Genetics

Risk assessment based on your current health history and our laboratory testing becomes more precise with genetic testing. Our Longevity Genetics Test Panel assesses the 7 most significant variants, that is, single nucleotide polymorphisms (SNP), associated with the risk for cardiovascular disease, stroke, clotting disorders, dementia, and Alzheimer’s Disease, as well as the response to certain medications to treat these conditions. This panel gives valuable insight into your disease risk and potential response to treatment that can be gained only through genetic testing, providing actionable information for managing risk.

Genetic Variants Tested

*Single nucleotide polymorphism

Genetic Variants Defined

APOE (Apolipoprotein E): Cardiovascular Disease Risk; All-Cause Dementia Risk Including Alzheimer’s Disease

Apolipoprotein E (apoE) is a protein consisting of 299 amino acids that has an important role in the removal of triglyceride-rich remnant lipoprotein particles in the bloodstream. More significantly, it is involved in the breakdown and removal of β-amyloid protein in the brain. β-amyloid protein is known to accumulate in the brains of individuals with all-cause dementia (70% of which is Alzheimer’s disease).

There are three forms of the apoE protein, depending on the amino acid at positions 112 and 158. The most common form is apoE3, which has a cysteine at position 112 and an arginine at position 158. The second most common form is apoE4, with an arginine at position 112 and an arginine at position 158. The least common form is apoE2, with a cysteine at position 112 and a cysteine at position 158.

ApoE3 is associated with the normal breakdown of triglyceride-rich remnant lipoprotein (TRL) particles in the bloodstream and β-amyloid in the brain. ApoE2 is associated with the decreased breakdown of TRL in the blood and less formation of low-density lipoprotein (LDL) particles and with increased breakdown of β-amyloid in the brain and less β-amyloid deposition. ApoE4 is associated with the increased breakdown of TRL in the blood and increased formation of LDL, resulting in the increased risk of cardiovascular disease (CVD). More importantly, apoE4 is associated with the decreased breakdown of β-amyloid in the brain, resulting in excess β-amyloid deposition in the brain and an increased risk of all-cause dementia and Alzheimer’s disease.

People with the APOE3/3 genotype, about 60% of the United States population, have a normal risk for CVD and all-cause dementia. Individuals with the APOE2/2 genotype (about 1% of the population) or APOE2/3 genotype (about 10% of the population) have a reduced CVD risk and a 50% reduction in the risk for all-cause dementia. Individuals with the APOE4/4 genotype (about 2% of the population) have about a 10-fold increased risk of dementia. Individuals with the APOE3/4 genotype (about 25% of the population) or APOE2/4 genotype (about 2% of the population) have about a 3-fold increased risk of dementia and an increased risk for high LDL cholesterol (“bad” cholesterol) levels and, hence, increased CVD risk.

Individuals with the APOE3/4 and APOE4/4 are more responsive to the restriction of dietary saturated fat and cholesterol and less responsive to statin-induced lowering of LDL cholesterol levels, compared to individuals with the APOE3/3 genotype.

Compared with individuals of European ancestry, individuals of Chinese, Japanese, and Korean ancestry have even greater dementia risk associated with the APOE4 genotypes and less risk reduction associated with the APOE2 genotypes. African Americans are less affected by the APOE genotype in terms of dementia risk.

MTHFR (Methylene Tetrahydrofolate Reductase): Cardiovascular Disease Risk; All-Cause Dementia Risk

Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methylation of folate (a B vitamin), thereby, converting the toxic amino acid homocysteine to methionine. Homocysteine can damage DNA, cause oxidative stress, and lead to apoptosis.

Homocysteine blood levels >14 µmol/L have been associated with two MTHFR genetic variants (677T and 1298C), as well as with deficient folate, vitamin B12, and vitamin B6 blood levels. Elevated homocysteine levels are an important risk factor for cardiovascular disease; they also double the risk for all-cause dementia. Lowering homocysteine with B vitamin supplementation (folate 2.5 mg/day; vitamin B6 50 mg/day; vitamin B12 1 mg/day) has been shown to lower the risk of stroke by 25% and the risk of all-cause dementia.

The normal (i.e., wildtype) MTHFR 677C/C protein has amino acid alanine at position 222. The heterozygote 677C/T variant, occurring in about 30% of the United States population, has amino acid valine at position 222; the substitution modestly decreases MTHFR enzymatic activity and folate methylation and modestly increases serum homocysteine levels. The homozygous 677T/T variant, occurring in about 9% of the population, is associated with a significant decrease in MTHFR activity and folate methylation and a significant increase in homocysteine levels. Individuals with the homozygous 677T/T variant may require methyl folate supplementation to reduce their homocysteine levels to <10 µmol/L if supplementation with folate, vitamin B12, and vitamin B6 is ineffective.

