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Comparative Study
. 2014 Apr;233(2):666-672.
doi: 10.1016/j.atherosclerosis.2014.01.035. Epub 2014 Jan 30.

RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women's Interagency HIV Study (WIHS)

Aditi Shendre  1 , Marguerite R Irvin  1 , Bradley E Aouizerat  2 , Howard W Wiener  1 , Ana I Vazquez  3 , Kathryn Anastos  4 , Jason Lazar  5 , Chenglong Liu  6 , Roksana Karim  7 , Nita A Limdi  8 , Mardge H Cohen  9 , Elizabeth T Golub  10 , Degui Zhi  3 , Robert C Kaplan  4 , Sadeep Shrestha  11
Affiliations
Comparative Study

RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women's Interagency HIV Study (WIHS)

Aditi Shendre et al. Atherosclerosis. 2014 Apr.

Abstract

Background: Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women's Interagency HIV Study (WIHS).

Methods: CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel's method and haplotype association analyses were conducted among the three races separately.

Results: SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41×10(-5)), rs11856930 among Whites (p=5.62×10(-4)), and rs2572204 among Blacks (p=2.45×10(-3)). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics.

Discussion: Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.

Keywords: CCA; HIV infection; RYR3; Single nucleotide polymorphisms; Subclinical atherosclerosis; cIMT.

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Conflict of interest statement

Potential conflict of Interest: None of the authors have any commercial or other association that poses any conflict of interest.

Figures

Figure 1
Figure 1
Locus-specific (−log10(p-value)) regional association plots for CCA cIMT in the RYR3 gene region (bottom) spanning 33603163 to 34158303 base pairs (bp) and ~20 kb flanking region in chromosome 15 (NCBI build 37, hg19) among HIV-infected women in WIHS. The circle in purple indicates the most strongly associated signal. Estimated recombination rates are plotted in light blue graphical lines (labeled in right y-axis) to reflect the local LD structure from the HapMap population. The spectrum of colors indicates LD of each SNP with the most strongly associated signal (r2 values from HapMap where bright red indicates highly correlated, dark blue indicates weakly correlated and grey indicates missing r2 values). The regional association plots of a) race/ethnicity adjusted analysis, b) Whites, c) Blacks, d) Hispanics and e) meta-analysis.
Figure 1
Figure 1
Locus-specific (−log10(p-value)) regional association plots for CCA cIMT in the RYR3 gene region (bottom) spanning 33603163 to 34158303 base pairs (bp) and ~20 kb flanking region in chromosome 15 (NCBI build 37, hg19) among HIV-infected women in WIHS. The circle in purple indicates the most strongly associated signal. Estimated recombination rates are plotted in light blue graphical lines (labeled in right y-axis) to reflect the local LD structure from the HapMap population. The spectrum of colors indicates LD of each SNP with the most strongly associated signal (r2 values from HapMap where bright red indicates highly correlated, dark blue indicates weakly correlated and grey indicates missing r2 values). The regional association plots of a) race/ethnicity adjusted analysis, b) Whites, c) Blacks, d) Hispanics and e) meta-analysis.
Figure 1
Figure 1
Locus-specific (−log10(p-value)) regional association plots for CCA cIMT in the RYR3 gene region (bottom) spanning 33603163 to 34158303 base pairs (bp) and ~20 kb flanking region in chromosome 15 (NCBI build 37, hg19) among HIV-infected women in WIHS. The circle in purple indicates the most strongly associated signal. Estimated recombination rates are plotted in light blue graphical lines (labeled in right y-axis) to reflect the local LD structure from the HapMap population. The spectrum of colors indicates LD of each SNP with the most strongly associated signal (r2 values from HapMap where bright red indicates highly correlated, dark blue indicates weakly correlated and grey indicates missing r2 values). The regional association plots of a) race/ethnicity adjusted analysis, b) Whites, c) Blacks, d) Hispanics and e) meta-analysis.
Figure 1
Figure 1
Locus-specific (−log10(p-value)) regional association plots for CCA cIMT in the RYR3 gene region (bottom) spanning 33603163 to 34158303 base pairs (bp) and ~20 kb flanking region in chromosome 15 (NCBI build 37, hg19) among HIV-infected women in WIHS. The circle in purple indicates the most strongly associated signal. Estimated recombination rates are plotted in light blue graphical lines (labeled in right y-axis) to reflect the local LD structure from the HapMap population. The spectrum of colors indicates LD of each SNP with the most strongly associated signal (r2 values from HapMap where bright red indicates highly correlated, dark blue indicates weakly correlated and grey indicates missing r2 values). The regional association plots of a) race/ethnicity adjusted analysis, b) Whites, c) Blacks, d) Hispanics and e) meta-analysis.
Figure 1
Figure 1
Locus-specific (−log10(p-value)) regional association plots for CCA cIMT in the RYR3 gene region (bottom) spanning 33603163 to 34158303 base pairs (bp) and ~20 kb flanking region in chromosome 15 (NCBI build 37, hg19) among HIV-infected women in WIHS. The circle in purple indicates the most strongly associated signal. Estimated recombination rates are plotted in light blue graphical lines (labeled in right y-axis) to reflect the local LD structure from the HapMap population. The spectrum of colors indicates LD of each SNP with the most strongly associated signal (r2 values from HapMap where bright red indicates highly correlated, dark blue indicates weakly correlated and grey indicates missing r2 values). The regional association plots of a) race/ethnicity adjusted analysis, b) Whites, c) Blacks, d) Hispanics and e) meta-analysis.
Figure 2
Figure 2
Haploblocks and haplotype analysis of the RYR3 gene region in Whites, Blacks, and Hispanics. Haploblocks were defined using Gabriel’s LD method [40]. The figure shows a) all haploblocks and degree of statistical significance of omnibus haplotype association (−log (pvalues) ranging from least significant (0) in blue to most significant (5.74) in red). The haploblock region that is indicated within a rectangle seems to be associated in all three races; b) haploblocks and haplotype analysis in the region of rs2229116 and rs7177922; c) haploblocks and haplotype analysis in the region of rs2291734; and d) haploblocks and haplotype analysis in the region of rs2278309.
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