The association of mannose-binding lectin 2 polymorphisms with outcome in very low birth weight infants

<div><p>Objectives</p><p>Studies on the influence of mannose-binding lectin (MBL) deficiency on infection susceptibility in preterm infants have yielded controversial results. We investigated the association of genotype-based MBL levels with outcome in very-low-birth weight infants (VLBWI).</p><p>Methods</p><p>We genotyped 3 genetic variants of MBL2 (rs1800450, rs1800451, rs5030737) in 6878 VLBWI. MBL plasma levels were categorized as normal (wild type, A/A), low (heterozygotes, A/O) or undetectable (homozygotes, O/O). Primary outcome was the effect of genotype-based MBL2 levels on blood-culture proven and clinical sepsis during primary stay in hospital. We also evaluated burden of infection within 24 months after discharge.</p><p>Results</p><p>We found no association between MBL levels and sepsis risk in the whole cohort. Infants without measurable MBL levels born between 32 0/7 to 36 6/7 weeks of gestation, however, had a higher rate of Gram-negative sepsis than infants with normal or reduced MBL levels. In a follow-up investigation at 24 months (n = 1070 infants), infants without measurable MBL levels suffered more frequently from stomatitis and urinary tract infection.</p><p>Conclusions</p><p>In a large cohort of VLBWI MBL2 deficiency had no major impact on infection risk unless children were born between 32 0/7 and 36 6/7 weeks of gestation.</p></div

Episodes of herpes stomatitis and bacterial urinary tract infection in the first 24 months of life.

<p>The mean±SD number of episodes of episodes of stomatitis and urinary tract infection (UTI) are based on parents’ responses to the KIGGS questionnaire at 24 months of age. Data are described according to genotype-based MBL levels. Infants without measurable MBL levels had a higher rate of herpes stomatitis as compared to infants with normal MBL levels (p = 0.004) and low MBL levels (p = 0.02) and a higher frequency of bacterial UTI as compared to infants with normal MBL levels (p = 0.03, Mann-Whitney U-test).</p

Clinical characteristics of VLBW cohort according to genotype-based MBL levels.

<p>Clinical characteristics of VLBW cohort according to genotype-based MBL levels.</p

Infection risk according to MBL levels in gestational age group 22 0/7–27 6/7 weeks of gestation.

<p>Infection risk according to MBL levels in gestational age group 22 0/7–27 6/7 weeks of gestation.</p

Episodes of infections in the first 24 months of life according to genotype-based MBL levels.

<p>Episodes of infections in the first 24 months of life according to genotype-based MBL levels.</p

Frequency of MBL2 polymorphisms in the European cohort and number of genotyped infants (PCR + Genome-Wide Association Study).

<p>Frequency of MBL2 polymorphisms in the European cohort and number of genotyped infants (PCR + Genome-Wide Association Study).</p

Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10−204) and 10 loci for sphingolipids (smallest P-value = 3.10×10−57). After a correction for multiple comparisons (P-value<2.2×10−9), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits

Variants significantly associated with circulating sphingolipid levels and proportions.

<p><i>P</i>-value_Corrected: Genome-wide association p-value after adjustment for number of independent vectors; MAF: Minor Allele Frequency.</p><p>*Loci significantly associated to lipid levels after Bonferroni correction.</p>⋈<p>Loci associated to sphingolipids for the first time.</p><p><>\vskip -3\raster="rg1"<>Loci significantly (<i>P</i>-value<2.2×10⁻⁹) associated to within class sphingolipid ratios.</p

Genome-wide association results for 115 phospholipid species.

<p>(A) Genome-wide association results for plasma levels of 115 phospholipid species. (B) Genome-wide association results for within-class proportions of 115 plasma phospholipid species. Manhattan plots show the combined association signals (−log₁₀(<i>P</i>-value)) on the y-axis versus SNPs according to their position in the genome on the x-axis (NCBI build 36). Novel genes are represented in red, while previously known loci are represented in black.</p

Study populations.

<p>Values for age and lipid concentrations are presented as mean (standard deviation).</p