Association of a BMP9 Haplotype with Ossification of the Posterior Longitudinal Ligament (OPLL) in a Chinese Population

<div><p>Direct or <em>ex vivo</em> BMP9 adenoviral gene therapy can induce massive bone formation at the injection sites and clearly promote spinal fusion. A comprehensive analysis of the osteogenic activity indicated that BMP9 was one of the most potent inducers of osteogenic differentiation both in vitro and in vivo among 14 types of human BMPs. However, genetic variations and whether they correlated with OPLL were not considered. We have sequenced the complete BMP9 gene in 450 patients with OPLL and in 550 matched controls. Analyses were performed on single markers and haplotypes. Single marker tests identified 6 SNPs, among which the minor alleles of rs7923671 (T>C; <em>P = 0.0026</em>; OR: 1.33, CI: 1.10–1.60), rs75024165 (C>T, Thr304Met; <em>P<0.001</em>; OR: 1.76, CI: 1.47–2.12) and rs34379100 (A>C; <em>P<0.001</em>; OR: 1.52, CI: 1.27–1.82) were associated with OPLL. Logistic regression analysis showed that the additive model of rs75024165 (TT vs. CT vs. CC; <em>P<0.001</em>; OR: 1.74) and rs34379100 (CC vs. AC vs. AA; <em>P = 0.003</em>; OR: 1.95) retained statistical significance when adjusted for clinical and demographic characteristics. Linkage disequilibrium (LD) analysis identified one 3 kb block of intense LD in BMP9 and one specific haplotype, CTCA (<em>P<0.001</em>; OR: 2.37), that contained the OPLL-associated risk alleles and was a risk factor for OPLL. This haplotype is associated with increased severity of OPLL, as shown by the distribution of ossified vertebrae in patients with OPLL (<em>P = 0.001</em>). In summary, in the Chinese population studied, SNPs in the BMP9 gene appear to contribute to the risk of OPLL in association with certain clinical and demographic characteristics. The severity of OPLL seems to be mediated predominantly by genetic variations in a 3kb BMP9 locus with the specific haplotype CTCA.</p> </div

Clinical and demographic characteristics.

<p><b>Note</b>: The data represent the means±SD. BMI: body mass index, FBG: fasting blood glucose level, BMD: Bone Mineral Density.</p

Analysis of the genotype distribution in BMP9 between the OPLL and control groups.

<p><b>Note:</b> P (χ²) calculated by χ² test of the additive model. P (Logistic) indicates correction for clinical and demographic characteristics and the additive model of each SNP using the binary logistic method (backward). <b>Gender (male)  =  (WALD: 4.10; </b><b><i>P</i></b><b> = </b><b><i>0.043</i></b><b>; OR: 1.32, CI: 1.01–1.73), FBG =  (SCORE: 65.86; </b><b><i>P<0.001</i></b><b>; OR: 5.42, CI: 3.60–8.15), rs7923671, rs75024165 and rs34379100 show statistical significance </b><b><i>(P<0.05).</i></b></p>*<p> = <i>P</i><b><i><</i></b><i>0.05</i>,</p>**<p> = <i>P</i><b><i><</i></b><i>0.01</i>,</p>***<p> = <i>P</i><b><i><</i></b><i>0.001.</i></p

Association between BMP9 Haplotypes and Extent of OPLL related to clinical and demographic characteristics: The upper panel shows Two-dimensional computed tomography (2D-CT) pictures of OPLL severities in cervical spines (C2–7).

<p>Patients A: other haplotypes, Patients B–H: haplotype CTCA. The Table shows ossification severity (B–H) in the CTCA and other haplotype groups related to demographic and clinical characteristics.</p

Haplotypes of the <i>BMP9</i> SNPs in cases and controls.

<p>Note: Haplotype 1 includes the risk alleles of rs75024165 *T and rs34379100 *C (<i>P<0.01</i>).</p>*<p>p-value of haplotype by χ² and Monte Carlo (Number of permutation = 100).</p

Association between CYP1A2 and CYP1B1 Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

<div><p>Background</p><p>The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial.</p><p>Methodology/Principal Findings</p><p>The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis.</p><p>Conclusions/Significance</p><p>In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: <i>I</i>² = 81.3%; heterozygote model: <i>I</i>² = 79.0).</p></div

Begg's funnel plot of the meta-analysis of colorectal cancer risk and CYP1B1 Leu432Val polymorphism (homozygote model and dominant model).

<p>Begg's funnel plot of the meta-analysis of colorectal cancer risk and CYP1B1 Leu432Val polymorphism (homozygote model and dominant model).</p

Results of meta-analysis for CYP1A2 and CYP1B1 polymorphisms on colorectal cancer risk.¹

1<p>All summary ORs were calculated using fixed-effects models. In the case of significant heterogeneity (indicated by *), ORs were calculated using random-effects models.</p>2<p>The results were excluded due to high heterogeneity.</p

Begg's funnel plot of the meta-analysis of colorectal cancer risk and CYP1A2*F polymorphism (homozygote model and dominant model).

<p>Begg's funnel plot of the meta-analysis of colorectal cancer risk and CYP1A2*F polymorphism (homozygote model and dominant model).</p

Study flow chart explaining the selection of the 23 eligible articles included in the meta-analysis.

<p>Study flow chart explaining the selection of the 23 eligible articles included in the meta-analysis.</p