ABSTRACT
BACKGROUND: Arsenic (III) methyltransferase (AS3MT) has been related to urine arsenic metabolites in association studies. Other genes might also play roles in arsenic metabolism and excretion. OBJECTIVE: We evaluated genetic determinants of urine arsenic metabolites in American Indian adults from the Strong Heart Study (SHS). METHODS: We evaluated heritability of urine arsenic metabolites [percent inorganic arsenic (%iAs), percent monomethylarsonate (%MMA), and percent dimethylarsinate (%DMA)] in 2,907 SHS participants with urine arsenic measurements and at least one relative within the cohort. We conducted a preliminary linkage analysis in a subset of 487 participants with available genotypes on approximately 400 short tandem repeat markers using a general pedigree variance component approach for localizing quantitative trait loci (QTL). RESULTS: The medians (interquartile ranges) for %iAs, %MMA, and %DMA were 7.7% (5.4-10.7%), 13.6% (10.5-17.1%), and 78.4% (72.5-83.1%), respectively. The estimated heritability was 53% for %iAs, 50% for %MMA, and 59% for %DMA. After adjustment for sex, age, smoking, body mass index, alcohol consumption, region, and total urine arsenic concentrations, LOD [logarithm (to the base of 10) of the odds] scores indicated suggestive evidence for genetic linkage with QTLs influencing urine arsenic metabolites on chromosomes 5 (LOD = 2.03 for %iAs), 9 (LOD = 2.05 for %iAs and 2.10 for %MMA), and 11 (LOD = 1.94 for %iAs). A peak for %DMA on chromosome 10 within 2 Mb of AS3MT had an LOD of 1.80. CONCLUSIONS: This population-based family study in American Indian communities supports a genetic contribution to variation in the distribution of arsenic metabolites in urine and, potentially, the involvement of genes other than AS3MT.
Subject(s)
Arsenic/urine , Genetic Linkage , Genome-Wide Association Study , Aged , Female , Humans , Life Style , Male , Middle AgedABSTRACT
OBJECTIVE: Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and IMT by examining the association of a genetic risk score with IMT. RESEARCH DESIGN AND METHODS: The sample was drawn from the Atherosclerosis Risk in Communities (ARIC) study and included 7,260 nondiabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose genome-wide association study in ARIC. The score was created by combining five single nucleotide polymorphisms (SNPs) (rs780094 [GCKR], rs560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SNP by its strength of association with fasting glucose. IMT was measured through bilateral carotid ultrasound. Mean IMT was regressed on the FGGRS and on the component SNPs, individually. RESULTS: The FGGRS was significantly associated (P = 0.009) with mean IMT. The difference in IMT predicted by a 1 SD increment in the FGGRS (0.0048 mm) was not clinically relevant but was larger than would have been predicted based on observed associations between the FFGRS, fasting glucose, and IMT. Additional adjustment for baseline measured glucose in regression models attenuated the association by about one third. CONCLUSIONS: The significant association of the FGGRS with IMT suggests a possible causal association of elevated fasting glucose with atherosclerosis, although it may be that these loci influence IMT through nonglucose pathways.
Subject(s)
Atherosclerosis/epidemiology , Atherosclerosis/genetics , Blood Glucose/metabolism , Fasting/physiology , Polymorphism, Single Nucleotide , Risk Assessment , Black People/genetics , Carotid Arteries/diagnostic imaging , Carotid Arteries/pathology , Female , Genome-Wide Association Study , Genotype , Humans , Hyperglycemia/complications , Male , Middle Aged , Patient Selection , Phenotype , Tunica Intima/diagnostic imaging , Tunica Intima/pathology , Tunica Media/diagnostic imaging , Tunica Media/pathology , Ultrasonography , White People/geneticsABSTRACT
PURPOSE OF REVIEW: To provide a brief review of methods used in genetic epidemiology studies, an update of recent significant findings in genome-wide studies of kidney disease, and a discussion of the clinical implications of these findings. RECENT FINDINGS: Recent developments in genetic epidemiology methodologies, specifically the use of genome-wide panels of single nucleotide polymporphisms (SNPs) for association analyses, have yielded exciting insights into the underlying pathogenesis of chronic kidney disease and its progression. The two most notable and promising genetic discoveries are those of MYH9 and UMOD, both of which have been replicated in separate populations. SUMMARY: Genomic studies have the potential to yield exciting new areas of biological research, potential targets for treatment, and ultimately markers of disease risk. This review addresses recent genetic studies and their implications in chronic kidney disease care.
