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1.  The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts 
BMC Medical Genetics  2009;10:56.
In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants.
Differences in mean body mass index (BMI) and other anthropometric measures including weight, waist circumference, and waist-to-hip ratio were assessed by a general linear model in individuals categorized by INSIG2 rs7566605 genotype. Multivariable logistic regression was used to predict the risk of obesity (BMI ≥ 30 kg/m2).
There was no discernable variation in the frequencies of the three INSIG2 SNP genotypes observed between white, Hispanic, and African-American obese individuals and non-obese study subjects. When the relationship between rs7566605 and BMI considered either as a categorical variable or a continuous variable was examined, no significant association with obesity was found for participants in any of the four study populations or in a combined analysis (p = 0.38) under a recessive genetic model. There was also no association between the INSIG2 polymorphism and the obesity-related quantitative traits except for a reduced waist-to-hip ratio in white ARIC study participants homozygous for the C allele, and an increased waist-to-hip ratio in African-Americans in the ARIC cohort with the same genotype (p = 0.04 and p = 0.01, respectively). An association with waist-to-hip ratio was not seen when the combined study sample was analyzed (p = 0.74).
These results suggest that the INSIG2 rs7566605 variant does not play a major role in determining obesity risk in a racially and ethnically diverse sample of 24,722 individuals from four cohorts.
PMCID: PMC2706232  PMID: 19523229
2.  Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies 
BMC Medical Genetics  2008;9:49.
The Framingham Heart Study (FHS) recently obtained initial results from the first genome-wide association scan for renal traits. The study of 70,987 single nucleotide polymorphisms (SNPs) in 1,010 FHS participants provides a list of SNPs showing the strongest associations with renal traits which need to be verified in independent study samples.
Sixteen SNPs were selected for replication based on the most promising associations with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and serum cystatin C in FHS. These SNPs were genotyped in 15,747 participants of the Atherosclerosis in Communities (ARIC) Study and evaluated for association using multivariable adjusted regression analyses. Primary outcomes in ARIC were CKD and eGFR. Secondary prospective analyses were conducted for association with kidney disease progression using multivariable adjusted Cox proportional hazards regression. The definition of the outcomes, all covariates, and the use of an additive genetic model was consistent with the original analyses in FHS.
The intronic SNP rs6495446 in the gene MTHFS was significantly associated with CKD among white ARIC participants at visit 4: the odds ratio per each C allele was 1.24 (95% CI 1.09–1.41, p = 0.001). Borderline significant associations of rs6495446 were observed with CKD at study visit 1 (p = 0.024), eGFR at study visits 1 (p = 0.073) and 4 (lower mean eGFR per C allele by 0.6 ml/min/1.73 m2, p = 0.043) and kidney disease progression (hazard ratio 1.13 per each C allele, 95% CI 1.00–1.26, p = 0.041). Another SNP, rs3779748 in EYA1, was significantly associated with CKD at ARIC visit 1 (odds ratio per each T allele 1.22, p = 0.01), but only with eGFR and cystatin C in FHS.
This genome-wide association study provides unbiased information implicating MTHFS as a candidate gene for kidney disease. Our findings highlight the importance of replication to identify common SNPs associated with renal traits.
PMCID: PMC2430944  PMID: 18522750
3.  Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLR1) with CAD 
BMC Medical Genetics  2008;9:23.
The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study.
ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD.
In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study.
Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.
PMCID: PMC2322963  PMID: 18384690
4.  Interactions between the adducin 2 gene and antihypertensive drug therapies in determining blood pressure in people with hypertension 
BMC Medical Genetics  2007;8:61.
As part of the NHLBI Family Blood Pressure Program, the Genetic Epidemiology Network of Arteriopathy (GENOA) recruited 575 sibships (n = 1583 individuals) from Rochester, MN who had at least two hypertensive siblings diagnosed before age 60. Linkage analysis identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in 7 positional candidate genes, including adducin 2 (ADD2).
To investigate whether blood pressure (BP) levels in these hypertensives (n = 1133) were influenced by gene-by-drug interactions, we used cross-validation statistical methods (i.e., estimating a model for predicting BP levels in one subgroup and testing it in a different subgroup). These methods greatly reduced the chance of false positive findings.
Eight SNPs in ADD2 were significantly associated with systolic BP in untreated hypertensives (p-value < 0.05). Moreover, we also identified SNPs associated with gene-by-drug interactions on systolic BP in drug-treated hypertensives. The TT genotype at SNP rs1541582 was associated with an average systolic BP of 133 mmHg in the beta-blocker subgroup and 148 mmHg in the diuretic subgroup after adjusting for overall mean differences among drug classes.
Our findings suggest that hypertension candidate gene variation may influence BP responses to specific antihypertensive drug therapies and measurement of genetic variation may assist in identifying subgroups of hypertensive patients who will benefit most from particular antihypertensive drug therapies.
PMCID: PMC2065870  PMID: 17854487
5.  Evidence for a gene influencing heart rate on chromosome 5p13-14 in a meta-analysis of genome-wide scans from the NHLBI Family Blood Pressure Program 
BMC Medical Genetics  2006;7:17.
Elevated resting heart rate has been shown in multiple studies to be a strong predictor of cardiovascular disease. Previous family studies have shown a significant heritable component to heart rate with several groups conducting genomic linkage scans to identify quantitative trait loci.
We performed a genome-wide linkage scan to identify quantitative trait loci influencing resting heart rate among 3,282 Caucasians and 3,989 African-Americans in three independent networks comprising the Family Blood Pressure Program (FBPP) using 368 microsatellite markers. Mean heart rate measurements were used in a regression model including covariates for age, body mass index, pack-years, currently drinking alcohol (yes/no), hypertension status and medication usage to create a standardized residual for each gender/ethnic group within each study network. This residual was used in a nonparametric variance component model to generate a LOD score and a corresponding P value for each ethnic group within each study network. P values from each ethnic group and study network were merged using an adjusted Fisher's combining P values method and the resulting P values were converted to LOD scores. The entire analysis was redone after individuals currently taking beta-blocker medication were removed.
We identified significant evidence of linkage (LOD = 4.62) to chromosome 10 near 142.78 cM in the Caucasian group of HyperGEN. Between race and network groups we identified a LOD score of 1.86 on chromosome 5 (between 39.99 and 45.34 cM) in African-Americans in the GENOA network and the same region produced a LOD score of 1.12 among Caucasians within a different network (HyperGEN). Combining all network and race groups we identified a LOD score of 1.92 (P = 0.0013) on chromosome 5p13-14. We assessed heterogeneity for this locus between networks and ethnic groups and found significant evidence for low heterogeneity (P ≤ 0.05).
We found replication (LOD > 1) between ethnic groups and between study networks with low heterogeneity on chromosome 5p13-14 suggesting that a gene in this region influences resting heart rate.
PMCID: PMC1413518  PMID: 16509988

Results 1-5 (5)