The wildtype MTHFR 1298A/A protein has amino acid glutamic acid at position 429. The heterozygote 1298A/C variant, occurring in about 25% of the United States population, has amino acid alanine at position 429, resulting in modestly decreased MTHFR enzymatic activity and folate methylation and modestly increased serum homocysteine levels. The homozygous 1298C/C variant, occurring in 8.0% of the population, is associated with significantly decreased MTHFR activity and folate methylation and increased homocysteine blood levels. Individuals with the homozygous 1298C/C variant usually require methyl folate to reduce their homocysteine levels to <10 µmol/L if supplementation with folate, vitamin B12, and vitamin B6 is ineffective.

4Q25: Atrial Fibrillation Risk

The 4q25 gene locus on chromosome 4, adjacent to the paired-like homeodomain 2 (PITX2) gene, plays a major role in the development of the heart, including the development of the sinus node which regulates heart rhythm and rate.

Two 4q25 variants, rs2200733 and rs10033464, occurring in about 20% of the United States population, have been associated with a 50-90% increase in the risk of atrial fibrillation, as shown in multiple clinical research studies. The association between 4q25 variants and increased risk of atrial fibrillation is especially apparent in people over 60 years of age.

Atrial fibrillation causes the heart to beat irregularly and often rapidly, with resulting palpitations, heart failure, and blood clots in the heart. The blood clots can go up into the brain, resulting in strokes.

Atrial fibrillation can be treated with cardioversion, a medical procedure that restores a normal heart rhythm using electricity or medication, or with medications like beta-blockers, calcium channel blockers, and, if necessary, amiodarone, to slow the heart rate. Maintaining anticoagulation by using apixaban (Eliquis®) is important to prevent blood clot formation and strokes.

Other major risk factors for atrial fibrillation, in addition to genetic variants and family history, include increased age, hypertension, diabetes, obesity, kidney disease, smoking, hyperthyroidism, and excess alcohol intake.

Factor V Leiden: Clotting Risk

Factor V is a clotting factor that forms prothrombinase with factor X. Factor X converts prothrombin to thrombin; thrombin converts fibrinogen into fibrin which forms the clot.

Factor V Leiden is the most common genetic variant causing hypercoagulability disorder among individuals of European descent, occurring in about 5% of the population. The genetic variant is due to the amino acid substitution of glutamine for arginine at position 506. The substitution decreases the inhibition of factor V pro-clotting activity by protein C and leads to the hypercoagulable state with an increased risk of blood clots, especially deep vein thromboses (DVT), pulmonary emboli (PE), and of strokes. The risk is increased in females on hormone therapy containing oral estrogen.

Individuals with the factor V Leiden variant have a significantly increased risk of having:

• A first occurrence of DVT or PE prior to 50 years of age
• Recurrent DVT and PE events
• A family history of DVT and PE events
• A DVT or PE during pregnancy
• A stroke

Up to 30% of individuals presenting with a first DVT or PE have the factor V Leiden variant.

The use of hormones, like oral contraceptive pills (OCP) and hormone replacement therapy (HRT) including estrogen and estrogen-like drugs taken after menopause, increases the risk of developing DVT and PE. Healthy females taking OCP have a 3- to 4-fold increased risk of developing a DVT and PE event, compared with healthy females not taking OCP. Females with the heterozygous factor V Leiden (-/+) variant who take OCP have about a 35-fold increased risk of developing a DVT or PE, compared with females without the factor V Leiden variant and those who do not take OCP. Postmenopausal females taking oral HRT have a 2- to 3-fold higher risk of developing a DVT or PE than females who do not take HRT. Females with factor V Leiden who take oral HRT have a 15-fold higher risk.

Females having either the heterozygous or homozygous factor V Leiden variant who are making decisions about OCP or HRT use should consider using alternative forms of birth control and not using oral HRT after menopause. They should consider alternative transdermal approaches.

Individuals having the heterozygous Factor V Leiden -/+ variant (occurring in about 5.0% of the American white population and less in Hispanic, African American, and Asian populations) should be treated for at least 3 months with anticoagulant therapy if they have a DVT or PE. Thereafter chronic low-dose aspirin therapy should be considered. Individuals with the homozygous factor V Leiden +/+ variant (occurring in about 0.05% of the population) are at 80 times the risk of developing a DVT or PE and should be considered for lifelong oral anticoagulation therapy such as apixaban.

