%0 Journal Article %J J Am Soc Nephrol %D 2004 %T Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. %A Seliger, Stephen L %A Siscovick, David S %A Stehman-Breen, Catherine O %A Gillen, Daniel L %A Fitzpatrick, Annette %A Bleyer, Anthony %A Kuller, Lew H %K Aged %K Alzheimer Disease %K Cardiovascular Diseases %K Creatinine %K Dementia %K Dementia, Vascular %K Female %K Humans %K Kidney %K Kidney Diseases %K Male %K Muscles %K Proportional Hazards Models %X

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

%B J Am Soc Nephrol %V 15 %P 1904-11 %8 2004 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/15213280?dopt=Abstract %R 10.1097/01.asn.0000131529.60019.fa %0 Journal Article %J PLoS Genet %D 2013 %T A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Peters, Ulrike %A North, Kari E %A Sethupathy, Praveen %A Buyske, Steve %A Haessler, Jeff %A Jiao, Shuo %A Fesinmeyer, Megan D %A Jackson, Rebecca D %A Kuller, Lew H %A Rajkovic, Aleksandar %A Lim, Unhee %A Cheng, Iona %A Schumacher, Fred %A Wilkens, Lynne %A Li, Rongling %A Monda, Keri %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Cooper, Richard %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Gu, C Charles %A Houston, Denise %A Bůzková, Petra %A Ritchie, Marylyn %A Matise, Tara C %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Haiman, Christopher A %A Kooperberg, Charles %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alleles %K Body Mass Index %K Chromosome Mapping %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Obesity %K Proteins %X

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

%B PLoS Genet %V 9 %P e1003171 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract %R 10.1371/journal.pgen.1003171