additional information about laboratory methods , study participants , and statistical analysis can be found in the supplementary data .
hs - crp level was assessed in plasma from 750 patients : 540 with a confirmed genetic diagnosis of mody ( 220 hnf1a , 245 gck , 54 hnf4a , and 21 hnf1b ) , 53 patients with type 1 diabetes , and 157 patients with type 2 diabetes .
hs - crp level was assessed in plasma from 750 patients : 540 with a confirmed genetic diagnosis of mody ( 220 hnf1a , 245 gck , 54 hnf4a , and 21 hnf1b ) , 53 patients with type 1 diabetes , and 157 patients with type 2 diabetes .
subjects ( 29/750 ; 10.5% ) had hs - crp results > 10 mg / l ( n = 16 gck - mody , n = 10 type 2 diabetes , and n = 3 hnf4a - mody ) and were considered to have an acute inflammatory response and excluded from further analysis .
plasma hs - crp was significantly lower in hnf1a - mody than type 1 diabetes and type 2 diabetes ( median [ iqr ] 0.3 [ 0.10.6 ] versus 1.1 [ 0.51.85 ] mg / l [ p < 0.001 ] and 1.4 [ 0.63.45 ] mg / l ; p < 0.001 ) , respectively ( fig .
1 ) . boxplot to show serum hs - crp in type 1 diabetes ( n = 53 ) , type 2 diabetes ( n = 157 ) , hnf1a - mody ( n = 220 ) , hnf4a - mody ( n = 54 ) , hnf1b - mody ( n = 21 ) , and gck - mody ( n = 245 ) .
 , outliers ( > 1.5 iqr ) ;  , extreme values ( > 3 iqr ) .
the data exclude all subjects with hs - crp levels > 10 mg / l . for discriminating hnf1a - mody from type 2 diabetes , receiver operating characteristic ( roc )
curve showed good discrimination ( area under the curve [ auc ] 0.84 ) and identified a cutoff hs - crp of 0.75 mg / l with 79% sensitivity and 71% specificity ( supplementary fig .
1 ) . this equates to a positive predictive value ( ppv ) of 2.7% and a negative predictive value ( npv ) of 99.7% , assuming a mody prevalence of 1% ( 7 ) .
hs - crp was less discriminative between hnf1a - mody and type 1 diabetes with a roc auc of 0.78 ( 79% sensitivity and 67% specificity at a cutoff of <
hs - crp was lower in hnf1a - mody ( median [ iqr ] 0.3 [ 0.10.6 ] ) than gck - mody ( 1.45 [ 0.462.88 ] mg / l ; p < 0.001 ) , hnf4a - mody ( 0.6 [ 0.31.8 ] mg / l ; p < 0.001 ) , and hnf1b - mody , although this did not reach statistical significance ( 0.6 [ 0.12.85 ] mg / l ; p = 0.07 ) . to discriminate hnf1a - mody from hnf4a - mody , roc curve analysis identified a cutoff hs - crp < 0.55 mg / l ( auc 0.76 ) achieving a sensitivity of 71% and a specificity of 70% . discriminating hnf1a - mody from all other mody subtypes ( hnf4a- , hnf1b- , gck - mody ) , a cutoff hs - crp < 0.55 mg / l ( auc 0.68 ) achieved 71% sensitivity and 55% specificity .
this relationship persisted when discriminating hnf1a - mody from all types of diabetes ( 71% sensitivity , 69% specificity ) .
plasma hs - crp was significantly lower in hnf1a - mody than type 1 diabetes and type 2 diabetes ( median [ iqr ] 0.3 [ 0.10.6 ] versus 1.1 [ 0.51.85 ] mg / l [ p < 0.001 ] and 1.4 [ 0.63.45 ] mg / l ; p < 0.001 ) , respectively ( fig .
1 ) . boxplot to show serum hs - crp in type 1 diabetes ( n = 53 ) , type 2 diabetes ( n = 157 ) , hnf1a - mody ( n = 220 ) , hnf4a - mody ( n = 54 ) , hnf1b - mody ( n = 21 ) , and gck - mody ( n = 245 ) . box , median and iqr ; whiskers , data range .
 , outliers ( > 1.5 iqr ) ;  , extreme values ( > 3 iqr ) .
the data exclude all subjects with hs - crp levels > 10 mg / l . for discriminating hnf1a - mody from type 2 diabetes , receiver operating characteristic ( roc )
curve showed good discrimination ( area under the curve [ auc ] 0.84 ) and identified a cutoff hs - crp of 0.75 mg / l with 79% sensitivity and 71% specificity ( supplementary fig .
