Multipoint LOD scores (a, b) and information content (%) (c, d) for the MS and the SNPs chromosome 3 (a, c) and chromosome 5 (b, d) regions for the affected-only strategy (MLB-binary) and the affected and unaffected strategy (MLB-categorical)

<p><b>Copyright information:</b></p><p>Taken from "Inclusion of unaffected sibs increases power in model-free linkage analysis of a behavioral trait"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S22-S22.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866764.</p><p></p> The vertical lines on the x-axes of 1 c and 1 d are for the MS (black) and SNPs (gray) marker position. LOD and information content are provided at positions corresponding to MS and SNPs

Association of <i>CORIN</i> rs2271036 and rs2271037 single nucleotide polymorphisms (SNPs) with preeclampsia (PE).

<p>Results are given in the discovery (S1), replication (S2) and combined (C) samples, in Caucasian subjects from Europe (Eur), Maghreb (Mgh) or Sub-Saharan-African subjects (Afr).</p><p><b>*</b>Genotypes are expressed as percentage (number) of patients with TT/TC/CC genotype for rs2271036 and as TT/TG/GG genotype for rs2271037, respectively.</p>†<p>ORs (95% IC, p values) calculated in a dominant model, adjusted for nulliparity and obesity, associated with the (CC+CT) versus the TT genotype (rs2271036) or with the (GG+GT) versus the TT genotype (rs2271037). MAF, minor allele frequency.</p>‡<p>Significantly different when compared to the control group (chi-square test adjusted for nulliparity and obesity).</p><p>Association of <i>CORIN</i> rs2271036 and rs2271037 single nucleotide polymorphisms (SNPs) with preeclampsia (PE).</p

Flow chart for the enrollment of the study population and the SNP analysis.

<p>Flow chart for the enrollment of the study population and the SNP analysis.</p

Quality control for the 19 <i>CORIN</i> single nucleotide polymorphisms (SNPs) found in the discovery sample (sample 1, n = 260).

<p>For each SNP, position on chromosome 4, minor allele frequencies (MAF) in both ethnic groups of subjects and results of testing for departure from Hardy Weinberg equilibrium (<i>p</i> (HWE)). Both SNPs of interest (rs2271036 and rs2271037) are in bold. SNPs with MAF below 1% in Caucasians are in italics.</p><p>del, deletion.</p><p>*Caucasian from Europe or Maghreb.</p>†<p>Sub-Saharan African patients.</p>‡<p>Genotypic association with preeclampsia in a dominant model: conditional logistic regression analysis adjusted for nulliparity and obesity.</p><p>Quality control for the 19 <i>CORIN</i> single nucleotide polymorphisms (SNPs) found in the discovery sample (sample 1, n = 260).</p

Family based sample and study design.

<p>Two sets of families were employed: those with T1R-affected offspring and those with leprosy but T1R-free offspring. The T1R-affected subset comprised 229 offspring belonging to 221 families while the T1R-free subset comprised 229 offspring in 209 families. Offspring were matched by clinical leprosy subtype in the two family sets. In a first analysis stage, the transmission disequilibrium test (TDT) was used to estimate significance of association of <i>LRRK2</i> variants with disease in each subset. In a second stage, a formal heterogeneity test was performed to identify <i>LRRK2</i> variants preferentially associated with T1R.</p

Multivariate analysis of <i>LRRK2</i> variants with T1R

<p>Multivariate analysis of <i>LRRK2</i> variants with T1R</p

Proposed mechanism for LRRK2 in T1R.

<p>The LRRK2 M2397T amino acid substitution affects protein turnover. The methionine variant of LRRK2 displays a half-life of approximately 8 hours while the half-life of the threonine variant is 18 hours [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref034" target="_blank">34</a>]. LRRK2 arrests the NFAT transcription factor in the cytoplasm through a complex mechanism mediated by Ca²⁺ [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref036" target="_blank">36</a>]. This prevents NFAT to migrate to the nucleus and trigger the expression of pro-inflammatory cytokines [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref035" target="_blank">35</a>]. The M2397 allele is in tight linkage disequilibrium with alleles of SNPs that promote an increase in <i>LRRK2</i> expression creating a compensatory mechanism to counterbalance the shorter LRRK2-M2397 half-life. This compensatory mechanism is abrogated in the presence of <i>M</i>. <i>leprae</i> antigen. Hence, the effect of the M2397T amino acid substitution is most pronounced in the presence of <i>M</i>. <i>leprae</i> antigen.</p

LRRK2 variants preferentially associated with T1R.

<p>LRRK2 variants preferentially associated with T1R.</p

Host versus pathogen control of <i>LRRK2</i> expression levels.

<p><i>LRRK2</i> expression levels for 53 unrelated subjects are indicated on the y-axis and stratified according to rs2404580 genotypes on the x-axis. The left panel represents baseline expression while the right panel indicates gene expression levels following stimulation with <i>M</i>. <i>leprae</i> antigen.</p

Haplotype analysis of independent signal of association with T1R.

<p>Haplotype analysis of independent signal of association with T1R.</p