Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
PLoS Genetics (Impact Factor: 7.53). 10/2010; 6(10):e1001184. DOI: 10.1371/journal.pgen.1001184
Source: PubMed


There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

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    • "PTPN11 plays an important role in a variety of diseases, such as atherosclerosis [21], glioma [22], myeloproliferative neoplasms [23] and gastric cancer [24,25]. Activating PTPN11 mutations have also been detected in acute myeloid leukemia [26], breast cancer [27], colorectal cancer [28], and CAD [29]. However, there is no published study focused on the association between the three SNPs and CAD risk in Han Chinese. "
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    ABSTRACT: Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.
    International Journal of Molecular Sciences 08/2014; 15(8):14058-76. DOI:10.3390/ijms150814058 · 2.86 Impact Factor
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    • "Interestingly, the reported 12q24 locus linkage to cat-specific IgE and total IgE in asthma [30] could offer a possible explanation of the pleiotropic effects of such locus. In fact, the identified 12q24 linkage to multiple disorders including T2D [24], micro- and macrovascular disease [25-27], hypertension [2], body mass index and C-reactive protein [29], dyslipidemia [28], depression [32] and bipolar disorder [31] supports the idea that there could be a common underlying pathogenetic factor triggering the above-mentioned multiple disorders, such as an exaggerated inflammatory response or a deregulated autoimmune response leading to disease status. And this hypothesis fits well with the role of PSMD9 in the proteasome complex 26S processing the antigens for the immune response ( "
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    ABSTRACT: Aims Obesity and obesity-associated phenotypes are linked to the chromosome12q24 locus, the non-insulin-dependent-diabetes 2 (NIDDM2) locus. The gene of proteasome modulator 9 (PSMD9) lies in the NIDDM2 region and is linked to type 2 diabetes (T2D), microvascular and macrovascular complications of T2D. We aimed at studying whether the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3+nt460, IVS3+nt437, and 197G are linked to obesity, overweight status and waist circumference in Italian T2D families. Methods and results We screened 200 Italians T2D siblings/families for PSMD9 variants. Using Merlin software, we performed non-parametric linkage analysis to test for linkage with obesity and overweight condition and variance component analysis to test for linkage with waist circumference in our T2D siblings/families dataset. Our study shows that the PSMD9 SNPs IVS3+nt460, IVS3+nt437, and 197G are in linkage with overweight condition and waist circumference in Italians. The statistical power tests performed via simulations on real data confirm that the results are not due to random chance. Conclusions In summary, the linkage strategy using a homogeneous family/subject dataset can identify a gene contributing to a complex trait. PMSD9 may be at least one of the genes responsible for the linkage to obesity and obesity-associated phenotypes at the locus 12q24 in other populations.
    Cardiovascular Diabetology 01/2013; 12(1):2. DOI:10.1186/1475-2840-12-2 · 4.02 Impact Factor
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    • "A recent study has shown that changes in retinal vascular caliber are linked to the chromosome 12q24 locus in a large Caucasian population [1]. Microcirculation is important in determination of hypertension [1] and retinal vascular changes reflect early microvascular disease and predict cardiovascular events. "
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    ABSTRACT: Chromosome 12q24 was recently associated with hypertension. Proteasome Modulator 9 (PSMD9) lies in the 12q24 locus and is in linkage with MODY3, type 2 diabetes (T2D), microvascular and macrovascular pathology, carpal tunnel syndrome, and hypercholesterolemia in Italian families. Our goal was to determine whether PSMD9 is linked to elevated blood pressure/hypertension in T2D families. We characterized the Italian T2D families' members for presence and/or absence of elevated blood pressure (≥ 130/80) and/or hypertension. The phenotypes were described as unknown in all cases in which the diagnosis was either unclear or the data were not available for the subject studied. We tested in the 200 Italians families for the presence of the linkage of the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3+nt460 A > G, IVS3+nt437 T > C and E197G A > G with elevated blood pressure/hypertension. The non-parametric linkage analysis was performed for this qualitative phenotype by using the Merlin software; the Lod score and correspondent P-value were calculated. Parametric linkage analysis was also performed. For the significant linkage score, 1000 replicates were run to calculate the empirical P-value. The PSMD9 gene SNPs studied are in linkage with elevated blood pressure/hypertension in our Italian families. We conclude that the PSMD9 gene and/or any variant in linkage disequilibrium with the SNPs studied contribute to the linkage to hypertension within our family dataset. This is the first report of PSMD9 linkage to hypertension within the 12q24 locus.
    Cardiovascular Diabetology 08/2011; 10(1):77. DOI:10.1186/1475-2840-10-77 · 4.02 Impact Factor
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