( p>0·25 ) . Interpretation The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal . Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence . These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes . Funding UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme OBJECTIVE The causal nature of associations between circulating triglycerides , insulin resistance , and type 2 diabetes is unclear . We aim ed to use Mendelian r and omization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance . RESEARCH DESIGN AND METHODS We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes ( reflecting glycemia and hepatic insulin resistance ) in 8,271 nondiabetic individuals from four studies . RESULTS Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels ( SD 0.59 [ 95 % CI 0.52–0.65 ] difference between the 20 % of individuals with the most alleles and the 20 % with the fewest alleles ) . There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes ( per weighted allele odds ratio [ OR ] 0.99 [ 95 % CI 0.97–1.01 ] ; P = 0.26 ) . In nondiabetic individuals , there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels ( SD 0.00 per weighted allele [ 95 % CI −0.01 to 0.02 ] ; P = 0.72 ) or increased fasting glucose levels ( 0.00 [ −0.01 to 0.01 ] ; P = 0.88 ) . Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk , fasting glucose , or fasting insulin and , for diabetes , showed a trend toward a protective association ( OR per 1-SD increase in log10 triglycerides : 0.61 [ 95 % CI 0.45–0.83 ] ; P = 0.0 
    Output:
    
Only for one biomarker was there strong observational evidence of association and evidence from genetic association studies that was compatible with an underlying causal association .
In additional search for T2D prediction , we found only half of biomarkers were examined with formal evidence of predictive value for a minority of these biomarkers .
Most biomarkers did not enhance the strength of prediction , but the strongest evidence for prediction was for biomarkers that quantify measures of glycaemia .