Looking for loci

June 11, 2019 0 By S Harachand

Asthma is a multifactorial disease with a complex genetic inheritance. Collective evidence suggests that genetic factors account for approximately 60–80% of its susceptibility. More than a hundred genetic variations positioned throughout the genome have been implicated in asthma susceptibility.  However, studies could replicate only a subset of these genes. Besides, the exact mechanism of the interaction of these genotypes with the environment is not clearly understood.

The incidence of asthma, which is the highest in childhood, tends to show a bias towards boys. While boys are at a higher risk of asthma in early childhood, girls are more frequently affected after puberty. Hypersensitivity to aeroallergens is the key feature of childhood-onset asthma. Atopic dermatitis and hay fever are closely associated with asthma, constituting what is known as the atopic triad.

Genetic factors determining the age of onset of asthma has been traced to diverse chromosomal loci. Two regions — 5q13 and 1p31 — with a suggestive linkage to time of onset of asthma, have been specifically identified in French families. Also, a region on 7q was found linked to asthma in the same population, but with different risks. The -28G allele of the RANTES promoter region at chromosome 17q increased the risk of late-onset asthma in Japanese individuals

A genome-wide association (GWA) study revealed that the 17q12-21 region (IKZF3-ZPBP2-GSDMB-ORMDL3 region) is predominantly a locus of childhood-onset asthma. Despite these findings, it is not clear whether sex differences in asthma risk at different ages can be explained by genetic factors.

Molecular genetic studies suggest an association of a variant on chromosome 5, situated within the TSLP gene, among patients with severe asthma. Similarly, polymorphisms within the beta2-adrenergic receptor gene, the IL-4 gene and the TGF-ß1 and CD14 genes have been shown to play a role in asthma severity.

Positional cloning identified five asthma genes or gene complexes, including ADAM33, PHF11, DPP10, GRPA and SPlNK5. Though the functions of these genes are largely obscure, the expression of DPP10, GRPA and SPlNK5 in terminally differentiating epithelium suggests that they respond to the external environment.

Many of the genes identified by candidate gene studies, including lL13 that modifies mucous production, FccRl-/J which modifies an allergic trigger on mast cells, and microbial pattern recognition receptors of the innate immune system, may also exert their effects within the cells that make up the mucosa.

There is also evidence of genetic heterogeneity within the clinical expression of asthma. In spite of the high heritability of asthma susceptibility, genetic factors account for only around 35% of the variation in the age at onset and for around 25% of the variation in the overall symptomatic severity of the disease and for even less of the variation in the severity of individual asthma symptoms such as wheezing, shortness of breath, chest tightness and cough, according to studies.