How a genome-wide linkage screen revealed a major susceptibility locus for systolic blood pressure in Mexican-Americans
Imagine two individuals with similar lifestyles, diets, and exercise routines—yet one develops high blood pressure in their forties while the other maintains healthy levels well into old age. This common scenario represents a mystery that has long puzzled both patients and physicians. What hidden factors could account for such dramatic differences in health outcomes? The answer may lie not in our environment alone, but deep within our genetic blueprint.
For decades, scientists have understood that blood pressure is influenced by both environmental factors and genetic inheritance, but the specific genetic components have remained elusive. Now, groundbreaking research from the Veterans Administration Genetic Epidemiology Study (VAGES) has identified a major susceptibility locus on chromosome 6q14.1 that significantly influences systolic blood pressure in Mexican-Americans—a discovery with profound implications for our understanding of cardiovascular health across all populations 1 .
Before we delve into this fascinating discovery, let's establish some key concepts that will help us appreciate its significance.
The proportion of observable differences in a trait between individuals that can be attributed to genetic differences.
A method to pinpoint chromosomal regions likely to contain genes that influence a particular trait.
Specific locations on chromosomes that correlate with variation in a measurable trait.
A statistical estimate of whether genes are linked. A score of 3+ indicates strong evidence.
The Veterans Administration Genetic Epidemiology Study (VAGES) represents a significant undertaking in genetic research. The study focused on 1,089 individuals distributed across 266 families of Mexican-American descent 1 . This population-specific approach is particularly valuable in genetic research, as studying relatively homogeneous groups can make it easier to detect genetic signals that might be obscured in more diverse populations.
Mexico has a rich genetic history characterized by a blend of Indigenous American and European ancestry, creating a unique genetic profile that can offer unique insights into disease susceptibility. By focusing on this population, researchers weren't excluding other groups—they were creating conditions that might reveal genetic factors relevant to all humans.
Individuals Studied
One particular challenge in blood pressure research is accounting for the effects of antihypertensive medications. When participants are taking blood pressure drugs, their measured values don't reflect their "natural" genetic predisposition. The VAGES researchers employed two sophisticated approaches to address this problem:
Added standard constants (15 mm Hg for systolic and 10 mm Hg for diastolic pressure) to the observed values of treated participants
Used threshold values (140/90 mm Hg) for treated participants whose medicated values fell below these standard hypertension thresholds
Primary Model
Secondary Model
After analyzing the genetic data, the researchers made a remarkable discovery: the strongest evidence for linkage appeared on chromosome 6q14.1, near the marker D6S1031 1 . The statistical strength of this finding was impressive—a LOD score of 5.0 in their primary model and 3.6 in their secondary model, both far exceeding the threshold for significance 1 .
To put this in perspective, a LOD score of 3.0 (which their results substantially exceeded) indicates odds of 1,000-to-1 that the linkage is real rather than a chance finding. Their finding of 5.0 makes this an exceptionally strong result in genetic terms.
But what does this region of chromosome 6 contain? While the exact gene or genes responsible weren't identified in this initial study, the chromosomal region 6q14.1 is known to contain several biologically interesting elements. Chromosome 6 overall houses the major histocompatibility complex, which contains over 100 genes related to immune function, though this particular finding lies outside that region 8 .
| Chromosomal Region | LOD Score (Model 1) | LOD Score (Model 2) | Nearest Marker |
|---|---|---|---|
| 6q14.1 | 5.0 | 3.6 | D6S1031 |
| 1q | Not specified | Not specified | Not specified |
| 4p | Not specified | Not specified | Not specified |
| 16p | Not specified | Not specified | Not specified |
While the chromosome 6 finding was the strongest, the study also found evidence of additional susceptibility loci on chromosomes 1q, 4p, and 16p, suggesting that multiple genes work in concert to influence blood pressure 1 . This multi-gene influence helps explain why high blood pressure doesn't follow simple Mendelian inheritance patterns like some single-gene disorders.
