Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis

Abstract

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.

Study of the effect of DNA polymorphisms in the mannose-binding lectin gene (MBL2) on disease severity in Slovak cystic fibrosis patients

“…However, other studies have substantiated our results that there is no effect of MBL2 variation on colonization or on the age of acquisition (Garred et al 1999;Yarden et al 2004;Collaco et al 2008). McDougal et al (2010) found that MBL2 genotypes corresponding to low levels of MBL2 were associated with earlier P. aeruginosa infection than the genotypes which corresponded to high levels of MBL. In our cohort, A0 patients with bacterial infection had a lower protein level than AA patients, but clinical symptoms and pulmonary function did not reflect these findings.…”

“…One of the first of these was the MBL2 gene, an important mediator component of the innate defence system. Variants in the MBL2 gene showed an association with multiple symptoms of CF in some studies but not in others (McDougal et al 2010).…”

Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients

“…Chronic Pa colonization is age-dependent and the majority of cystic fibrosis patients become colonized over time. Age at onset of Pa colonization is a more useful outcome parameter as earlier age correlates with poor prognosis [6,30,4,7,8,31].…”

“…Finally, we grouped the different genotypes into 2 groups: MBL sufficient (YA/YA, YA/XA, XA/XA, YA/YO) and MBL deficient group (XA/YO and YO/YO) [6][7][8][9].…”

“…MBL2 and MASP2 polymorphisms might predispose to Pa acquisition [4][5][6][7][8][9]. MBL2 and MASP2 are proteins of the third (lectin) pathway of the complement system.…”