A High Incidence of Patients with MTHFR (methylenetetrahydrofolate reductase) Gene Mutations Noted in An Appalachian Population Seen for Thrombophilia at the West Virginia University Outpatient Hematology Clinic, 2006–2008

Mudussara Asad Khan, Vijaya k Gadiyaram, Thomas Hogan, Ramin Altaha, Edward Crowell, Peter Perrotta and Gerald Hobbs


Background: One or more risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE), either hereditary or acquired, can be identified in up to 80% of patients with venous thromboembolism (VTE). Some patients have more than one form of inherited thrombophilia and appear to be at greater risk for thrombosis. We noted a higher than expected incidence of MTHFR gene mutations C677T or A1298C in Appalachian patients referred to our benign hematology clinic. Studies have suggested an increased risk of venous thromboembolism (VTE) in patients with hyperhomocysteinemia, and the C677T mutation in the MTHFR gene has been thought responsible for hyperhomocysteinemia. However, the association of MTHFR gene mutations C677T and A1298C and VTE remains controversial.

Methods: We reviewed the records of 72 patients for risk factors for acquired or inherited thrombophilia. These patients were referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first VTE through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody (ACA), MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI.

Results: 72 patients were seen from 2006–2008. Of these, 45 patients (63%) had established VTE per ATS clinical practice guidelines and are the subject of this report. Excluded patients had stroke only (CVA) without other VTE, or were screened for thrombophilia based of family history or prior fetal loss. Of the 45 patients with established VTE, median age at first clot was 34 years (range 14–65) and median age at consultation was 41 years (range 19–72). There were 21 men and 24 women (47% and: 53%). Recorded sites of VTE were legs (54 events), arms (8 events), pulmonary embolism (22 events) and stroke with VTE (3 events). Review of risk factors showed that 90 % of the patients had good performance status (NCI 0,1); 47% were obese with BMI > 30 (median BMI was 29.6); 47% were smokers; 49 % had a positive family history of VTE; 42 % had dyslipidemia; 9% had cancer (3 prior, 1 active germ cell testis tumor); and 16% used oral contraceptives or hormones. 33 of the 45 VTE patients had homocysteine levels available, and the median homocysteine level was 10 micromol/L (range 5.8 –63); 7 (21%) had an elevated homocysteine level, greater than 14. 32 of the 45 VTE patients had MTHFR gene mutation testing done, and 28 of the 32 (88 %) had one or more positive mutations, with alleles C677TT (10%-high risk), C677T (68%), A1298CC (14%), A1298C (39%). Further, 9 of the 32 patients (32%) and the “high risk” C677T-A1298C mutation. Thus, 42% of all patients tested had a “high risk” MTHFR gene mutation for VTE.

Coagulation Profile of 45 Thrombophilia Clinic Patients with established VTE

# tests (+)# tests done%
Anti-Cardiolipin Antibody53613
Anti-Thrombin III2366
Factor II 20210 Gene Mutation2406
Factor V Leiden Gene Mutation104025
Lupus Anti-coagulant2316.4
xMTHFR Gene Mutation283288
Protein C2307
Protein S32910

Conclusion: Patients with established VTE in our clinic population inherited risk factors as tabulated above. The Factor II and Factor V mutation incidences of 6% and 25%, as well as the number of abnormalities in Protein C, Protein S, and Anti-Cardiolipin Antibody, appear similar to data reported in the literature for Caucasian populations. However, Rodrigues et al reported a C677TT and C677T prevalence of 14–19% and 36–47% respectively in 1,277 normal persons and a A1298 CC and A1298C prevalence of 7–11 % and 28–35 % respectively (Am J Clin Nutr 2006;83:701).,. In our Appalachian population, the overall incidence of MTHFR genetic mutations (88 %) and the number of “high risk” MTHFR mutations (42%) appears excessive and deserves further investigation.