Perhaps the most compelling aspect of this discovery emerged when the researchers looked beyond their own dataset. The same chromosome 6 region was independently confirmed in a Caucasian population, where it showed a LOD score of 3.3 1 . This replication is critically important in genetic research, as it significantly reduces the likelihood that the finding represents a false positive or population-specific fluke.
Initial discovery in VAGES study with LOD score of 5.0
Independent confirmation with LOD score of 3.3
Meanwhile, other research has identified different regions of chromosome 6 that may influence blood pressure. One study found associations between pulse pressure and specific SNPs on chromosome 6p22.3 3 . The relationship between these different chromosomal regions and their collective influence on cardiovascular health remains an active area of investigation.
| Chromosomal Region | Phenotype | Population | Study |
|---|---|---|---|
| 6q14.1 | Systolic BP | Mexican-American | VAGES 1 |
| 6p22.3 | Pulse Pressure | African American & European American | HyperGEN 3 |
The genetic investigation of blood pressure extends well beyond chromosome 6. Earlier genome-wide scans have identified potential susceptibility regions on chromosomes 1p, 2p, 5p, 7q, 8q, and 19p, among others 6 . This complex genetic architecture explains why hypertension risk can vary so dramatically between individuals and why it clusters in families without following predictable inheritance patterns.
To understand how these discoveries are made, it helps to know what tools scientists use in this type of research. Genetic epidemiology relies on sophisticated laboratory techniques and statistical methods.
| Research Tool | Function | Application in VAGES |
|---|---|---|
| Microsatellite Markers | Short, repetitive DNA sequences that vary between individuals, serving as chromosomal landmarks | Used as genetic markers throughout the genome to track inheritance patterns 1 |
| Multipoint Linkage Analysis | Statistical method that uses multiple markers simultaneously to map trait locations | Applied to identify regions linked to blood pressure variation 1 |
| Phenotype Adjustment Methods | Techniques to account for medications or other confounding factors | Two different models used to adjust for antihypertensive medication effects 1 |
| Genome-wide SNP Arrays | Chips that genotype hundreds of thousands of single nucleotide polymorphisms | Used in similar studies to dense map regions of interest 3 |
Recruitment of 266 Mexican-American families with 1,089 individuals
Blood pressure measurements and genetic sampling
Microsatellite markers analyzed across the genome
Linkage analysis with adjustment for medication effects
Identification of chromosome 6q14.1 locus
Replication in independent Caucasian population
The identification of this major susceptibility locus on chromosome 6q14.1 represents more than just a scientific curiosity—it opens exciting new pathways for understanding cardiovascular biology and developing improved treatments.
Locating this region provides a starting point for identifying specific genes that influence blood pressure regulation.
Understanding genetic factors might eventually lead to personalized approaches to hypertension prevention and treatment.
Highlights the importance of including diverse populations in genetic studies to benefit all communities.
While the VAGES study represented a significant step forward, science has marched onward since its publication. Researchers have continued to explore the human genome for blood pressure influences, with large consortium studies now identifying hundreds of genetic variants with small but measurable effects.
The emerging picture suggests that our blood pressure is influenced by a complex interplay of many genetic factors—some with large effects like the one on chromosome 6q14.1, and many others with more modest contributions. Additionally, we now understand that the relationship between our genes and our health is not deterministic; rather, our genetic makeup creates predispositions that interact with our environment, behaviors, and lifestyle choices.
As genetic research continues to evolve, the hope is that these discoveries will translate into better prevention strategies, more targeted treatments, and ultimately reduced burden of hypertension and its complications across all populations. The journey from statistical linkage on a chromosome to improved human health is long and complex, but studies like VAGES provide the crucial starting points that make such advances possible.
| Term | Definition |
|---|---|
| Genome-wide linkage screen | A method to scan the entire genome for regions linked to a trait |
| Susceptibility locus | A specific location on a chromosome associated with increased disease risk |
| LOD score | A statistical measure of the evidence for linkage between genetic markers and traits |
| Systolic blood pressure | The pressure in arteries when the heart beats (the higher number) |
| Mexican-American | Americans of Mexican descent, a population with specific genetic characteristics |