Publications

Systemic carnitine deficiency (SCD) is a rare autosomal recessive disease resulting from defects in the OCTN2 (SLC22A5) gene, which encodes the high-affinity plasma membrane carnitine transporter. Although OCTN2 is fairly well studied in its relationship with SCD, little is known about the carrier frequency of disease-causing alleles of OCTN2, or of more common functional polymorphisms in this gene. To address these issues, we screened for genetic variants in the OCTN2 coding region by direct sequencing of the exons and flanking intronic region of OCTN2 in a large sample (n = 276) of ethnically diverse subjects. In addition, we established lymphoblastoid cell lines from subjects homozygous for either allele of the previously identified promoter region variant, -207G>C. We found eight amino acid sequence variants of OCTN2, of which three (Phe17Leu, Leu144Phe, and Pro549Ser) were polymorphic in at least one ethnic group. When assayed for functional activity by expression in human embryonic kidney 293 cells, using as probes both the endogenous substrate (l-carnitine) and the organic cation tetraethylammonium, three variants showed functional differences from the reference OCTN2 (Phe17Leu, Tyr449Asp, Val481Phe; p < 0.05). Further studies of the Phe17Leu polymorphism showed a reduced V(max) for l-carnitine transport to approximately 50% of the reference OCTN2. Confocal microscopy studies using an OCTN2-GFP fusion protein showed that Phe17Leu had distinct subcellular localization from the reference OCTN2, with diffuse cytoplasmic retention of Phe17Leu, in contrast to reference OCTN2, which localized specifically to the plasma membrane. Lymphoblasts from subjects homozygous for the -207G allele showed increased l-carnitine transport compared with the -207C/C homozygotes (p < 0.05). This study suggests that although loss-of-function mutations in OCTN2 are likely to be rare, common variants of OCTN2 found in healthy populations may contribute to variation in the disposition of carnitine and some clinically used drugs.

BACKGROUND

The relationship between stress and quality of life in adults with asthma has not been well studied. Stress, quantified by negative life events, may be linked to quality of life in asthma through multiple pathways, including increase in disease severity and adverse effects on socioeconomic status (SES).

METHODS

The responses to a self-completed questionnaire assessing negative life events (NLEs) in the previous 12 months (from a 24-item checklist) among 189 adults with asthma from a well-characterised cohort were analysed. The relationship between the number of NLEs reported and asthma-specific quality of life (AQOL) was measured with the Marks instrument. General linear modelling was used to test the conjoint effects of NLEs, SES and disease severity based on the Severity of Asthma Score, a validated acute and chronic disease measure.

RESULTS

Those with annual family incomes < 60,000 dollars reported significantly more NLEs than those with higher incomes (p = 0.03). The number of NLEs did not differ significantly between those with forced expiratory volume in 1 s <80% predicted and those with >80% predicted, nor among those with lower compared with higher Severity of Asthma Score. The frequency of NLEs was associated with poorer (higher numerical score) AQOL (p = 0.002). When studied together in the same model, combinations of income level and asthma severity (greater or lesser Severity of Asthma Score; p < 0.001) and number of NLEs (p = 0.03) were both significantly associated with AQOL.

CONCLUSION

NLEs are associated with quality of life among adults with asthma, especially among those of lower SES. Clinicians should be aware of this relationship, especially in vulnerable patient subsets.