Prothrombin or Factor II: Clotting Risk

Prothrombin or factor II, which is encoded by the F2 gene, is a clotting factor that is converted to thrombin by prothrombinase. Thrombin in turn converts fibrinogen into fibrin, which forms the clot.

The factor II variant in the 3’ untranslated region of the gene at nucleotide 20210 occurs in about 2% of individuals of European ancestry. It causes increased prothrombin production and a hypercoagulable state. The heterozygous factor II -/+ variant increases the risk of deep vein thromboses (DVT) and pulmonary emboli (PE) 2.5-fold. The homozygous factor II +/+ variant increases the risk for DVT and PE 20-fold. Individuals with both the heterozygous factor II variant and the heterozygous factor V Leiden have a 20-fold increased risk for DVT and PE.

Females who have the heterozygous factor II variant and also take oral contraceptive pills or hormone replacement therapy have a 5-fold increased risk of DVT and PE.

Individuals with the heterozygous factor II variant (-/+) should be treated for at least 3 months with anticoagulant therapy (e.g., apixaban) after a DVT or PE event. Thereafter, chronic low-dose aspirin therapy should be considered. Individuals having both the heterozygous factor II variant and the heterozygous factor V Leiden and individuals who have the homozygous variant should consider lifelong low-dose aspirin therapy.

LPA: Cardiovascular Disease Risk and Aspirin Benefit

Lipoprotein(a) (Lp(a)), encoded by the LPA gene, is a low-density lipoprotein (LDL)-like particle containing the protein apolipoprotein(a) (apo(a)) attached to the protein apoB-100 in the particle. Lp(a) blood levels are genetically determined, mainly due to the number of kringle IV2 repetitions in the LPA gene. Lp(a) blood levels ≥125 nmol/L (≥50 mg/dL) have been associated with a significantly increased risk for cardiovascular disease (CVD). About 20% of families with premature CVD have Lp(a) levels above the 90th percentile.

The LPA gene variant rs3798220, occurring in 4% of the United States population, causes the amino acid isoleucine to be replaced by methionine at position 4399 of the apo(a) amino acid sequence, in the protease-like domain, the region of apo(a) that affects clotting. The LPA T/C and C/C variants encode a form of apo(a) that increases clot formation, doubles the risk for CVD, and significantly elevates Lp(a) blood levels. This risk can be normalized with daily low-dose aspirin (81-100 mg/day). Individuals with the LPA T/C or C/C variant should also make every effort to normalize all other known CVD risk factors.

SLCO1B1: Statin-Induced Myopathy Risk

Statins are the most widely prescribed lipid-lowering therapy for the treatment and prevention of cardiovascular disease (CVD). They lower LDL cholesterol blood levels by inhibiting intracellular cholesterol synthesis and have been shown to decrease the risk of CVD events and mortality in many placebo-controlled clinical trials. They are generally safe and well-tolerated in most individuals.

Some individuals, however, may develop statin-associated muscle symptoms (SAMS). In some individuals, very significant muscle inflammation can be observed, associated with marked increases in creatine kinase blood levels. Patients frequently discontinue statin therapy as a result, leading to higher rates of CVD events and mortality. Hypothyroidism, vitamin D deficiency, use of amiodarone, and co-enzyme Q10 deficiency increase an individual’s risk for SAMS.

The organic anion-transporting polypeptide 1b1, which is encoded by the solute carrier anion transporter 1B1 (SLCO1B1) gene, is responsible for the uptake and breakdown of statins in the liver. Individuals with the SLCO1B1 variant rs4149056, which occurs in about 14% of the United States population, were found in a large placebo-controlled statin trial to have a 4-fold increase in the risk of SAMS; individuals with the homozygous SLCO1B C/C variant had a 17-fold increased risk of SAMS. Another SLCO1B1 variant, rs4363657, results in the amino acid valine being replaced by the amino acid alanine at position 174 in the transporter sequence. This substitution results in decreased statin liver uptake, excess statin plasma levels, and increased risk of SAMS.

Simvastatin and atorvastatin at high doses are most likely to cause SAMS in individuals with the SLCO1B1 variant. Individuals with the variant, especially those with the homozygous SLCO1B1 C/C variant, should be given low doses of rosuvastatin (5-10 mg/day). For all individuals on statin therapy, supplementation with co-enzyme Q10 300 mg/day is recommended, in our opinion, since statin therapy depletes the body of this byproduct of cholesterol synthesis that is important for normal muscle function. Supplementation with co-enzyme Q10 100 mg three times daily in individuals with heart failure has been shown to reduce their all-cause mortality by 44% over 2 years.

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