Key haplotypes in <i>MSRA</i> region showing association with MI in TSS cohort.

<p><b>^a</b>Numbers in parentheses indicate physical position on chr8 in base pairs (NCBI Build 36).</p><p><b>^b</b>All observed haplotypes with frequency >1% are shown; bold indicates haplotypes noted in text.</p><p>*Protective haplotypes that reached statistical significance after Bonferroni correction for all 2,890 haplotypes tested (<i>P</i><1.73×10⁻⁵).</p>‡<p>Near significant risk haplotype containing rs614197 (italicized), the SNP that was most highly associated with MI in the initial analysis.</p

Kaplan-Meier survival curves in CF mice according to <i>Msra</i> genotype.

<p>A. CF mice homozygous for a null <i>Cftr</i> allele (<i>Cftr</i>^−/−) and wild-type for <i>Msra</i> show high mortality due to intestinal obstruction around the time of weaning (ca. 21 days; n = 30). In contrast, survival is markedly improved in <i>Cftr</i>^−/− mice lacking one (n = 33) or two <i>Msra</i> alleles (n = 46) compared to wild-type (<i>P</i> = 0.022 and <i>P</i> = 0.0001, respectively; log-rank test). B. CF mice homozygous for a missense <i>Cftr</i> allele (<i>Cftr</i>^R117H/R117H) and wild-type for <i>Msra</i> display a low rate of mortality due to intestinal obstruction around the time of weaning (n = 14). Survival is not affected in <i>Cftr</i>^R117H/R117H mice lacking one (n = 51) or two (n = 51) <i>Msra</i> alleles compared to wild-type.</p

Regional association of SNPs within a region of linkage to MI on chromosome 8p23.1.

<p>The inset plot shows the locus linked to MI on chromosome 8 identified by Blackman, et al <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen.1002580-Blackman1" target="_blank">[12]</a>. The green shaded region under the peak extending from 17.9 cM (8.2 Mb) to 29.0 cM (17.2 Mb), where LOD score >1, indicates the region analyzed in the main plot. The map position of <i>MSRA</i> is denoted by an arrow at ∼20.2 cM. In the main plot, <i>P</i> values are plotted in log scale versus physical location in Mb. The SNP showing the strongest association with MI, rs614197, is represented by a diamond (<i>P</i> = 8.35×10⁻⁶). SNPs surrounding rs614197 are color coded to reflect their LD with this SNP (pair-wise r² using 1000 Genomes CEU, August 2009). The dashed line indicates the threshold for region-wide significance after Bonferroni correction for 2,896 SNPs (P<1.73×10⁻⁵). Genes, exon positions, and direction of transcription are denoted below plot (human genome build 18). Nine genes outside this interval were omitted for display purposes: <i>C8orf12</i>, <i>FAM167A</i>, <i>DEFB136</i>, <i>DEFB135</i>, <i>DEFB134</i>, <i>FAM66D</i>, <i>LOC392196</i>, <i>USP17L2</i>, and <i>FAM86B1</i>. The blue shaded region represents the 2 Mb encompassing rs614197 in which haplotype association was tested (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen.1002580.s001" target="_blank">Figure S1</a>).</p

Patient characteristics.

<p><b>^a</b>Primary analysis included subjects from 133 “MI families” in which at least one sibling had MI.</p><p><b>^b</b><i>CFTR</i> mutation-specific analysis (i.e. p.Gly551Asp vs. p.Phe508del) utilized the entire TSS sample.</p

Haplotype association in <i>MSRA</i> region.

<p>In this schematic, haplotypes comprised of three consecutive SNPs are represented as dots connected by a line. Two overlapping haplotypes localized within intron 3 of <i>MSRA</i> had a statistically significant protective effect on MI (<i>P</i><1.73×10⁻⁵ after Bonferroni correction for 2,890 haplotypes tested in a 2 Mb region): rs10903323 T – rs4840475 G – rs17151637 A and rs4840475 G – rs17151637 A – rs6601427 C. A “risk” haplotype upstream of <i>MSRA</i>, rs586123 G – rs614197 G – rs2055729 C, was just below the threshold for significant association. Linkage disequilibrium patterns (pairwise r²) are displayed below the rs numbers corresponding to each SNP (physical location provided in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen-1002580-t002" target="_blank">Table 2</a>).</p