***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: CONTEXT High levels of lipoprotein(a ) are associated with increased risk of myocardial infa rct ion ( MI ) . OBJECTIVE To assess whether genetic data are consistent with this association being causal . DESIGN , SETTING , AND PARTICIPANTS Three studies of white individuals from Copenhagen , Denmark , were used : the Copenhagen City Heart Study ( CCHS ) , a prospect i ve general population study with 16 years of follow-up ( 1991 - 2007 , n = 8637 , 599 MI events ) ; the Copenhagen General Population Study ( CGPS ) , a cross-sectional general population study ( 2003 - 2006 , n = 29 388 , 994 MI events ) ; and the Copenhagen Ischemic Heart Disease Study ( CIHDS ) , a case-control study ( 1991 - 2004 , n = 2461 , 1231 MI events ) . MAIN OUTCOME MEASURES Plasma lipoprotein(a ) levels , lipoprotein(a ) kringle IV type 2 ( KIV-2 ) size polymorphism genotype , and MIs recorded from 1976 through July 2007 for all participants . RESULTS In the CCHS , multivariable-adjusted hazard ratios ( HRs ) for MI for elevated lipoprotein(a ) levels were 1.2 ( 95 % confidence interval [ CI ] , 0.9 - 1.6 ; events/10,000 person-years , 59 ) for levels between the 22nd and 66th percentile , 1.6 ( 95 % CI , 1.1 - 2.2 ; events/10,000 person-years , 75 ) for the 67th to 89th percentile , 1.9 ( 95 % CI , 1.2 - 3.0 ; events/10,000 person-years , 84 ) for the 90th to 95th percentile , and 2.6 ( 95 % CI , 1.6 - 4.1 ; events/10,000 person-years , 108 ) for levels greater than the 95th percentile , respectively , vs levels less than the 22nd percentile ( events/10,000 person-years , 55 ) ( trend P < .001 ) . Numbers of KIV-2 repeats ( sum of repeats on both alleles ) ranged from 6 to 99 and on analysis of variance explained 21 % and 27 % of all variation in plasma lipoprotein(a ) levels in the CCHS and CGPS , respectively . Mean lipoprotein(a ) levels were 56 , 31 , 20 , and 15 mg/dL for the first , second , third , and fourth quartiles of KIV-2 repeats in the CCHS , respectively ( trend P < .001 ) ; corresponding values in the CGPS were 60 , 34 , 22 , and 19 mg/dL ( trend P < .001 ) . In the CCHS , multivariable-adjusted HRs for MI were 1.5 ( 95 % CI , 1.2 - 1.9 ; events/10,000 person-years , 75 ) , 1.3 ( 95 % CI , 1.0 - 1.6 ; events/10,000 person-years , 66 ) , and 1.1 ( 95 % CI , 0.9 - 1.4 ; events/10,000 person-years , 57 ) for individuals in the first , second , and third quartiles , respectively , as compared with individuals in the fourth quartile of KIV-2 repeats ( events/10,000 person-years , 51 ) ( trend P < .001 ) . Corresponding odds ratios were 1.3 ( 95 % CI , 1.1 - 1.5 ) , 1.1 ( 95 % CI , 0.9 - 1.3 ) , and 0.9 ( 95 % CI , 0.8 - 1.1 ) in the CGPS ( trend P = .005 ) , and 1.4 ( 95 % CI , 1.1 - 1.7 ) , 1.2 ( 95 % CI , 1.0 - 1.6 ) , and 1.3 ( 95 % CI , 1.0 - 1.6 ) in the CIHDS ( trend P = .01 ) . Genetically elevated lipoprotein(a ) was associated with an HR of 1.22 ( 95 % CI , 1.09 - 1.37 ) per doubling of lipoprotein(a ) level on instrumental variable analysis , while the corresponding value for plasma lipoprotein(a ) levels on Cox regression was 1.08 ( 95 % CI , 1.03 - 1.12 ) . CONCLUSION These data are consistent with a causal association between elevated lipoprotein(a ) levels and increased risk of MI A size polymorphism ( K IV VNTR ) and largely unknown sequence variation in the apolipoprotein(a ) [ apo(a ) ] gene on chromosome 6q26–q27 together determine most of the extreme variation in apo(a ) glycoprotein expression and  lipoprotein(a )  [ Lp(a ) ] plasma concentration in Caucasians . We have determined Lp(a ) plasma concentrations , the number of kringle IV ( K IV ) repeats in the apo(a ) gene and the expression of the apo(a ) glycoprotein in four ethnic groups ( Khoi San , South African Blacks , Hong Kong Chinese and Caucasians from the Tyrol , total n = 788 ) . The distributions of Lp(a ) concentrations , the frequencies of expressed and non-expressed apo(a ) K IV alleles , and the impact of the size polymorphism on Lp(a ) concentrations were all heterogeneous across population s. In contrast , the effect of the K IV repeat alleles appeared homogeneous . Lp(a ) concentrations were higher in Africans and Chinese than in Caucasians , but this was not explained by differences in K IV repeat allele frequencies among population s. Lp(a ) concentrations were highest in Khoi San , suggesting that high Lp(a ) is an old African trait . When expressed as Spearman rank correlations the impact of the size polymorphism was smallest in African Blacks ( R = −0.386 ) and largest in the Chinese ( R = −0.692 ) . In all four population s , the distribution of non-expressed apo(a ) alleles was non-r and om . Rather they were significantly associated with distinct size alleles and overall positively with high K IV repeat numbers . The negative correlation of K IV repeat length with Lp(a ) concentration was nonlinear in Khoi San and the average apo(a)-size-allele-associated Lp(a ) concentrations were markedly different between all population s. We conclude that besides the apo(a ) size variation , other factors affect Lp(a ) concentrations to different degrees in the study population s. Most likely , this is sequence variation in apo(a ) which is not the same in the different ethnic groups BACKGROUND Experimental studies have suggested