***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: Malnutrition substantially increases susceptibility to Entamoeba histolytica in children . Leptin is a hormone produced by adipocytes that inhibits food intake , influences the immune system , and is suppressed in malnourished children . Therefore we hypothesized that diminished leptin function may increase susceptibility to E. histolytica infection . We prospect ively observed a cohort of children , beginning at preschool age , for infection by the parasite E. histolytica every other day over 9 years and evaluated them for genetic variants in leptin ( LEP ) and the leptin receptor ( LEPR ) . We found increased susceptibility to intestinal infection by this parasite associated with an amino acid substitution in the cytokine receptor homology domain 1 of LEPR . Children carrying the allele for arginine ( 223R ) were nearly 4 times more likely to have an infection compared with those homozygous for the ancestral glutamine allele ( 223Q ) . An association of this allele with amebic liver abscess was also determined in an independent cohort of adult patients . In addition , mice carrying at least 1 copy of the R allele of Lepr were more susceptible to infection and exhibited greater levels of mucosal destruction and intestinal epithelial apoptosis after amebic infection . These findings suggest that leptin signaling is important in mucosal defense against amebiasis and that polymorphisms in the leptin receptor explain differences in susceptibility of children in the Bangladesh cohort to amebiasis Recent animal studies indicate that leptin is involved in the regulation of blood pressure through the leptin receptor . Therefore , 51-yr-old men ( N = 284 ) were selected ; and anthropometric , endocrine , metabolic , and hemodynamic variables were examined in relation to polymorphisms of the leptin receptor gene ( LEPR ) , by restriction fragment length polymorphism technique . Three polymorphisms were examined : Lys109Arg in exon 4 , Gln223Arg in exon 6 , and Lys656Asn in exon 14 . In comparison with Lys109 homozygotes , Arg109 homozygotes ( 9 % ) showed lower body mass index ( BMI ) and abdominal sagittal diameter , as well as lower systolic ( 10.0 mm Hg ) and diastolic ( 7.8 mm Hg ) blood pressure . Additionally , Arg223 homozygotes ( 26.8 % ) showed lower blood pressure ( 7.6/5.7 mm Hg ) than Gln223 homozygotes . These lower blood pressure levels were independent of other variables . No differences were found with the Lys656Asn polymorphism . Measurements of body fat mass correlated with leptin concentration in Lys109 homozygotes and in Lys109 heterozygotes but not in Arg109 homozygotes . Blood pressure correlated with leptin only in men carrying the wild-type allele Lys109 . With both elevated BMI and leptin , Lys109 homozygotes had higher blood pressure than the Arg109 homozygous men ( 12.4/6.9 mm Hg ) . Men with blood pressure  > or = 140/90 mm Hg had , in comparison with normotensive men , increased BMI and leptin levels , and Lys109 homozygotes were significantly more prevalent . These results suggest that leptin is associated with blood pressure regulation in men through the leptin receptor . When BMI and leptin are elevated , increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223 , whereas variants of this receptor seem to protect from hypertension . This might explain why not all obese men are hypertensive CONTEXT Plasma levels of C-reactive protein ( CRP ) are independently associated with risk of coronary heart disease , but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain . OBJECTIVE To investigate association of genetic loci with CRP levels and risk of coronary heart disease . DESIGN , SETTING , AND PARTICIPANTS We first carried out a genome-wide association ( n = 17,967 ) and replication study ( n = 13,615 ) to identify genetic loci associated with plasma CRP concentrations . Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008 . We carried out a mendelian r and omization study of the most closely associated single-nucleotide polymorphism ( SNP ) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls , to investigate the association of CRP variants with coronary heart disease . We compared our finding with that predicted from meta- analysis of observational studies of CRP levels and risk of coronary heart disease . For the other loci associated with CRP levels , we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls . MAIN OUTCOME MEASURE Risk of coronary heart disease . RESULTS Polymorphisms in 5 genetic loci were strongly associated with CRP levels ( % difference per minor allele ) : SNP rs6700896 in LEPR ( -14.8 % ; 95 % confidence interval [ CI ] , -17.6 % to -12.0 % ; P = 6.2 x 10(-22 ) ) , rs4537545 in IL6R ( -11.5 % ; 95 % CI , -14.4 % to -8.5 % ; P = 1.3 x 10(-12 ) ) , rs7553007 in the CRP locus ( -20.7 % ; 95 % CI , -23.4 % to -17.9 % ; P = 1.3 x 10(-38 ) ) , rs1183910 in HNF1A ( -13.8 % ; 95 % CI , -16.6 % to -10.9 % ; P = 1.9 x 10(-18 ) ) , and rs4420638 in APOE-CI-CII ( -21.8 % ; 95 % CI , -25.3 % to -18.1 % ; P = 8.1 x 10(-26 ) ) . Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio ( OR ) of 0.98 ( 95 % CI , 0.94 to 1.01 ) per 20 % lower CRP level . Our mendelian r and omization study of variants in the CRP locus showed no association with coronary heart disease : OR , 1.00 ; 95 % CI , 0.97 to 1.02 ; per 20 % lower CRP level , compared with OR , 0.94 ; 95 % CI , 0.94 to 0.95 ; predicted from meta- analysis of the observational studies of CRP levels and coronary heart disease ( z score , -3.45 ; P < .001 ) . SNPs rs6700896 in LEPR ( OR , 1.06 ; 95 % CI , 1.02 to 1.09 ; per minor allele ) , rs4537545 in IL6R ( OR , 0.94 ; 95 % CI , 0.91 to 0.97 ) , and rs4420638 in the APOE-CI-CII cluster ( OR , 1.16 ; 95 % CI , 1.12 to 1.21 ) were all associated with risk of coronary heart disease . CONCLUSION The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease INTRODUCTION Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course . Leptin ( LEP ) significantly affects metabolism and numerous functions of the organism . To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor ( LEPR ) genes , we analysed the frequencies of the -2548 G/A and + 19 G/A LEP , as well as the K109R , Q223R , and K656N LEPR polymorphisms in centenarians and in control groups . MATERIAL AND METHODS The frequencies of the LEP and LEPR polymorphisms  were tested by restriction fragment length polymorphism in 128 centenarians , 414 young controls ( Y ) , 226 myocardial infa rct ion ( MI ) patients , and 190 type 2 diabetes mellitus ( DM2 ) patients . RESULTS The GG genotype of the -2548 G/A LEP polymorphism  was significantly more common in centenarians than in the Y , MI and DM2 groups ( p = 0.048 , p = 0.003 , p = 0.049 , respectively ) . In addition , the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y , MI , and DM2 groups ( p = 0.026 , p = 0.013 , and p = 0.001 , respectively ) . CONCLUSIONS We suggest that the leptin pathway plays a role in the regulation of longevity , possibly by modulating the risk of development of MI and of DM2 Two leptin receptor single nucleotide polymorphisms , Lys109Arg and Gln223Arg , have been shown to associate with several risk factors for cardiovascular disease . In addition , we have previously shown that Arg109 and Arg223 homozygotes displayed lower intima-media thickness in our well-defined OPERA ( Oulu Project Elucidating Risk of Atherosclerosis ) study . This current research investigated the impact of these LEPR polymorphisms on cardiovascular events and related death as well as to total mortality in the 19-year follow-up of OPERA . Subjects were r and omly selected , middle-aged drug-treated hypertensives and their age- and sex-matched control subjects recruited to the OPERA study between 1990 and 1993 . Mortality and hospital events of 1045 subjects were followed up until 2009 . A total of 151 coronary heart disease ( CHD )  and 211 cardiovascular disease ( CVD ) events or deaths including 58 CHD and 69 CVD deaths occurred . Furthermore , during this follow-up , a total of 165 subjects died . Logistic regression analysis was performed to assess the impact of Lys109Arg and Gln223Arg on the events and death . Further modeling was performed with Cox regression for Lys109Arg . The logistic regression analysis revealed a significant protective impact of Arg109Arg genotype on CHD ( OR 0.433 ; CI 95 % 0.217 - 0.863 ) and CVD ( OR 0.540 ; CI 95 % 0.309 - 0.942 ) events or death as well as on total mortality ( OR 0.390 ; CI 95 % 0.196 - 0.775 ) when adjusted with age , sex and study group . Even after further adjustment with BMI , smoking status , systolic blood pressure and low-density lipoprotein cholesterol , the protective effect of Arg109Arg on CHD events or death and total mortality still remained statistically significant ( OR 0.463 ; CI 95 % 0.230 - 0.931 and OR 0.442 ; CI 95 % 0.218 - 0.896 , respectively ) . Arg109Arg was also shown to confer protection against CHD mortality ( HR 0.224 ; CI95 % 0.055 - 0.919 ) and overall mortality ( HR 0.413 ; CI95 % 0.218 - 0.783 ) also in Cox regression analysis . In conclusion , the Arg109Arg genotype of LEPR seems to be protective from cardiovascular events and death and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis 
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Furthermore , stratified group analysis revealed that the association was more pronounced for stroke .
Race-differences might also cause the considerable heterogeneity and non-significant association .
This is the first systematic review and meta- analysis to investigate the association between LEPR gene variants and CVD risk .
Some LEPR gene variants were significantly associated with the increased risk of CVD .