A Crucial Genetic Factor for Peanut Allergy (HLA)

The HLA System

The human leukocyte antigen (HLA) system is a group of human genes encoding HLA proteins. These proteins are also referred to as major histocompatibility complex (MHC) proteins. HLAs are receptors, found on the surface of white blood cells. They help flag and remove agents that may harm the body or cause infection. These harmful agents are known as antigens [R].

The HLA system has three classes; HLA-DQ and -DR belong to class II. HLA-DQ and -DR receptors can present antigens to T-helper cells, which causes these cells to be activated. Upon activation, T-helper cells stimulate B cells. B cells, in turn, make antibodies  that target specific antigens for removal [R].

For those willing to dive deeper into the immunological background, here’s a great chart published by Medscape: 

Peanut Allergy

Over the last few decades, the incidence of food allergies has steeply increased, and has become a major public health concern. Food allergies strain healthcare from both medical and financial perspectives [R, R].

Peanut allergy is one of the most common food allergies, affecting 1-3% of infants worldwide. Unlike other types of food allergies, peanut allergy usually lasts for the duration of one’s life and often results in severe, life-threatening reactions. The main risk factors for the development of peanut allergy include [R, R, R]:

• Family history of peanut allergy
• Atopy (allergic tendency)
• Peanut consumption during pregnancy
• Specific oils used to fry and roast peanuts

Genes account for up to 80% of susceptibility to peanut allergy [R].

Peanut allergy is one of the most common and dangerous food allergies with a strong genetic background.

The Role of HLA Genes

HLA genes come in many different forms, and there are millions of possible HLA combinations. Their diversity ensures protection against a wide array of external threats. Still, it can be a double-edged sword, as HLA variants correlate with different allergies & autoimmune disorders [R].

Tiny changes in their structure can make HLA receptors mistakenly flag our own proteins (autoimmunity) or food components (allergies), and trigger an inflammatory reaction [R, R].

In particular, HLA-DR and -DQ receptors have well-known roles in allergic reactions. Due to specific gene variants, they may present peanut proteins to T-helper cells, recognizing them as threats. This leads to the production of peanut-specific IgE antibodies [R, R].

Genetic variations can cause HLA receptors to mistakenly flag peanut and other food components as dangerous and trigger an inflammatory reaction.

Despite the well-known role of the HLA system in peanut allergy, earlier studies have failed to confirm this link with HLA gene variants [R, R].

A pivotal 2015 study included over 2,000 subjects and identified a robust association between two HLA variants and peanut allergy [R]:

• rs7192 (HLA-DRA): the “T” allele correlated with 70% higher odds of peanut allergy
• rs9275596 (HLA-DQ): the “C” allele correlated with 70% higher odds of peanut allergy

Accounting for approximately 20% of susceptibility, these SNPs are likely the most significant genetic factors behind peanut allergy. However, their impact may be limited to European descendants [R].

A team of Canadian authors conducted a trial of 1,776 people and included it into a meta-analysis, along with six more trials. They confirmed a robust association between the HLA region and peanut allergy. Most SNPs were inherited together with rs7192 or rs9275596, so rs7192 and rs9275596 likely present with the same genetic risk factor for peanut allergy [R].

HLA-DQ and -DR variants correlate with different autoimmune disorders, confirming the shared genetic background between allergies and autoimmunity [R, R].

Two HLA SNPs—rs7192 and rs9275596—may present as the primary genetic risk factors of peanut allergy in people of European ancestry.

How It Works

The rs7192 variant changes one amino acid in the HLA-DRA receptor and likely increases gene expression. As discussed, altered HLA structures can bind otherwise benign components, such as peanut proteins [R].

Both discussed SNPs could change gene expression and receptor binding by influencing DNA methylation, a well-established mechanism in allergies and autoimmunity [R, R, R].

MTHFR is another gene that connects methylation with allergies and asthma.

SNP Summary and Table

Primary SNPs:

HLA-DRA rs7192

• ‘G’ = not associated with peanut allergy
• ‘T’ = associated with higher rates of peanut allergy

Population Frequency: Around 44% of people worldwide carry one copy and 12% carry both copies of the “T” allele. Its frequency doesn’t vary a lot between populations.

HLA-DQ rs9275596

• ‘T’ = not associated with peanut allergy
• ‘C’ = associated with higher rates of peanut allergy

Population Frequency: Around 39% of European descendants carry one copy and 12% carry both copies of the “C” allele. It’s less common in East Asian (25%) and South Asian (34%) populations.