1 ) . this equates to a positive predictive value ( ppv ) of 2.7% and a negative predictive value ( npv ) of 99.7% , assuming a mody prevalence of 1% ( 7 ) .
hs - crp was less discriminative between hnf1a - mody and type 1 diabetes with a roc auc of 0.78 ( 79% sensitivity and 67% specificity at a cutoff of <
hs - crp was lower in hnf1a - mody ( median [ iqr ] 0.3 [ 0.10.6 ] ) than gck - mody ( 1.45 [ 0.462.88 ] mg / l ; p < 0.001 ) , hnf4a - mody ( 0.6 [ 0.31.8 ] mg / l ; p < 0.001 ) , and hnf1b - mody , although this did not reach statistical significance ( 0.6 [ 0.12.85 ] mg / l ; p = 0.07 ) . to discriminate hnf1a - mody from hnf4a - mody , roc curve analysis identified a cutoff hs - crp < 0.55 mg / l ( auc 0.76 ) achieving a sensitivity of 71% and a specificity of 70% . discriminating hnf1a - mody from all other mody subtypes ( hnf4a- , hnf1b- , gck - mody ) , a cutoff hs - crp < 0.55 mg / l ( auc 0.68 ) achieved 71% sensitivity and 55% specificity .
this relationship persisted when discriminating hnf1a - mody from all types of diabetes ( 71% sensitivity , 69% specificity ) .
we have confirmed in a large cohort of patients that plasma hs - crp levels are lower in hnf1a - mody than type 2 diabetes , type 1 diabetes , and gck - mody ( 5 ) .
we have shown for the first time that low hs - crp levels are not seen in mody because of mutations in other related transcription factors ( hnf4a , hnf1b ) .
the best discrimination achieved with hs - crp is between hnf1a - mody and type 2 diabetes ( 79% sensitivity , 70% specificity ) .
however , because mody is rare ( 1% of all diabetes ) compared with type 2 diabetes , this equates to a modest ppvof only 2.7% .
therefore , if hs - crp was used as a marker for identifying hnf1a - mody ( hs - crp < 0.75 mg / l ) in isolation the false - positive rate and number of unnecessary genetic testing would be high ( 37 to 1 ) , suggesting that hs - crp should be used in combination with other clinical characteristics .
mg / l ) , gives an npv of 99.7% and therefore is good at ruling out hnf1a - mody .
unlike type 1 diabetes where robust biomarkers , including pancreatic autoantibodies and persistent c - peptide production ( 1,8 ) , already exist , few biomarkers currently distinguish type 2 diabetes from mody .
hs - crp was only reduced in hnf1a - mody patients and not in the other genetic subtypes of mody .
this result may have been predicted since the hs - crp gene has hnf1a binding sites in its promoter ( 9 ) .
this may prove to be useful as a tool to help prioritize the order of gene testing in patients with a high clinical suspicion of mody . an hs - crp level < 0.55 mg / l should suggest hnf1a sequencing first , and levels > 0.55 mg / l may warrant consideration of the other subtypes of mody . this result may prove to be helpful as an adjunct to identify hnf4a - mody patients , who are phenotypically similar to hnf1a - mody .
current crp assays , used to identify inflammation , measure down to levels of 0.20.3 mg / l and , therefore , a specific hs - crp assay may not be necessary
. it would be important to determine the comparability between routine crp and hs - crp assays before testing .
a limitation of crp is that it will be raised in inflammatory states , reducing its potential use as a discriminative tool .
in addition , certain medications reduce crp levels , such as statins ( 10 ) , aspirin ( 11 ) , and -blockers ( 12 ) , which are believed in some cases to reduce crp by 2030%
. we did not have drug history available on individual patients , so we were unable to assess the impact of pharmacological agents on our results ; however , owen et al .
( 5 ) showed that removing subjects on statins and/or aspirin in their study did not alter their results . in conclusion , we have confirmed that hs - crp levels are lower in patients with hnf1a - mody than other types of mody , type 1 diabetes , and type 2 diabetes .
hs - crp is potentially a cheap , widely available biomarker that might aid in the cost - effective identification of patients with hnf1a - mody .
 objectivematurity - onset diabetes of the young ( mody ) as a result of mutations in hepatocyte nuclear factor 1- ( hnf1a ) is often misdiagnosed as type 1 diabetes or type 2 diabetes . 
 recent work has shown that high - sensitivity c - reactive protein ( hs - crp ) levels are lower in hnf1a - mody than type 1 diabetes , type 2 diabetes , or glucokinase ( gck)-mody . 
 we aim to replicate these findings in larger numbers and other mody subtypes.research design and methodshs - crp levels were assessed in 750 patients ( 220 hnf1a , 245 gck , 54 hnf4- [ hnf4a ] , 21 hnf1- ( hnf1b ) , 53 type 1 diabetes , and 157 type 2 diabetes).resultshs - crp was lower in hnf1a - mody ( median [ iqr ] 0.3 [ 0.10.6 ] mg / l ) than type 2 diabetes ( 1.40 [ 0.603.45 ] mg / l ; p < 0.001 ) and type 1 diabetes ( 1.10 [ 0.501.85 ] mg 
 / l ; p < 0.001 ) , hnf4a - mody ( 1.45 [ 0.462.88 ] mg / l ; p < 0.001 ) , gck - mody ( 0.60 [ 0.301.80 ] mg / l ; p < 0.001 ) , and hnf1b - mody ( 0.60 [ 0.102.8 ] mg / l ; p = 0.07 ) . 
 hs - crp discriminated hnf1a - mody from type 2 diabetes with hs - crp < 0.75 mg / l showing 79% sensitivity and 70% specificity ( receiver operating characteristic area under the curve = 0.84).conclusionshs - crp levels are lower in hnf1a - mody than other forms of diabetes and may be used as a biomarker to select patients for diagnostic hnf1a genetic testing . 
RESEARCH DESIGN AND METHODS
Study participants
RESULTS
HNF1A-MODY versus type 2 diabetes and type 1 diabetes
HNF1A-MODY versus other MODY subtypes
CONCLUSIONS
Supplementary Material