both atherogenic and thrombogenic properties of lipoprotein(a ) [ Lp(a ) ] , depending on Lp(a ) plasma concentrations and varying antifibrinolytic capacity of apolipoprotein(a ) [ apo(a ) ] isoforms . Epidemiological studies may contribute to assessment of the relevance of these findings in the general population . METHODS AND RESULTS This study prospect ively investigated the association between Lp(a ) plasma concentrations , apo(a ) phenotypes , and the  5-year progression of carotid atherosclerosis assessed by high-resolution duplex ultrasound in a r and om sample population of 826 individuals . We differentiated early atherogenesis ( incident nonstenotic atherosclerosis ) from advanced ( stenotic ) stages in atherosclerosis that originate mainly from atherothrombotic mechanisms . Lp(a ) plasma concentrations predicted the risk of early atherogenesis in a dose-dependent fashion , with this association being confined to subjects with LDL cholesterol levels above the population median ( 3.3 mmol/L ) . Apo(a ) phenotypes were distributed similarly in subjects with and without early carotid atherosclerosis . In contrast , apo(a ) phenotypes of low molecular weight emerged as one of the strongest risk predictors of advanced stenotic atherosclerosis , especially when associated with high Lp(a ) plasma concentrations ( odds ratio , 6.4 ; 95 % CI , 2.8 to 14 . 9 ) . CONCLUSIONS Lp(a ) is one of the few risk factors capable of promoting both early and advanced stages of atherogenesis . Lp(a ) plasma concentrations predicted the risk of early atherogenesis synergistically with high LDL cholesterol . Low-molecular-weight apo(a ) phenotypes with a putatively high antifibrinolytic capacity in turn emerged as one of the leading risk conditions of advanced stenotic stages of atherosclerosis International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol ( HDL-C ) and elevated triglycerides for patients at moderately high to high coronary heart disease ( CHD ) risk . Combination therapy is often required to achieve multiple lipid treatment goals , and > or = 50 % reduction in low-density lipoprotein cholesterol ( LDL-C ) is needed in some patients to achieve aggressive LDL-C targets . In this context , we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin ( niacin ER ) , a statin plus ezetimibe , and a highly potent statin alone . This was an open-label , multicenter , 12-week study in 292 patients ( 50 % women ) who qualified for drug therapy based on number of CHD risk factors . Patients were r and omized to four parallel arms , titrated from low to moderate or high doses : atorvastatin/niacin ER , rosuvastatin/niacin ER , simvastatin/ezetimibe , or rosuvastatin alone . Baseline mean values were , for LDL-C 197 mg/dL ( 5.1 mmol/L ) , HDL-C 49 mg/dL ( 1.3 mmol/L ) , triglycerides 168 mg/dL ( 1.9 mmol/L ) . There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment . All groups lowered LDL-C by approximately 50 % or more ( range -49 to -57 % ) , achieving mean levels of 82 - 98 mg/dL ( 2.1 - 2.5 mmol/L ) . Changes in non-HDL-C ( range -46 to -55 % ) mirrored those for LDL-C and did not differ among treatment groups . Statin/niacin ER combination regimens also increased HDL-C and large HDL ( HDL2 ) and lowered triglycerides and lipoprotein ( a ) significantly more than other regimens . No drug-related myopathy or hepatotoxicity was observed . In this study , low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD The objective of the present study was to examine the possible associations between low molecular weight ( LMW ) apolipoprotein(a ) ( apo(a ) ) isoforms ( F , B , S1,S2 ) and  coronary heart disease ( CHD ) . We conducted a nested case-control ( prospect i ve ) study of five cohorts of white men : The 1936 cohort ( baseline 1976 , n = 548 ) and four cohorts from MONICA I born in 1923 ( n = 463 ) , 1933 ( n = 491 ) , 1943 ( n = 504 ) and 1953 ( n = 448 ) studied at baseline in 1983 . At follow up in 1991 , 52 subjects had developed a first myocardial infa rct ion and 22 had been hospitalized with angina pectoris . Plasma sample s obtained at baseline were stored frozen until 1993 - 94 , when case sample s ( n = 74 ) were analyzed together with sample s from matched ( disease free ) controls ( n = 190 ) . In a statistical model ( conditional logistic regression ) including all age groups , cholesterol ( or apo B ) level ( P < 0.01 ) , systolic blood pressure ( P = 0.05 ) and smoking ( P = 0.02 ) predicted CHD . In the statistical model Lp(a ) interacted significantly with age ( OR = 5.7 ; 95 % CI : 1.4 - 23.6 ; P = 0.016 ) , and high Lp(a ) ( over 45 mg/dl ) was associated with significantly increased risk in subjects under 60 years ( OR = 3.82 ; 95 % CI : 1.47 - 9.96 ) , but not in older men ( OR = 0.67 ; 95 % CI : 0.235 - 1.89 ) . Therefore , we studied the impact of Lp(a)/apo(a ) and other variables in subjects who had been under 60 years when they became cases . Among the younger subjects the presence of LMW apo(a ) isoforms significantly predicted the development of CHD ( OR = 3.83 ; 95 % CI : 1.18 - 12.4 ) . The increased risk pertained to 
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CONCLUSIONS People with smaller apo(a ) isoforms have an approximately 2-fold higher risk of CHD or ischemic stroke than those with larger proteins .